Keystone Symposia Turns Its Attention to Autism
For the world’s top scientists, prestigious small meetings such as the summer courses at Cold Spring Harbor, NY and the winter Keystone Symposia represent the most fertile opportunities for coming together from a variety of fields to learn about a specific topic.
In the summer of 2007, Cold Spring Harbor offered a workshop dedicated to autism. Approximately six months later, in February of this year, Keystone turned its attention to autism for the very first time, holding a symposium “Towards Identifying the Pathophysiology of Autistic Syndromes” in Santa Fe, NM (February 24-28, 2008).
Autism Speaks was represented by Geri Dawson, Ph.D., Chief Scientific Officer, and one of the main lecturers, who enthusiastically noted two significant developments: that the attendance was actually dominated by non-autism scientists eager to learn more about autism and share their knowledge in their own respective fields, and that there was a surprisingly large number of young scientists wanting to direct their careers towards the study of autism. These made this conference an extremely important event in the future success of autism research.
The keynote address was provided by Patrick Bolton, Ph.D. (King’s College, London) who focused on unifying autism with the many medical conditions associated with autism (for example, Tuberous Sclerosis, Fragile X, Rett; see below). Dr. Bolton noted the increase in the number of medical conditions that are now associated with autism, and emphasized studying them to find insights into the underlying mechanisms of autism as well as to test theories about autism.
Indeed, it was no accident that the majority of speakers at this symposium were from these medical fields, as the purpose of the meeting, organized by Pat Levitt, Ph.D. and Joe Piven, M.D., was to begin laying down the converging pathophysiological pathways from these associated medical conditions in order to build one for autism. Dr. Bolton concluded that only through an integration of experimental approaches (genetic, biochemical, imaging, cognitive & behavioral, etc.) and disease pathways will it be possible to explain the plethora of symptom combinations and severities observed in the autism spectrum.
Because so many of the attendees were from outside the field, a series of lectures from autism experts served to introduce what is currently known about autism and the active areas of investigations.
Dr. Dawson discussed behaviors seen in autistic infants including lack of eye contact and response to name, passivity/decreased activity, narrow interests/fixation on objects, decreased social smiling, and delayed gestures and language acquisition. Using sophisticated techniques to record brain physiology, researchers are now making progress in understanding the brain dysfunctions that underlie some of these behaviors. She noted that the variable developmental course of autism underscores the need for longitudinal follow-up of as many cases as possible to clarify and define them. She also presented a case of success in early intervention that begged the questions: can early intervention alter the developmental course of autism, and is there a temporal window of opportunity that allows for the reversal of symptoms? If so, perhaps these are different among the autism spectrum disorders (ASDs) and this needs to be further tested.
Dr. Dawson accentuated strategically placing our resources into defining these windows of intervention opportunity. Finally, she presented a scheme for the development of autism where “risk factors” (genes, the environment) interact with “risk processes” (experience, biological events) resulting in abnormal development. The hope is that early diagnosis combined with interventions targeted against “risk processes” will prevent or cure autism.
Dan Geschwind, M.D., Ph.D., (UCLA) began tackling the complexity of the genetic causes of autism by enumerating gene defects already known to be associated with some cases of autism, observing that many of these are known to be involved in patterning and wiring the brain. He commented that the heterogeneous presentations of autism will naturally lead to the discovery of more genetic culprits, though not without difficulty. After proposing several options to facilitate the process, he concluded that since autism is genetically diverse, it is important to study the single gene disorders associated with autism as a complementary approach. These diseases may explain some of the symptoms seen in autism. He further suggested that in the future, genetic evaluation should be part of the diagnosis and work-up of autism in order for intervention/treatment to be more specifically directed.
David Amaral, Ph.D. (UC Davis) described the many recent pathological studies in autism including abnormal minicolumn density and underconnectivity, chronic neuroinflammatory events and immune dysregulation, and pathological findings in the amygdala. Mark Lewis, Ph.D. (Univ of Florida) focused on restricted-repetitive behavior (RB), which is diagnostic of autism but not exclusive to it. RB has been modeled extensively in animals and may result from CNS insults of genetic or environmental origin.
According to Dr. Lewis, even though many parts of the brain circuitry responsible for RB have been uncovered through animal models, very little is actually known about the genetics of RB. In some cases of autism the defective genes found are actually those responsible for brain circuitry formation, so it seems very likely that there will be common genetic components between clinical autism and RB animal models. Whereas animal models are used often to shed light on diseases, in this case autism research may contribute in uncovering the genetic basis of repetitive behaviors modeled in animals.
Joseph Piven, M.D. (Univ of North Carolina, Chapel Hill) closed the didactic sessions by calling attention to the fact that different brain pathologies may present with similar behavioral symptoms. For example, the same symptoms may be observed in an individual diagnosed with autism and an individual diagnosed with combined autism and Fragile X Syndrome (different brains, similar behaviors). Thus, the elaboration of the pathophysiology of the autism spectrum disorders benefits immensely from the study of the more homogenous associated medical conditions because there are likely common pathways that can be used as initial building blocks for such an effort. Until the unique characteristics of ASDs are more precisely defined, it seems a good bet to start with what is already known from these associated medical conditions that are immediately available for study.
The participant presentations that followed over the next few days highlighted these different medical conditions associated with autism, and identified areas of study that intersect with autism on genetic, molecular, cellular, metabolic and cognitive/behavioral grounds. Clearly these are not the only diseases that share co-morbidities with autism, however, they are among the most studied and best defined. They offer the most pertinent platform for identifying a pathophysiology for autism, and for developing therapeutic drug candidates and other interventional approaches. As many of the speakers demonstrated, research identifying the specific disrupted molecules and biochemical pathways in these other autism-associated disorders is already leading to development of biomedical therapeutics, which may ultimately also be useful for autism.
Individuals with Tuberous Sclerosis (TS) suffer from learning and behavioral deficits akin to those observed in autism as well as epilepsy. In TS, depending on the study, up to 60% of patients also meet the diagnostic criteria for autism. The defective genes are TSC1 (hamartin) and TSC2 (tuberin) which normally function in a complex of molecules important in cell growth and division. The complex is a suppressor of mTOR signaling. The link to autism turns out to be the PTEN molecule, which similarly functions as a suppressor of mTOR signaling. Some individuals with autism have been found to have mutations in the PTEN gene. Mice deficient in the mouse PTEN gene display autism-like behaviors, as do mice that have low levels of TSC1 and TSC2. Importantly, there is a drug that can function like PTEN, TSC1 and TSC2 in suppressing mTOR — rapamycin. In the animal models, rapamycin normalizes learning deficits and reverses some of the abnormal phenotypes. Therefore, rapamycin is undergoing clinical trials to determine whether it can be an effective medication to alleviate the symptoms of TS. (Drs. Alcino Silva, Kevin Ess and Luis Parada)
Neurofibromatosis Type I (NFI) is a disorder resulting from a defect in the gene of a signaling molecule called Ras-GAP. It can occur in individuals with no family history and present with symptoms that are not only shared with autism but also found in epilepsy and other learning disorders. It is thought that problems in the synapse, the communications conduit between brain cells, underlie the symptoms. More specifically, there seems to be an imbalance in excitation and inhibition mechanisms (brain cells communicate using molecules that cause excitation or inhibition of electrical impulses) because Ras signaling, which functions to increase the release of inhibitory molecules, is out of order. Following this discovery, it was found using animal models that the defect can be rescued with the introduction of a normal functioning Ras molecule. Intriguingly, statins, the cholesterol-lowering drugs, may also have therapeutic efficacy in animal models, but how statins work in this setting is still under investigation. (Dr. Alcino Silva)
Fragile X Syndrome
Fragile X syndrome is the most common form of inherited mental retardation. In this syndrome, a defective FMR1 gene constricts the X chromosome making it appear fragile when observed through a microscope, hence the name Fragile X (FX). Research has found that the defect in the FMR1 gene leads to excessive protein production in the synapse. Synapse pruning (a normal component of nerve development) is decreased in FX, which may lead to the classic symptoms (deficits in intelligence and learning, social anxiety and emotion, speech and language acquisition, sensory) that are shared with autism. Most cases of autism are not associated with FMR1 gene mutations (only 1-4%). However, approximately one third of the individuals with FX also have a diagnosis of autism, raising the possibility that the two may be superimposed disorders with common disease pathways. Molecularly, FX may be the result of the unchecked activation of mGluR5 protein, a cell surface receptor that results in excitatory neurotransmission at synapses. If so, the delicate balance between excitation and inhibition is swayed towards the former, and this is detrimental to normal development and functioning of the nervous system. Antagonists of mGluR5 activity are currently under development as potential therapeutic agents for both Fragile X and autism. (Drs. Declan Murphy, David Nelson, William Greenough and Gul Dolen)
Rett Syndrome’s defective gene, MeCP2, also resides on the X chromosome. Affected males rarely survive to full-term, which is why it is seen to affect girls almost exclusively. A deficiency in MeCP2 results in altered protein production in the synapse. This leads to the less than ideal number of synapses between nerve cells, which may also be the cause of the autism-like symptoms. Very interestingly, the opposite scenario, an overproduction of MeCP2 (for example, a duplication of the gene), is also pathological — reminiscent of copy number variation gene defects in autism. Evidently, the correct dosage of gene activity (neither too much nor too little) is required for some genes to function normally in the nervous system. (Drs. Huda Zoghbi and Sarika Peters)
Smith Lemli Opitz Syndrome
Only 1 in 50,000 individuals are diagnosed with Smith Lemli Opitz syndrome (SLOS) and about 50% of them present with features of autism. SLOS results from a defect in a gene (DHCR7) for an enzyme involved in cholesterol production. Cholesterol is often thought a health risk, but it is actually an essential component of cells and nerves. The defect in DHCR7 leads to the combined underproduction of cholesterol and the accumulation of cholesterol precursor chemicals that are toxic. That cholesterol supplementation improves some symptoms (social, communication), but not others (repetitive behaviors), reveals that the defect in cholesterol synthesis can account for some autism symptoms but not all. In typical autism (without SLOS), research using samples derived from Autism Speaks’ Autism Genetic Resource Exchange(AGRE) has observed a high rate of abnormal cholesterol levels. This means that aspects of cholesterol metabolism may be involved in autism and potentially worth investigating further. (Dr Forbes B. Porter and Elaine Tierney)
The symptoms that connect these associated medical conditions and autism seem to be masterminded by common signaling, protein synthesis and metabolic pathways that all ultimately affect how synapses develop and function. Synapses and the balance between excitatory and inhibitory molecules are important in nerve cell-to-cell communication. How much communication occurs at an individual synapse, how many synapses there will be overall, and where they will be located all necessitates a fine-tuned developmental process. We know that autism is a neurodevelopmental disorder in that it develops over time and during the period that the brain grows and matures, but at the moment, unlike many of the associated medical disorders discussed at this meeting, the mechanisms and molecular players are not completely known. This is largely why we do not yet have a unified pathophysiology of autism. As discussed at this meeting, however, as evidence implicating synaptic communication accumulates, other emerging molecular players in synapse development and functioning may eventually be integrated into the scheme. This includes the serotonergic system, c-Met tyrosine receptor kinase signaling (which also converges with PTEN), and other molecules that regulate synapse number (including immune molecules that play a role in synapse elimination). (Drs. Randy Blakely, Pat Levitt, Takao K. Hensch, Lisa Boulanger. Michael E. Greenberg and Beth Stevens)
Finally, while it is clear that genetic defects cause many of the autism-like symptoms in these associated medical conditions and likely participate in autism as well, factors that modify gene function (known as “epigenetic” factors) may also play a role. In this case, genes that are otherwise normal may interact with each other, with other cellular components, or with the environment and result in an alteration of gene function. It will be interesting to identify the epigenetic mechanisms operating in autism, determine their contribution, and see whether these may provide amenable approaches to intervention. (Drs. Yi Eve Sun, Arthur L. Beaudet, Jonathan Sebat and Marylyn D. Ritchie)
Autistic people have fought the inclusion of ABA in therapy for us since before Autism Speaks, and other non-Autistic-led autism organizations, started lobbying legislation to get it covered by insurances and Medicaid.
ABA is a myth originally sold to parents that it would keep their Autistic child out of an institution. Today, parents are told that with early intervention therapy their child will either be less Autistic or no longer Autistic by elementary school, and can be mainstreamed in typical education classes. ABA is very expensive to pay out of pocket. Essentially, Autism Speaks has justified the big price tag up front will offset the overall burden on resources for an Autistic’s lifetime. The recommendation for this therapy is 40 hours a week for children and toddlers.
The original study that showed the success rate of ABA to be at 50% has never been replicated. In fact, the study of ABA by United States Department of Defense was denounced as a failure. Not just once, but multiple times. Simply stated: ABA doesn’t work. In study after repeated study: ABA (conversion therapy) doesn’t work.
What more recent studies do show: Autistics who experienced ABA therapy are at high risk to develop PTSD and other lifelong trauma-related conditions. Historically, the autism organizations promoting ABA as a cure or solution have silenced Autistic advocates’ opposition. ABA is also known as gay conversion therapy.
The ‘cure’ for Autistics not born yet is the prevention of birth.
The ‘cure’ is a choice to terminate a pregnancy based on ‘autism risk.’ The cure is abortion. This is the same ‘cure’ society has for Down Syndrome.
This is eugenics 2021. Instead of killing Autistics and disabled children in gas chambers or ‘mercy killings’ like in Aktion T4, it’ll happen at the doctor’s office, quietly, one Autistic baby at a time. Different approaches yes, but still eugenics and the extinction of an entire minority group of people.
Fact: You can’t cure Autistics from being Autistic.
Fact: You can’t recover an Autistic from being Autistic.
Fact: You can groom an Autistic to mask and hide their traits. Somewhat. … however, this comes at the expense of the Autistic child, promotes Autistic Burnout (this should not be confused with typical burnout, Autistic Burnout can kill Autistics), and places the Autistic child at high risk for PTSD and other lifelong trauma-related conditions.
[Note: Autism is NOT a disease, but a neurodevelopmental difference and disability.]
Fact: Vaccines Do Not Cause Autism.