Of mice and men and autistic fruit flies

Autism is a hot topic for scientists engaged in brain research. If you can link your research to autism it may help you to access additional funding that is available in the USA. In response to a determined campaign by parents and lobby groups  Congress passed the Combating Autism Act which sanctioned a substantial increase in the funds available for research into the causes of autism. At the same time the high profile pressure group Autism Speaks has, by a series of mergers and alliances, notably with Cure Autism Now! and the National Alliance for Autism Research, emerged as a leading funder of autism research.  In June it announced research grants of $15.2 million USD. Then there are private trusts like the Simons Foundation which is providing long term funding for autism research at Yale($2.5 million USD), Cold Spring Harbour, ($13.8 million USD), Michigan($2.8 million USD), MIT($7.5 million USD) and Rockefeller ($7.7 million USD).

This is serious money. One hopes that it attracts serious research. The Chapel Hill School of Medicine at the University of North Carolina is a serious research institute. According to Science Daily  they have made an important discovery that

may lead to advances in understanding autism spectrum disorders, as recently, human neurexins have been identified as a genetic risk factor for autism.

They made this important discovery while researching the role of neurexin in Drosophila, that is fruit flies to the rest of us. Drosophila are an important part of the biological research toolkit. Their relatively simple genome and rapid reproductive cycle have made them a favourite of biologists researching the mechanics of evolution. But autistic fruit flies? Autism is a complex social disorder. Fruit flies are not complex social beings.

Neurexin is a basic prerequisite for  neuronal connectivity. Without it the fruit flies barely survived. Movement was severely impaired. These are primitive creatures compared to us. I would anticipate that a similar lack in humans would have far more devastating results. Autism would be the least of our worries. Never mind. The putative autism connection cannot have done any harm in obtaining funding from

  • the National Institute of General Medical Sciences,
  • National Institute of Neurological Disorders and Stroke
  • the National Institute of Mental Health 
  • the state of North Carolina.

Moving up the food chain we find a mouse study. Thanks to Mady Hornig mouse studies  of autism have received a bad press. But this one is different. Thanks again to Science Daily for telling us that

Howard Hughes Medical Institute researchers have genetically engineered mice that harbor the same genetic mutation found in some people with autism and Asperger syndrome.

The gene in question codes for for a protein called neuroligin-3.

This protein functions as a cell adhesion molecule in synapses, the junctions that connect neurons in the brain and allow them to communicate with each other. Synapses are essential to all brain activities, such as perception, behavior, memory, and thinking. Südhof said that the neuroligin-3 mutation that his team recapitulated in the mice has been identified in some people with genetic conditions known as autism spectrum disorders (ASDs). Mutations in proteins that interact with neuroligin-3 have also been detected in some people with ASDs.

Neurexin is one of these detected proteins.  (remember the fruit flies?) Is this a double whammy that damns autistic people/mice forever? Apparently not. These genetically engineered, autistic mice did rather more than “barely survive.” They showed diminished social interaction but improved cognitive performance compared to neurotypical mice. This is automatically seen as a deficit. But surely progress is driven by those individuals who turn their back on the herd and consider the external world? Never mind. In the wacky world of autism research, conformity is valued over diversity and sociability scores higher than intelligence.

But my take home message is that geek mice rule OK! [or at least they ought to]

NIMH Chelation Study

Two weeks ago I wrote to Karin Lee at the National Institute for Mental Health (NIMH) press office after reading a press release that said that NIMH was going to conduct a trial to see if chelation therapy improved the behaviour of autistic children.

I asked what I thought was an obvious question.

Can you point me to any published research that demonstrates that autistic children do have elevated levels of heavy metals in their blood?

I wanted to know if NIMH had any evidence that blood levels of mercury are higher in autistic children than their neurotypical(NT) peers. To judge from Karin’s reply, NIMH do not have any evidence. Instead of giving me references Karin suggested that I

conduct a search on PubMed, a service of the National Library of Medicine. To access PubMed go to the Web site http://www.ncbi.nlm.nih.gov/pubmed and type your topic in the search field.

Thank you Karin. I do know how to search PubMed. I found a recent study that showed no difference between mercury levels in autistic and NT children. I found another study that gave reference values for mercury in the blood of children as 1 microgram per litre (1 microgram =1 millionth of a gram) and for lead as 50 micrograms per litre. Karin also refered me to a more detailed description of the clinical trial. This contains the following inclusion criteria.

  • Male or female subjects, four to ten years of age.
  • Meets research criteria for ASD (specifically, autism, Asperger Disorder, or Pervasive Developmental Disorder – Not Otherwise Specified).
  • Detectable (greater than 0.1 microgram per deciliter) levels of blood lead and/or blood mercury.
  • Each legal guardian must have a level of understanding sufficient to agree to all required tests and examinations. Each legal guardian must understand the nature of the study and must provide written consent to study protocol.

Note the figure for levels of lead or mercury is equivalent to the reference figure for mercury of one microgram per litre and way below the reference point for lead. These levels are so tiny that everybody has them. Here are the exclusion criteria.

  • History of allergic reaction to sulfur or thiol-containing substances
  • History of previous chelation therapy for autism
  • History of uncontrolled epilepsy
  • Weight less than 15 kg at screening
  • Presence of a chronic medical condition that might interfere with study participation or where study participation would be contraindicated or clinically significant abnormal baseline laboratory results.
  • Level of lead above 10 microgram per d, or Level of mercury over 44 microgram per deciliter (toxic levels which require intervention with chelation and preclude placebo assignment) or other evidence of heavy metal toxicity.
  • Recent (less than two months prior to study entry) initiation of behavior therapy

Note that autistic children with heavy metal poisoning are not eligible for this study. They need treatment and it would be unthinkable to put them on a placebo. But this means that to be eligible for a study in which you may be treated for heavy metal poisoning you must be completely healthy and not have heavy metal poisoning.

Autistic children with traces of heavy metals in their blood that are no different from the levels in NT children are going to be subject to unnecessary medical treatment to see if it alters their behaviour. Well, it would certainly alter mine!

I wonder why they are only recruiting autistic children? Perhaps NT children with the same reference levels of mercury would also benefit from a dose of chelation therapy. But what self respecting parent of a healthy child would submit their child to that? And that goes for the parents of healthy autistic children as well.

I am guessing that NIMH will only attract parents who believe their child is sick. They believe their child is mercury poisoned. NIMH will have to have a very good screening programme to exclude parents who have already tried chelation on their child. I am guessing that, even then, they will only attract parents who are already using other biomedical interventions. There is nothing in the description of the clinical trial that takes account of any of the other possible confounds arising from unorthodox biomedical interventions.

There is a final ethical consideration I would like to raise.

Parents approach DAN! practitioners with a false belief about their child’s health, seeking treatment for that child. The DAN! practitioner shares their belief and provides the treatment.

Parents approach a NIMH doctor with a false belief about their child’s health, seeking treatment for that child. The NIMH doctor does not share their belief. In fact they have to establish that the child is not ill. But they still provide the treatment requested by the parent.

Who has made a moral decision here; the DAN! practitioner or the NIMH doctor?