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An Autism-Gene in a Dish v In Vivo Veritas

F. Edward Yazbak MD

 

Many thousands of American children have developed autism.  

The Institute of Medicine’s Immunization Safety Review Committee held its ninth and probably its most important meeting on vaccination and autism on February 9, 2004. The purpose of the meeting was to review all “pro and con research” on the subject.

Relying in part on findings reported in certain Danish studies[1], the committee concluded in its May 14, 2004 report [2] that the “body of epidemiological evidence” favored rejection of a causal relationship between vaccination and autism. It also recommended “that available funding for autism research be channeled to the most promising areas.”

Since then, enormous amounts of money have been poured into “genetic” research. 

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For some time now, autism and autism research have been the responsibility of the National Institute of Mental Health (NIMH).[3] [4]

Heading the NIMH since 2002 is Director Thomas R. Insel MD, a psychiatrist and a former Psychiatry Professor at Emory University. Excluding Dr. Robert H. Felix who served as the first Director of NIMH from 1949 to 1964, Director Insel has served longer than anyone else.

In addition to his many Institute activities and responsibilities, Dr. Insel has also been Chairman of the Interagency Autism Coordinating Committee (IACC) since it was first convened in January 2007.

Dr. Insel regularly attends all full-day IACC meetings including the most recent on July 9, 2013. The next meeting was scheduled for Wednesday October 9, 2013 from 9:00AM to 5:30PM EST but according to a notice[5] on the website on Thursday October 3, 2013: “This meeting will take place as an in-person meeting only if the government reopens by Monday, October 7, 2013. If the government reopens on Tuesday, October 8, 2013, the meeting will be held as a phone meeting only, and public comments will be accepted in writing only and will not be shared with the committee until after the meeting due to lack of time for staff to process the comments. If the government remains closed on October 8, 2013, the meeting will be canceled and will not be rescheduled.”

As NIMH Director, Dr. Insel also regularly attends a multitude of other official hearings, meetings, conferences and activities. He has published [6] “over 250 scientific articles and four books…” including nine publications in 2012 and seven so far in 2013.

Dr. Insel also posts commentaries on mental health issues on his NIMH Blog.

Note

From this point on, remarks by Dr. Insel will appear in Italic

while my comments will continue in regular script.

One of Dr. Insell’s 2012 posts is titled “Autism Prevalence: More Affected or More Detected?” [7]

It started with:  

Autism is always surprising. Earlier today, the CDC released new numbers from their ongoing surveillance of autism prevalence, the Autism and Developmental Disability Monitoring (ADDM) Network. What was once considered a rare disorder is now reported as affecting 1 in 88 children, 1 in 54 boys. These new numbers, up 78 percent from 2002 and 23 percent from 2006, raise immediate questions. Are more children affected or more detected? Does the increase reflect a growing problem, or do these new numbers reflect an improvement in our ability to diagnose and serve those affected?       

I personally don’t know any parent who referred to the catastrophic diagnosis of autism as merely a surprise. On the other hand, I am pretty sure that a multitude of parents and grandparents of children with autism would be thoroughly surprised to see the Director of the national Institute of Mental Health enumerate such awful statistics and then attempt to attribute them to better diagnosis.

Does the Director really believe that pediatricians who practiced in the 70’s and 80’s were not astute enough to diagnose autism? Does he really think that we “missed” all these children who suddenly stop talking, who scream all day, who walk on their toes and who throw themselves on the floor in supermarkets and parking lots?

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Dr. Insel’s Blog most recent five posts were:

Healing Invisible Wounds: An Action Plan August 13, 2013

Infantile Amnesia August 19, 2013

Antipsychotics: Taking the Long View August 28, 2013

Accessing and Assessing Science September 5, 2013

In Vitro Veritas? September 16, 2013

The last title was particularly interesting: In Vitro: “In glass”, in a dish, in a lab, outside the body ---- Veritas: Truth. It intimated that a solid and believable fact had been found in the laboratory.   

http://www.nimh.nih.gov/about/director/2013/in-vitro-veritas.shtml

The post started:

“Over the past 6 months we have turned a corner in our studies of the genetic basis of schizophrenia and autism. For years the field of psychiatric genetics has struggled: family and twin studies demonstrated that these disorders were heritable, but findings from small studies reporting specific risk genes could not be replicated. With larger samples and better tools, we have gone from famine to feast, with almost too many genetic findings to follow up. A new report has just described 13 new genetic findings associated with schizophrenia, resulting in over 100 common variants now identified as risk factors.”

It is gratifying to see Dr. Insel concede at the very onset:

  • That the field of genetics has struggled for years
  • That past studies had been small and not too impressive
  • That specific risk genes that were discovered could not be replicated causing terminal stalls

Maybe the Director should have mentioned, for the sake of completion, the thousands of dollars needlessly committed to genetic research … that went nowhere.  

The rest of the opening paragraph was schizophrenia-related and effusive: “In the past six months”, “we have gone from famine to feast with almost too many genetic findings to follow up”, “13 new genetic findings”, over 100 common variants” …

The problem now is not how to find the genetic variation associated with mental disorders, but how to understand these genetic changes and, specifically, link them to changes in brain circuits.”

The Director seems as bewildered as most of us. We keep hearing about “amazing genetic discoveries” and then we are told that no one seems to know what to do with them - even though we have great experts, excellent facilities and an abundant flow of taxpayers’ dollars.

“Adult-derived stem cells that can be differentiated into neurons are an obvious tool. Either the person’s own cells can be used or standard stem cells can be engineered to have the same genetic variations associated with autism or schizophrenia. An extraordinary new method called CRISPR uses an enzyme from bacteria found in yogurt to edit DNA so that a genetic variant can be inserted quickly, accurately, and inexpensively.2 Turning stem cells into neurons with a risk gene is now straightforward.”

After gently weaving Autism into the Schizophrenia tableau, the Director described how a way was found to “edit” DNA so as to be able to slip in a genetic variant precisely, promptly and at a low cost. His statement that “turning stem cells into neurons with a risk gene is now straightforward” is literally correct but it fails to describe how intricate the process remains and how few are the centers conducting any research in that specific field.

“This approach, sometimes called “disease in a dish,” has already been used for Timothy syndrome, a rare form of autism caused by a single gene. Neurons grown in vitro from children with Timothy syndrome show abnormal dendrites and unusual dendritic responses to activation, possibly revealing a mechanism of the disorder. Stem cells differentiated into neurons are now being tested for a number of other neurodevelopmental disorders for which we know the genetic cause. Complex disorders, with multiple genes involved, will be more of a challenge but with CRISPR for DNA editing, what seemed impossible only last year begins to look plausible.”

Although the Director’s description seems to point to a solid genetic achievement, the fact is that the ultimate result of this particular research is clearly of limited scope because Timothy Syndrome (TS), otherwise known as “The “Long QT syndrome with syndactyly”, is so extremely rare.   

The Genetics Home Reference (GHR), a service of The National Library of Medicine, lists the following information [8] about the disorder:

  • “Researchers have found that many children with Timothy syndrome have the characteristic features of autism or similar conditions known as autistic spectrum disorders. Affected children tend to have impaired communication and socialization skills, as well as delayed development of speech and language. Other nervous system abnormalities, including intellectual disability and seizures, can also occur in children with Timothy syndrome”
  • Researchers have identified two forms of Timothy syndrome. Type 1, which is also known as the classic type … Type 2, or the atypical type, causes a more severe form of long QT syndrome and a greater risk of arrhythmia and sudden death but usually no syndactyly
  • Timothy syndrome is a rare condition; fewer than 20 people with this disorder have been reported WORLDWIDE. The classic type of Timothy syndrome appears to be more common than the atypical type, which has been identified in only two individuals

So far, I am unable to find too many experts sharing the Director’s enthusiasm over this “breakthrough.”

I personally do not think:

  • That one can say that Timothy Syndrome is “a rare form of autism” just because some individuals with the syndrome also have certain features of autism
  • That one can actually extrapolate findings in 20 individuals to the whole world population with autism and autistic spectrum disorders
  • That we can rejoice that after spending years spinning in place we have found a gene
  • That we can really call that a “significant” start
  • That we can assert with confidence - on the basis of the presumed discovery of a single finding in a minute population - that “complex” disorders, where multiple genes are involved, are now looking plausible

“But growing neurons in this way may not be enough. If the neurodevelopmental disease is due to a dysfunctional circuit we need to study neurons as they develop in an environment where they can wire and fire with other cells. A new paper by Madeline Lancaster and her colleagues in Vienna has just described a cerebral “organoid” – a sort of budding brain growing in a dish.4 The organoid is built from human stem cells, following the steps required for human brain development in utero. To be clear, this is not a whole brain, it is a 3-dimensional in vitro culture system in which stem cells are induced to form many of the different kinds of cells and tissues found in the human cortex and other areas. What is amazing – eclipsing earlier “disease-in-a-dish” discoveries – is that, over weeks and months, these cells organize themselves according to the architecture that we see in a functioning human brain. But this is not a functioning brain -- the full organoid is smaller than a kernel of corn and it lacks a circulatory system or the complex circuitry needed for function.”   

Here again, the Director’s enthusiasm seems somewhat unjustifiably exuberant:   

  • This is not a brain but a 3-D “culture system” with different kinds of brain cells
  • Over weeks and months, the cells may organize themselves according to the architecture we see in a functioning human brain

However … this is NOT a functioning brain but rather an “organoid”, an organism smaller than a kernel of corn – and that CANNOT POSSIBLY FUNCTION because as the Director points out, “it lacks a circulatory system or the complex circuitry needed for function.”  

***

Somewhat dampening Director Insell’s enthusiasm about all this is a recent publication (September 2013) in the Journal of Autism and Developmental Disorders titled: “Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype?”

According to the scientists who conducted related research of another genetic disorder in which a “High prevalence of autism spectrum disorders (ASD)” had indeed been reported: “ASD is not as common as previously reported” [9]     

Reports based on a News Release by the University of California, Davis listed the following details:

  • The “22q11.2 deletion syndrome” affects about one in 4,000 people
  • Rates of autism in children with “22q11.2 deletion syndrome” had been reported at between 20-50 percent yet the MIND Institute study found that, when rigorously evaluated, none of the 29 children with the syndrome (0%) "met strict diagnostic criteria" for autism
  • The level of social impairment in children with “22q11.2 deletion syndrome” was unlike that in children with autism: They were usually quite socially-skilled, they interacted with pleasure with their younger siblings and their friends and related well to accommodating adults.
  • The usual autism treatments did not work for children with “22q11.2 deletion syndrome” who usually only required some gentle assistance to improve their communication skills, to help them remain more focused and to alleviate their anxiety.  http://tinyurl.com/lah2u62

I will respectfully submit that the findings of this study by the MIND Institute at UC Davis are immensely more impressive in scope than those of the study on Timothy Syndrome quoted by the NIMH Director as a breakthrough.

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Millions of dollars have been and are being spent on research aimed at finding “purely” genetic causes for autism. So far, it seems evident that all of that research has not resulted in the discovery of any convincing evidence that autism is primarily a genetic disorder.  

There are actually two simple yet strong arguments against such a pure genetic etiology:

  1. Genetic disorders do not present as epidemics
  2. Only a certain percentage - but not 100% - of mono-chorionic , mono-amniotic twins - otherwise known as “identical twins” - develop autism

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Maybe the Director and the distinguished experts at the National Institute of Mental Health should start talking with parents of children with autism and hearing their stories.

They will discover that many of those parents, even those who concede that a genetic predisposition to autism exists, will still insist that some precipitating trigger preceded the appearance of their children’s symptoms.   

The NIMH must investigate all causes that could trigger this awful disorder – including those that the IOM Immunization Safety Review Committee judged unworthy to examine.

So far, it does not seem that we have discovered much in small glass dishes in big glass buildings!  

Maybe it is time to ask the parents in the trenches what they think…

After all, isn’t it more likely that In Vivo Veritas.

 

F. Edward Yazbak MD

Falmouth, Massachusetts

10-15-2013