Archive | July, 2014

NYC’s Korean Community Launches Autism Hotline

24 Jul

Ask someone about autism and Korea and, if you get any answer at all, you will likely hear about the whole population prevalence study that showed 2.64%. What about autism in Korean communities outside Korea? The U.S. has large Korean populations, especially in Los Angeles and New York. And these communities are terribly underserved.

Autism Speaks, George Washington University and the University of Pennsylvania have teamed up with the Korean Community Services (KCS) of Metropolitan New York to create a hotline for autism information.

Two people I respect greatly are involved with this: David Mandel (U. Penn) and Richard Grinker (GWU).

korean_kids_line[1]

I’ve copied the part of the Autism Speaks article (the Korean part) below, in the hopes that adding more information in Korean to search engines will result in more people finding the information.

뉴욕한인봉사센터 (KCS)가 오티즘스픽스, 펜실베니아 대학교 정신건강정책서비스 연구소, 그리고 조지워싱턴 대학교의 지원 하에 KCS키즈라인 서비스를 시작하였습니다. 이 프로젝트를 위한 오티즘스픽스의 지원은 블룸버그 가족 재단의 기금을 통하여 이루어졌습니다.

KCS 키즈라인은 자폐(Autism Spectrum Disorder) 또는 발달지체와 관련된 걱정거리를 안고 있는 한인 가족들에게 필요한 정보를 제공하고, 자폐 관련 서비스로의 연결을 돕기 위한 한국어 전화서비스입니다.

오티즘스픽스 공공보건부 어시스턴트 디렉터인 에이미 대니얼스는, “KCS 키즈라인은 한인 지역사회 내 자폐에 관한 인식을 높이고 정보를 제공하기 위한 이전의 노력들에서 한 단계 더 나아가, 자녀들에 대한 우려를 가진 가족들에게 꼭 필요한 정보를 즉각적으로 제공하게 됩니다. 우리는 이 서비스를 통해 가족들이 필요로 하는 도움을 좀더 직접적이고 시기 적절하게 받을 수 있도록 돕기를 희망합니다.” 라고 말했습니다.

미주 아시안 연합 인구조사 센터 (The Asian-American Federation Census Information Center)에 의하면, 한국인은 뉴욕시에서3번째로 큰 아시안 그룹으로 현재 10만명 이상의 한인들이 뉴욕에 거주하고 있습니다. 뉴욕시 교육부는 아시안 학생이 전체 뉴욕시 학생의 16%를 차지하고 있는 것에 비해, 자폐 진단을 받은 아동들 중 아시안은 단 8% 뿐이라고 밝혔습니다. 이러한 수치의 차이는 한인사회 내에서도 자폐 진단이 제대로 이루어지지 않고 있을 가능성을 시사합니다. 오티즘스픽스 재단의 연구비 지원 하에 2011년 한국에서 실시된 자폐 발생률에 관한 연구 결과에서도 비슷한 결과를 볼 수 있었는데, 자폐의 범주 안에 있는 아동 중 2/3가 사전에 진단을 받지 못하였고 적합한 서비스 또한 받지 못했던 것으로 나타났습니다.

한인사회 내에서 자폐 진단이 잘 이루어 지지 않는 이유는 자폐에 대한 인식 부족, 사회적 낙인, 그리고 문화를 고려한 서비스의 부족으로 보이며, 언어장벽 또한 서비스를 이용하는 데에 있어 장애요소가 됩니다. KCS 키즈라인의 목표는 뉴욕시 내 자폐를 가진 한인 어린이들이 빠른 시간 내에 적절한 서비스를 받도록 하는 데 중점을 두고, 그 부모와 가족들을 좀더 효과적으로 지원하며, 궁극적으로는 한인사회의 자폐에 대한 인식을 증진시키고, 자폐 관련 자료들을 많은 사람들이 쉽게 이용할 수 있도록 돕는 데 있습니다.

KCS 키즈라인은 아동의 연령에 제한을 두지 않으며, 주된 대상은 출생 이후 3세까지의 자폐 및 발달지체의 증상을 보이는 아이의 부모들입니다. 부모님이나 보호자들은 전화, 이메일, 또는 방문을 통해 정보를 받을 수 있습니다. 또한, 오티즘스픽스 재단의 지원을 통해 한국어로 번역된 100-Day Toolkit (자폐 진단 후 첫 100일 동안 아동을 케어하기 위한 정보) 및 여러 가지 자폐에 관한 자료들을 오티즘스픽스 웹사이트에서 무료로 다운로드 받을 수도 있습니다: http://autismspeaks.org/korean. KCS는 자폐와 관련된 서비스 자료들을 꾸준히 모으고, 더 높은 연령대의 아동들과 그 가족들 또한 도움을 받을 수 있도록 뉴욕시 내의 학교 및 커뮤니티 기관들과 지속적으로 연계함으로써, 더 많은 한인 가족들이 필요로 하는 서비스를 제공받을 수 있도록 노력할 것입니다.


By Matt Carey

Press Release: Common gene variants account for most genetic risk for autism

23 Jul

This press release is from NIH: Common gene variants account for most genetic risk for autism

Common gene variants account for most genetic risk for autism
Roles of heritability, mutations, environment estimated – NIH-funded study

Most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the National Institutes of Health have found. Heritability also outweighed other risk factors in this largest study of its kind to date.

About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.

nimh-20_l

The bulk of risk, or liability, for autism spectrum disorders (ASD) was traced to inherited variations in the genetic code shared by many people. These and other (unaccounted) factors dwarfed contributions from rare inherited, non-additive and spontaneous (de novo) genetic factors. Source: Population-Based Autism Genetics and Environment Study
“Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture,” explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City. “Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together.”

Buxbaum, and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.

“Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now detect common as well as rare genetic variation associated with risk,” said Thomas R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH). “Knowing the nature of the genetic risk will reveal clues to the molecular roots of the disorder. Common variation may be more important than we thought.”

Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive. Recently, evidence has been mounting that genomes of people with autism are prone to harboring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.

More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect. Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.
Differences in methods and statistical models also resulted in sometimes wildly discrepant estimates of autism’s heritability – ranging from 17 to 50 percent.

Meanwhile, recent genome-wide studies of schizophrenia have achieved large enough sample sizes to reveal involvement of well over 100 common gene variants in that disorder. These promise improved understanding of the underlying biology – and even development of risk-scores, which could help predict who might benefit from early interventions to nip psychotic episodes in the bud.

With their new study, autism genetics is beginning to catch up, say the researchers. It was made possible by Sweden’s universal health registry, which allowed investigators to compare a very large sample of about 3,000 people with autism with matched controls. Researchers also brought to bear new statistical methods that allowed them to more reliably sort out the heritability of the disorder. In addition, they were able to compare their results with a parallel study in 1.6 million Swedish families, which took into account data from twins and cousins, and factors like age of the father at birth and parents’ psychiatric history. A best-fit statistical model took form, based mostly on combined effects of multiple genes and non-shared environmental factors.

“This is a different kind of analysis than employed in previous studies,” explained Thomas Lehner, Ph.D., chief of NIMH’s Genomics Research Branch. “Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry.”

Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications of genetic material and spontaneous mutations. Even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches makes them important clues to understanding the molecular underpinnings of the disorder, say the researchers.

“Within a given family, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member,” said Buxbaum. “The family may have common variation that puts it at risk, but if there is also a de novo [spontaneous] mutation on top of that, it could push an individual over the edge. So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder.”

New Study: Most genetic risk for autism resides with common variation

23 Jul

A new large study on autism genetics just came out: Most genetic risk for autism resides with common variation. The study is in Nature Genetics, one of the top journals.

The study is the latest in the evolved view of autism genetics. Contrary to political statements made by some groups, autism genetics is not about searching for a single “autism gene”. Here’s a quote from the CNN Blog that makes this clear:

Chris Gunter, an autism researcher at the Marcus Autism Center and professor at the Emory University School of Medicine, says the findings of this study are similar to those reported in other studies.

“There is no one gene for autism,” Gunter said. “Instead there are many different genetic variations which each contribute a little bit to the risk of developing the group of symptoms we diagnose as autism.”

No single autism gene. You might carry one or more genes which are associated with autism and not be autistic. But the more you have, the more your risk goes up. It may be linear: each variant has a “score” and you add them up and if your score is very high, you are autistic. Or it may be nonlinear: some genes in combination may create a greater risk than the sum of their individual risks. I don’t think they understand or have cataloged the genes well enough to say.

The researchers in this current paper are estimating about 60% of autism risk is genetic. Here’s a graphic showing the breakdown of the various risks–different types of genes (common genes that are inherited, rare genes that are inherited, new (de novo) mutations, etc.):

nimh-20_l

What does this mean for the future of autism research? It means that continuing to look at both genetics and environmental risk factors is valuable. As I’ve said before, from my perspective if autism risk is 10% genetic or 90% genetic, you still need to apply resources to both genetics and environmental risk factors.

Now to answer the more mundane questions. What does this mean for the vaccine epidemic? You can’t have a genetic epidemic (not really true, but good enough for this discussion)! This doesn’t fit with the idea that about 99% of autism is now caused by vaccines.

Yep. These data are yet another reason why your idea doesn’t work.

But isn’t this just blaming the mothers?

I’m always amazed when that argument comes up on autism genetics. And, yes, it does come up. Your children’s genetic makeup is neither a source of pride nor of blame. You really didn’t have any say in the matter. You didn’t create nor change your genes, how can you be blamed for the genes that your child inherits?

Won’t genetic research lead to aborting babies?

Maybe. If it does, it will be much different than the current situation with Down Syndrome. Autism doesn’t have many examples of single-genes, as this study points out. There have already been groups claiming to be working on tests involving multiple genes and autism risk scores.

Does this mean that the story is finished? That we have the last answer about how much risk is genetic and how much is environmental?

No. There will be more papers and more estimates. These are tough questions and knowledge evolves.

Here is the paper’s abstract:

A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism’s genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.


By Matt Carey

Is Boyd Haley resurrecting OSR#1 as a chelator?

22 Jul

Boyd Haley was a professor of chemistry who was very active in the failed thimerosal-causes-autism movement. He earned extra notoriety for trying to coin the phrase “mad child disease” (yes, a variation of mad cow disease) for autistic children. He also found notoriety for marketing a synthetic chemical as a “nutritional supplement”, calling it OSR#1. Prof. Haley is certainly persistent. He’s working on a clinical trial.

How did this come to pass? Well, one of the professors in Prof. Haley’s department found that a certain compound could effectively treat mining waste, removing mercury. Given his own interests, Mr. Haley started a company with an investor with the intent to bring this chelator to the public. The chelators used in medicine today were developed for lead and have been expanded to also treat mercury. I.e. there is no mercury specific chelator and this new compound would fill that gap.

All well and good, but in his zeal to bring this product to market, Prof. Haley cut a few corners. Chelators are drugs. The compound he was working on was synthetic. But Prof. Haley chose to rush the product to market as a “nutritional supplement”. Instead of calling it a chelator, he called it OSR#1. OSR standing for “oxidative stress relief”. Mr. Haley skipped the process to prove that his drug was safe and effective. Supplements have a much lower standard for safety and efficacy testing.

The FDA was not fooled. Mr. Haley and his company were given a warning letter which pointed out that the compound is not a supplement, it is a drug:

Your firm markets OSR#l as a dietary supplement; however, this product does not meet the definition of a dietary supplement in section 201(ff) of the Act, 21 U.S.C. § 321(ff). To be a dietary supplement, a product must, among other things, “bear[ ] or contain[ ] one or more … dietary ingredients” as defined in section 201(ff)(1) of the Act, 21 U.S.C.§ 321(ff)(1). Section 201 (ff)(1) of the Act defines “dietary ingredient” as a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract or combination of any dietary ingredient from the preceding categories. The only substance listed as a dietary ingredient on the labeling of OSR#1 is N1,N3-bis(2-mercaptoethyl)isophthalamide. N1,N3-bis(2mercaptoethyl) isophthalamide is not a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet by increasing the total dietary intake. Further, N1,N3-bis(2-mercaptoethyl)isophthalamide is not a concentrate, metabolite, constituent, extract or combination of any such dietary ingredient. Thus, because OSR#1 does not bear or contain a dietary ingredient as defined in section 201(ff)(1) of the Act, this product does not qualify as a dietary supplement under section 201(ff) of the Act.

Also that the company was making claims that the drug could treat medical conditions and that the labeling was misleading in this regard. Further, that the toxicity was not adequately tested nor reported.

Your website states that” [s]ome reports of temporary diarrhea, constipation, minor headaches have been reported but these are rare and the actual causes are unknown,” as well as “OSR#1 is without detectable toxicity” and “OSR#1® … has not exhibited any detectable toxic effects even at exceptionally high exposure levels.” However, animal studies that you conducted found various side effects to be associated with OSR#1 use, including, but not limited to, soiling of the anogenital area, alopecia on the lower trunk, back and legs, a dark substance on lower trunk and anogenital area, abnormalities of the pancreas, and lymphoid hyperplasia. Based on these animal studies and side effects known to be associated with chelating products that have a similar mechanism of action to OSR#1, we believe the use of your product has the potential to cause side effects, and the before-mentioned website statements falsely assert that the product does not have the potential to cause side effects. Therefore, these statements render your product’s labeling false or misleading. As such, OSR#1 is misbranded under section 502(a) of the Act, 21 U.S.C. § 352(a).

That was in 2010. Prof. Haley and his company are now back, trying to get a clinical trial started on their compound. Essentially, they are trying to do what they should have done in the first place: get proper approval for a drug. An article in Chemical & Engineering News discusses this effort. Actually, it’s part of the cover story, “Building Pharma Molecules”

buildingpharma

The story on Mr. Haley’s Company, CTI Science, has contracted with another company, PCI Synthesis, to manufacture the new compound.

haley2

The article is, well, a bit of a sales pitch and gets a few facts wrong. There’s a bit of spin on the FDA warning letter, for example:

“The effort to develop the compound as a mercury poisoning therapy accelerated in 2010 when the company received notification from FDA that it couldn’t market NBMI as a nutritional supplement until it underwent the full drug approval process”.

As we’ve just seen above, the compound is not a nutritional supplement at all. It needs the drug approval process because it is a drug.

The CEO of PCI is quoted as stating:

“The main starting material is cysteamine hydrochloride, which is basically an amino acid and found naturally. So it has attributes that could qualify it as a natural product.”

Which was part of the sales pitch for the OSR#1 in the old days and, again, the FDA disagreed. Just because something is synthesized from a natural product, that doesn’t make it a natural product. Otherwise there would be no synthetic products at all. Everything at some level comes from a natural product.

The article discusses how to qualify for a clinical trial the product must meet current Good Manufacturing Practices (cGMP). The article states:

The primary challenge was the removal of impurities to a level that meets cGMP standards

Think about that a moment. Apparently OSR#1 was sold with more impurities than would meet this standard–a standard for food and dietary supplements.

The article notes that, yes, this compound was sold as a product at one time

Sales to date: $1.5 million, as a nutritional supplement

$1.5M in sales. And the only reason it wasn’t higher was because the FDA stepped in. It was only out for about a year, as I recall.

I found this statement interesting, from the Wikipedia page for the compound:

In animal experiments, the amount of mercury in brain tissue was not increased, but also not decreased

So, even if you believe in the failed mercury hypothesis. What exactly were you supposed to get from this compound? I somehow doubt that even the strong believers in the mercury hypothesis think that removing mercury from, say, your liver will cure autism.

It does seem that Mr. Haley and his company are doing some of the right things now. Show that this drug is safe and effective for its intended purpose: chelation. There are some problematical statements that they may market this not as a drug but as a nutritional supplement, which is a non-starter.


By Matt Carey

Robert Kennedy, where did you go wrong? And I’m not talking about thimerosal.

22 Jul

Robert Kennedy is one of the Kennedy’s. He also is known within the autism communities for his irresponsible and flawed “Deadly Immunity” article which appeared in Rolling Stone and Salon.com and which fueled much of the conspiracy theory mindset in a generation of autism parents. That was almost 10 years ago. A year or so back, Mr. Kennedy appeared at the AutismOne parent convention talking about thimerosal again. It’s hard to find a more receptive audience for his message. AutismOne is a staunch supporter of failed ideas like thimerosal and MMR cause autism. AutismOne is also a place that promotes the ideas that one can cure autism by chemically castrating disabled children, or making disabled children drink bleach or take bleach enemas until they pass their intestinal mucosa (which are relabeled as worms) and more.

If readers will indulge me, let me shift to addressing Mr. Kennedy:

While multiple outlets are taking turns pointing out that you have taken a very irresponsible stance on vaccines, I’ll just ask: Mr. Kennedy, did you spend any time looking around AutismOne? If so–why the hell have you not come forward to distance yourself from the junk science that goes on there? Why the hell did you lend your family’s name to that operation? Your family basically built the special education system in our country. The National Institute of Child Health and Human Development is named for a relative of yours. And you are loaning that name to a convention where the keynote speaker abuses autism parents? Have you sunk so low that you are lending your family’s credibility to Andrew Wakefield?

If you were unaware of what AutismOne is, shame on you for lending your name. If you are aware of these goings on, and don’t distance yourself, your stance on thimerosal is the least of your problems.


By Matt Carey

Environmental risk factor related research funded by the NIH in 2014

18 Jul

There is a great interest from some in the autism parent community for environmental risk factor research. There is also a belief that this work is not being performed. While the amount of environmental risk factor research is less than the IACC has advised be performed (a point I made in my first IACC meeting), the amount of attention to environmental risk factors has been increasing.

Given this, I thought it would be interesting to see what projects and how many have been funded by the NIH this year (I believe they work on a fiscal year ending Sept. 30, so we have much but not all of the 2014 information available). I used the NIH Reporter website and did a very unscientific search for autism and environment, autism and risk and similar searches.

Below are the funded projects I’ve found. Some are directly on topic. Some more peripherally. And I know I’ve left some out (some on purpose–like Zebrafish studies–and some I missed). I think there are 33 projects below. Something like $20M. Keep in mind, not all Federally funded autism research goes through the NIH and not all autism research is Federally funded.

As I like to point out in these articles, you won’t find this information on the websites of the autism organizations which claim to be focused on environmental risk factor research. In fact, you are more likely to find statements that there is no such research ongoing or it is being blocked.

Here’s a quote from Sallie Bernard of SafeMinds, a quote that was repeated by Congressman Posey at a hearing held last year on autism:

“By ignoring the environmental component to autism, the government and scientific community have made a massive strategic error, wasting enormous amounts of money and time in mostly fruitless genetics-only research that has not helped us stop new cases of autism or helped people living with severe autism”

I think one can argue that more investment should be made. But “ignoring”? I realize that very few people will go to NIH Reporter and search for these projects. But I expect accuracy from those claiming to lead the autism community and acting as though they know the research landscape on autism and the environment.

I was going to ignore the “fruitless” comment above, but I just can’t. I sat on the subgroup writing the IACC’s updates on risk factor research in the Strategic Plan (question 3). As part of that I had the honor of working with some excellent researchers, both on the genetics and the environmental side. If I may be so bold as to relate what I heard in those discussions: I never heard these researchers claim that the genetics research was “fruitless”. Quite the opposite. Was there a strong sense that environmental risk factor research could be better funded? That was certainly my take away. And I agree. My predecessors on the IACC wrote a Plan that called for more research in this area.

That said, I am reminded of my favorite old saying

There’s more politics in science than science in politics.

Except quite frankly, I don’t think the message that environmental risk factor research is being “ignored” and “fruitless” has anything to do with science. It’s just politics.

Here’s that list of funded research (in no particular order):

POPULATION-BASED AUTISM GENETICS & ENVIRONMENT STUDY $655,813

PROSPECTIVE EVALUATION OF AIR POLLUTION, COGNITION, AND AUTISM FROM BIRTH ONWARD $545,679

PESTICIDE EXPOSURE AND CHILDHOOD AUTISM $184,503

PRENATAL TIMING OF HEAVY METAL EXPOSURES FROM AUTISTIC AND NON-AUTISTIC CHILDREN $231,692

MD CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT, SEED PHASE II $91,706

ANTECEDANTS SEQUELAE OF CHILDHOOD ONSET DISEASE $432,000

MITOCHONDRIAL DYSFUNCTION DUE TO ABERRANT MTOR-REGULATED MITOPHAGY IN AUTISM $183,568

PRENATAL AND NEONATAL BIOLOGIC MARKERS FOR AUTISM $784,863

AUTISM RISK, PRENATAL ENVIRONMENTAL EXPOSURES, AND PATHOPHYSIOLOGIC MARKERS $1,793,611

THE ROLES OF ENVIRONMENTAL RISKS AND GEX IN INCREASING ASD PREVALENCE $537,756

METHYLOMIC AND GENOMIC IMPACTS OF ORGANIC POLLUTANTS IN DUP15Q SYNDROME $341,921

EPIDEMIOLOGICAL RESEARCH ON AUTISM IN JAMAICA – PHASE II $564,795

EARLY PREGNANCY STRESS PROGRAMMING OF OFFSPRING EMOTIONALITY $396,000

GENOME-WIDE IDENTIFICATION OF VARIANTS AFFECTING EARLY HUMAN BRAIN DEVELOPMENT $413,630

EPIGENETIC AND TRANSCRIPTIONAL DYSREGULATION IN AUTISM SPECTRUM DISORDER $531,208

EPIGENETIC INFLUENCE ON THYROID HORMONE ACTION IN THE BRAIN AND ON BEHAVIOR $391,250

MATERNAL ADVERSITY AND EPIGENETIC AND BEHAVIORAL PROGRAMMING ACROSS GENERATIONS $583,246

EXPLORING INTERACTIONS BETWEEN FOLATE AND ENVIRONMENTAL RISK FACTORS FOR AUTISM $118,717

MD CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT, SEED PHASE II $1,600,000

CALIFORNIA CADDRE-SEED PHASE II $1,100,000

NC CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT (SEED) PHASE II $1,100,000

COLORADO CADDRE STUDY TO EXPLORE EARLY DEVELOPMENT CADDRE_SEED II $1,100,000

PA-CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT (SEED) PHASE II $1,100,000

SEX-DEPENDENT MICROGLIAL COLONIZATION AND VULNERABILITY TO A NEONATAL INFECTION $272,270

PRENATAL SEX STEROIDS, BISPHENOL A, PHTHALATES, AND SEXUALLY DIMORPHIC BEHAVIORS $244,996

ENVIRONMENT, IMPRINTING, AND NEURODEVELOPMENT $799,726

IN UTERO ANTIDEPRESSANT EXPOSURES AND RISK FOR AUTISM $348,000

SEX DIFFERENCES IN DEVELOPING MICROGLIA: IMPLICATIONS FOR SYNAPTIC PRUNING $392,500

ARE ENDOCRINE DISRUPTING COMPOUNDS ENVIRONMENTAL RISK FACTORS FOR AUTISM? $237,750

THE EFFECT OF MATERNAL OBESITY AND INFLAMMATION ON NEURONAL AND MICROGLIAL FUNCTI $78,250

TRANSCRIPTIONAL AND EPIGENETIC SIGNATURES OF HUMAN BRAIN DEVELOPMENT AND AUTISM $1,542,279

PROJECT 2: THE IMPACT OF ASSISTED REPRODUCTIVE TECHNOLOGIES ON THE LONG-TERM EPI $266,000

PRENATAL FACTORS AND RISK OF AUTISM IN A FINNISH NATIONAL BIRTH COHORT $579,293

One last note: I don’t see funding for the EARLI network. That strikes me as a shame.


By Matt Carey

Note: I serve as a public member to the IACC but all statements are my own.

More of that vaccine/autism research that doesn’t exist

17 Jul

There are some parents who want research on vaccines and autism. I may not agree that this is the best way to spend our limited resources, but there’s no denying that this group exists and is very vocal. One thing that surprises me is that these parents appear to be unaware of vaccine/autism research that is ongoing. Not just the studies that come out that show us over and over again that autism risk is not increased by vaccines. But other projects. Biology. Studies on regression. And more. I pointed out recently that using NIH Reporter, one can find a number of projects on autism and vaccines or autism and mercury.

But NIH is not the only Federal agency funding autism research. And there are private funders as well. As I mentioned in my previous article, another place to look for funded research projects is the IACC/OARC Autism Spectrum Disorder Research Portfolio Analysis Web Tool as this includes work the various groups represented on the IACC–both Federal and Private. Unfortunately, this tool only has 2008, 2009 and 2010 projects (had the GAO not required OARC to provide a lot of information last year, perhaps this tool would be updated by now. But such is the government.) But, even with this limitation in years, let’s see what projects come up with searches for vaccines or mercury. I’ll give the titles first, and then the abstracts for these projects below.

It’s understandable that parent advocates are not aware of these projects. I’ve written about this before (“What projects are being funded in autism research? Part 1: vaccines and GI issues”) but I think it’s safe to say that parents who believe in the vaccine/autism connection do not frequent Left Brain/Right Brain. There are places on the web that carry that message (for example, the Age of Autism blog and the sites of the organizations that sponsor it). They aren’t telling their constituencies about the ongoing research efforts. As an example, as I was finishing this article, SafeMinds came out with a letter discussing how no work is being performed on vaccines and autism.

Again, this list is only for 2008, 2009 and 2010. More recent projects from NIH were discussed here.

Vulnerability phenotypes and susceptibility to environmental toxicants: From organism to mechanism (funded by Autism Speaks)

Evaluation of the immune and physiologic response in children with autism following immune challenge (funded by Autism Speaks)

Vaccination with regression study (funded by Autism Speaks)

Vaccine safety datalink thimerosol and autism study (Federally Funded)

Analysis of developmental interactions between reelin haploinsufficiency, male sex, and mercury exposure (Funded by Autism Speaks)

MeHG stimulates antiapoptotic signaling in stem cells (Federally funded: DoD)

Etiology of autism risk involving MET gene and the environment (Funded by Autism Speaks)

Epidemiological research on autism in Jamaica (Federally Funded, NIH)

investigation on the potential harmful effects of mercury in the nonhuman primate (Funded by SafeMinds)

Investigating the effect of mercury on ASD, AD and ASD regression (Funded by SafeMinds)

The effect of mercury and neuropeptide triggers on human mast cell release of neurotoxic molecules (Funded by SafeMinds)

Does mercury and neurotension induce mitochondrial DNA release from human mast cells and contribute to auto-immunity in ASD? (Funded by SafeMinds)

Toxicant-induced autism and mitochondrial modulation of nuclear gene expression (Federally Funded: DoD)

Below are the abstracts for these research projects.

Vulnerability phenotypes and susceptibility to environmental toxicants: From organism to mechanism (funded by Autism Speaks)

One hypothesis regarding the association between genetic changes, environmental factors and autism is that many mutations or polymorphisms make the organism more vulnerable to later exposure in some individuals. Called the “vulnerability phenotype”, the Noble lab hypothesizes that one potential unifying theme of the vulnerability phenotype of children with ASD is that they are more oxidized. This elevated oxidation state has been shown to be sufficient to cause dramatic changes in cellular function. In this project, Dr. Noble will test the hypotheses that genetically-based differences in oxidative status are associated with differences in vulnerability to physiological stressors in vitro and in vivo, with even greater increases in vulnerability to combinations of physiological stressors. Specifically, thimerosal and other vaccine adjuvants will be studied. The second part of the study will determine if these effects on a novel regulatory pathway called redox/Fyn/c-Cbl is a necessary mechanistic convergence for increases in vulnerability caused by a more oxidized metabolic status. These results will provide a better understanding of the biochemical effects and mechanisms of possible toxicity of vaccines and vaccine additives. What this means for people with autism: These studies will initially focus on the combination of vaccine additives, but then examine whether a background genetic vulnerability phenotype affects the response to these additives. The results would provide new targets for intervention against the adverse effects of increased oxidative status in children with autism.


Evaluation of the immune and physiologic response in children with autism following immune challenge
(funded by Autism Speaks)

The overall goal of this proposal is to address immune function in children with autism, including the response to vaccine challenge, and how that relates to behavior. Evidence suggests that autism is associated in some cases with altered immune function, but the response of the immune system in children with autism to specific immune challenges, such as vaccines, has not been investigated directly. While it has been reported that some children with autism respond poorly following vaccination with symptoms ranging from rash, diarrhea, irritability, seizures, and loss of skills, no careful, thorough approach has been undertaken to fully characterize this issue, both at the biology and behavior level. We propose to use our current CHARGE (Childhood Autism Risks from Genetics and the Environment) and Autism Phenome Project (APP) study population to address this critical issue. The overall approach would include an examination of the immune response to both viral and bacterial vaccines in children with autism, as compared to typically developing age-matched controls, in real time following vaccination at 5 years of age. Vaccines have advantages for directly studying the immune response as they provide a known, scheduled immune challenge, whose dose is well characterized – making it possible to collect and interpret immune response data at the time that it occurs. Therefore, we think that exposure to an immune challenge with vaccine would result in an increase in inflammation compared to controls in a subpopulation of children with autism. However, we also anticipate that some children will respond to vaccine challenge differently, depending on form of the vaccine, i.e. viral vs. bacterial. Thus, we propose to address the issue of immune function in children with autism through a careful analysis of the immune system, medical and mitochondrial issues, and behavioral response to both viral and bacterial vaccines.

Vaccination with regression study (funded by Autism Speaks)

A major challenge to studying autism with a suspected vaccine-related regression is identifying children with acute regressive-type symptoms following MMR vaccination; there are no specific codes, tests, or procedures that identify this occurrence with a high degree of specificity. This study will explore the Kaiser Permanente electronic databases to ascertain whether we can identify children with regressive type autism and identify the timing of the regression in relation to the period directly following MMR vaccination. In order to see if identification of regressive autism from medical records is possible, the investigators will attempt to identify children vaccinated with MMR who then abruptly undergo a ‘cluster’ of visits, tests, and/or procedures in the time period directly following vaccination. The researchers feel that there may be a number of children who receive a diagnosis (such as ‘prolonged crying’) in the emergency department on the day after vaccination, followed shortly thereafter (1-2 days later) by another set of diagnoses (such as ‘fever’ & ‘irritability’) in the pediatric office or other outpatient department, and then receive either diagnostic or laboratory tests indicating (at least) a moderate degree of severity of concern, such as CT scans, metabolic testing, or referral to neurology. If this study is successful in using medical databases to identify a specific group of children with demonstrable autism-related regression that clearly follows vaccination, it may point to the feasibility of further studies concentrating on this specific population.

Vaccine safety datalink thimerosol and autism study (Federally Funded)

The Thimerosal and Autism Study is a case-control study conducted in three U.S. managed care organizations (MCOs). Data collection began in 2005 and took three years to complete. In this study, children who were diagnosed with autism were matched with control children. The autism diagnosis of the case samples was confirmed by a standardized clinical assessment protocol. Vaccination histories and information on other potential confounding factors were confirmed by reviewing the medical records for all children. In addition, the mothers of both cases and matched controls were interviewed.

Analysis of developmental interactions between reelin haploinsufficiency, male sex, and mercury exposure (Funded by Autism Speaks)

This project will investigate the role of three separate factors in an animal model of autism spectrum disorder: a) genetic susceptibility, b) hormonal environment, and c) possible environmental triggers. A mouse model with a mutation of the reelin gene, implicated in autism spectrum disorders, will be studied after exposure to methyl and ethyl mercury. Both behaviors and neuropathological endpoints will be explored. Finally, the role of endogenous sex hormones will be examined by eliminating the testosterone “surge” around the time of puberty. The individual effects of each will be examined, as well as the interaction of the three components (genetic liability, environmental exposure, hormonal influences) to determine gene x environment interactions. What this means for people with autism: This study will use a unique design to study multiple factors in the etiology of autism spectrum disorder in a mouse model, isolating and combining factors which previously have been implicated in the pathophysiology and behavioral phenotype.

MeHG stimulates antiapoptotic signaling in stem cells (Federally funded: DoD)

This project is a study of the antiapoptotic effect of low concentration of methly mercury and cadmium in cells.

Etiology of autism risk involving MET gene and the environment (Funded by Autism Speaks)

Two independent lines of evidence indicate that the maternal immune system and a functional genetic variant contribute to autism spectrum disorder (ASD) risk. Here, the Van De Water lab will partner with scientists at Vanderbilt University to examine whether these two seemingly unrelated contributions may converge to define a unique ASD susceptibility. Preliminary evidence collected by the Van De Water lab indicates an association between the Mesenchymal epithelial transition factor (MET) gene ‘C’ type, which reduces MET protein expression, and the presence of specific maternal anti-fetal brain autoantibodies. This relationship suggests that this as a pathway for production of the maternal autoantibodies, leading to a gene x environment interaction underlying ASD susceptibility. The next line of experiments will examine the relationship in an even larger sample and assess the functional effect of the MET gene polymorphism on immune cell activity as well as further examine the impact of environmental toxins (including ethyl mercury) on the gene expression-dependent function of maternal immune cells.

Epidemiological research on autism in Jamaica (Federally Funded, NIH)

The prevalence of autism spectrum disorders (ASD) appears to be on the rise in developed countries and has become a serious public health concern. In most developing countries, however, the nature and prevalence of factors associated with ASDs are unknown. The long term goal of this planning project is to develop capacity for conducting large scale population-based ASD studies in Jamaica. First, the diagnostic criteria used in Jamaica and the United States will be compared. Then, questionnaires regarding the demographic and socioeconomic position, occupation, and drinking habits of each child’s parents will be used, and information will be gathered about family history of developmental disorders, family size, birth order of the affected child, and whether the child is taking any medications. An age and sex matched case-control study, including a dietary questionnaire, will also be conducted to investigate whether environmental exposures to mercury, lead, arsenic, and cadmium play a role in autism. Blood and saliva samples will be collected to determine if any DNA polymorphisms that might affect interactions with heavy metals are present in children with ASD. New knowledge of potential environmental risk factors for ASD may arise from this research, thereby reducing physical, psychological, and economic burdens on the child, family, and society and helping parents make decisions about avoiding exposure to environmental contaminants.

An investigation on the potential harmful effects of mercury in the nonhuman primate (Funded by SafeMinds)

An investigation into the effect of mercury on neurons, astrocytes, and microglia on the central nervous system of the nonhuman primate.

Investigating the effect of mercury on ASD, AD and ASD regression (Funded by SafeMinds)

An investigation into the influences of demographics and environmental variables in the development of neurodevelopmental problems such as AD, ASD, and ASD-regression

The effect of mercury and neuropeptide triggers on human mast cell release of neurotoxic molecules (Funded by SafeMinds)

An investigation to determine the pro-inflammatory effects of mitochondrial DNA with and without mast cell triggers.

Does mercury and neurotension induce mitochondrial DNA release from human mast cells and contribute to auto-immunity in ASD? (Funded by SafeMinds)

Further investigation into preliminary data that neurotensin (NT) stimulates mast cell activation and that NT is elevated in young children with autism spectrum disorder.

Toxicant-induced autism and mitochondrial modulation of nuclear gene expression (Federally Funded: DoD)

Autism has been associated with epigenetic changes: Tiny chemical tags in the regulatory regions of genes that affect how genes express themselves by turning them on or off. One gene often decreased in expression in the brain tissue of autistic individuals is MECP2, a gene that governs the expression of genes crucial to brain development. Exposure to environmental pollutants is also thought to play a role in autism. These two phenomena both involve a small cellular organ called mitochondria. The suspect environmental pollutants are toxic to mitochondria, which play a critical role in epigenetics: Pollution exposure can lower the amount of mitochondrial DNA (mtDNA) in a cell, causing an increase in placement of epigenetic tags by DNMT1 that leads to gene silencing. We hypothesize that exposure during pregnancy to pollutants toxic to mitochondria causes a decrease in mtDNA copy number and increased placement of epigenetic tags by DNMT1 on key developmental genes, affecting pathways that have direct roles in the development of autism. We will expose mice, during pregnancy, to selected toxicants and evaluate adult behavior and associated biochemical changes in brain tissue. Valproic acid will be used as a positive control, with saline as a negative control. The environmental pollutants lead, arsenic, cadmium, manganese, mercury, and permethrin will be investigated for their potential to induce autistic behavior changes. Brain tissue will then be used for molecular studies of mtDNA copy number, expression of DNMT1, and alterations to the epigenome on both a genomewide and gene-specific level.


By Matt Carey

Note: I serve as a public member to the IACC. My views here and elsewhere are my own, not those of the Committee.

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