This is a guest post by Kristin and Brian Thompson, supporters of Autism Speaks’ Autism Tissue Program (ATP).
On October 17, 2010 parents and friends of Reid Thompson will be running in the Long Beach Marathon to raise funds and awareness for Autism Speaks’ Autism Tissue Program (ATP). Reid, an 11-year-old boy with autism from Thousand Oaks, CA tragically and unexpectedly died in his sleep in August 2007. “It is our way of honoring Reid’s memory and helping an organization dedicated to autism research,” said Brian Thompson, Reid’s father.
Even though this was a catastrophic loss for the family, the Thompsons courageously made the decision to donate Reid’s brain tissue to the ATP within the critical time period of less than 36 hours after his death. The cause of Reid’s death is unknown as the autopsy results were all normal, with the exception of his brain being slightly heavier than average (this is common among individuals with autism). Although medical experts cannot provide a definitive cause of death, they hypothesize that Reid died from a massive seizure, even though he had no history of seizures.
Reid’s parents continue to seek answers about his untimely death, not only for their own closure, but also to help other families affected by autism. “Reid had autism but we don’t know exactly why his life here with us was cut short,” said Thompson. “Leading scientists are working with the ATP and are already using tissue donated by Reid in hopes of providing our family, friends, and others impacted by autism with the answers we seek. Reid is a teacher and we hope his contribution along with the ground-breaking work being done by the ATP helps scientists understand autism, which will lead to a cure”.
The ATP makes brain tissue available to as many qualified scientists as possible to advance autism research and unravel the mysteries of this and related neurological conditions. In fact, it is the only program solely dedicated to increasing and enhancing the availability of post-mortem brain tissue for basic research in autism. Each precious donation to this program greatly adds to our understanding of the complexities of the human brain and the factors that contribute to autism.
Months after Reid’s passing, Brian met another parent, Ben Fesagaiga, who had just founded an all-volunteer non-profit called Train 4 Autism. Train 4 Autism helps people raise funds for various autism-related charities through participating in athletic events such as 5Ks, 10Ks, half marathons, full marathons, and triathlons. In about three years time, the organization has grown to 35 chapters across the United States and has raised more than $100,000 for autism-related charities.
Team Reid’s Long Beach Marathon participants will include Reid’s father Brian, Brian’s wife Kristin, and Team Captain and Train 4 Autism Director of Communications Molly Rearick, Reid’s former teacher. Team Reid has participated in this event since 2008 and also has a presence at the annual Los Angeles Walk Now For Autism Speaks event in support of Autism Speaks.
To support Team Reid and their efforts at the Long Beach Marathon in 2010, click here.
More information on the ATP can be found at: www.autismtissueprogram.org or by calling (877) 333-0999. The ATP is deeply grateful to the Thompson family for their efforts to advance research into the causes and treatments for autism.
About one in every 10,000 babies is born with two few or too many genes on chromosome 15. The likelihood that these babies will be on the autism spectrum is as high as 80%, making these rare genetic events a target for autism research.
Gene targets. Of the estimated 30,000 genes that make up the human genome, between 700-900 genes lie on chromosome 15. Specific segments of this chromosome are associated with autism, narrowing the number of genes of interest to fewer than 30. These genes are located on the long arm of chromosome 15, called q. The most studied region so far is known as 15q11-13, where 11-13 describes an exact physical location on the chromosome (the region in red in the picture). Sometimes babies will have extra copies within this area, beyond the normal two parental 15q11-13 regions, resulting in 3, 4, 5, or even 6 extra copies of all the genes in the duplicated region. In other cases, portions of this region are deleted, leaving no copies of these genes.
How do chromosome copy variations occur? Autism Speaks interviewed a key researcher, Dr. Carolyn Schanen, in an article ‘Understanding the Role of Chromosome 15 in Autism’, that explains these events in detail (link to e-Speaks). The basic concept is that, during cell division, the DNA sequences of our chromosomes literally break apart and recombine; during this process, sometimes there is an aberrant duplication of genetic material. Some forms of 15q11-13 duplications are inherited and some occur in the child and are not found in the parents. Sorting out all of the possibilities is one of the goals of the research of 15q duplication and deletions.
Overlapping syndromes in 15q11-13. Deletions of genes in the 15q11-13 region are associated with Angelman’s Syndrome or Prader-Willi Syndrome, whereas duplication of such genes results in a different syndrome (15q11-13 Duplication Syndrome). A syndrome is named when common physical features or behaviors are observed. Prader-Willi occurs in about 1 in every 10,000 births and is characterized by hypotonia, hyperphagia (obsessive eating = characteristic weight gain) and diagnosis of an Autism Spectrum Disorder (ASD) in 25-45% of individuals. The occurrence of Angleman Syndrome is about 1/12,000 and is characterized by sleep disturbance, ataxia (unstable walking), frequent laughter, excitable personality and hand flapping movements. ASD is also linked with this syndrome.
Babies with 15q11-13 duplications typically have hypotonia (low muscle tone), minor facial differences (nose, eyes, ears), intellectual disability and are diagnosed with autism spectrum disorder. Seizures can be present in the newborn or develop later resulting in epilepsy that is hard to control, and sometimes lethal.
What are these genes doing? A gene’s job is to be a faithful blueprint of information, such as the code for the production of a protein. The level of production of any particular protein is carefully regulated by the cell and irregularities in the levels of proteins can impair cell function, or even lead to cell death.
For example, the product of gene UBE3A in the 15q11-13 region is involved in targeting proteins to be broken down (degraded) within cells and deficits are linked to brain pathology in both Angelman’s Syndrome and autism. Another gene in the region, called ABPA2, makes a protein crucial in getting neurotransmitters out of neurons. And the CHRNA7 gene is an acetylcholine receptor that mediates fast signal transmission at synapses. The general idea is that too little of these gene products would be linked to low muscle tone and ataxia. A new report from an international group shows that deletion of genes at 15q13.3 is linked to epilepsy. Three genes in the 15q11-13 region make protein subunits that need to aggregate with other subunits to form the receptor for the brain’s main inhibitory neurotransmitter, GABA. The extra copies are thought to create an unstable receptor and the lack on inhibition leads to excessive cell firing (seizures). Researchers are just beginning to measure gene products in brain cells of those with 15q duplications.
Changes in the brain. A special project evolved to thoroughly examine postmortem brain tissue of young adults and children with 15q duplications. In 2006, sudden deaths in otherwise healthy individuals with 15q duplications created a concern about mortality risk in these families (Isodicentric 15q Exchange Advocacy and Support– IDEAS) posted a Physician Advisory on their site at to provide information to concerned parents. The group also encouraged families to request an autopsy in the event of death as well as brain donation to the Autism Speaks’ Autism Tissue Program (ATP). Since then there have been 10 brain donations and in collaboration with the New York Institute for Basic Research, this tissue has been made available for research. The preliminary results show a disorganization of cell production and placement. The arrow in this picture of a brain section of a preadolescent boy shows a whole extra row of cells that are not typically seen in a region of the hippocampus termed the dentate gyrus, an area of the brain associated with memory and attention functions. Disturbances of brain architecture like this are linked to alterations in brain cognitive function, and often to seizure activity.
Many more changes have been observed that will be described as the research continues. The goal is to link anatomical changes to specific types of gene copy variations and behavioral characteristics linked to autism that include social deficits, communication deficits, ritualistic behaviors, mental retardation, aggression, anxiety, epilepsy, sensory abnormalities, sleep disorder as well as unique abilities. These behaviors are generated by the brain and it will take time, effort and funds to keep up with the discovery of syndromes identified by chromosome copy variations (an abnormal number of chromosomes is called aneuploidy) and the particular characteristics of those with the disorders and the patterns of brain changes seen by researchers.
This understanding of how genes contribute to physical features and behavioral characteristics requires ongoing support by dedicated families who are partnering with scientists to help better understand their child’s disorder. With increased understanding of the underlying biological processes, we may someday be able to develop treatments that can significantly reduce the impairments associated with these conditions. Contribution of biomaterial resources like DNA and brain donation is vital to this effort.
Additional reading. An excellent open access article by another of the science advisors, Agatino Battaglia, is http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613132. Brain research papers by investigators focused on autism and related disorders are posted on www.atpportal.org.
Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. We wish to recognize the commitment and generosity by our ATP donor families. More information can be found at www.autismtissueprogram.org or call 877-333-0999 for information or to initiate a brain donation.
By Geri Dawson, Chief Science Officer, Autism Speaks
When I am giving talks to families about the research Autism Speaks funds, I am sometimes asked why we are funding a particular study when that study appears to have very little to do with the majority of people who actually are living and struggling with autism. This especially comes up when I am talking about studies involving animal models, brain tissue, and rare genetic conditions. Parents often express their frustration that scientists have not yet developed medications that can improve the quality of life for people with autism, medications that can help a child or adult with autism spectrum disorders (ASD) communicate better or be more comfortable around other people. I realize then that the connection between many of the studies we fund and our goal of developing medications that can help people with autism may not be clear. In this article, I hope to illustrate how many of the individual studies that we fund – which in isolation may not seem relevant – are part of a discovery and development process ultimately aimed at providing medications that can improve the life of individuals with ASD.
I will begin with some background on the process of moving from basic laboratory studies to delivery of a useful medication to the community, a process often referred to as “translational research.” The process of drug discovery begins with identification of a “drug target.” A drug target is a component of a biochemical pathway, sometimes referred to as a “signaling” or “metabolic” pathway. How do we figure out what signaling or metabolic pathways are affected in ASD? One way is to closely examine the actual brain cells of persons with autism, which is only possible with post-mortem brain tissue donated by families (view a recently funded study using post-mortem brain tissue).
Another way is to use animal models (see a perspective on mouse models from Craig Powell) to study the effects of a genetic mutation that is known to result in ASD or ASD symptoms. It has also been useful to start by studying conditions such as Rett syndrome and Fragile X syndrome because the genetics of these conditions are well understood. In addition, we know that these conditions are often associated with autism (e.g., about 30 percent of individuals with Fragile X also have autism). Animal models of these syndromes are becoming well developed, allowing scientists to study how the genetic mutation influences the biochemistry and brain functioning (view a recently funded study of synaptic alterations in the amygdala). These types of studies pointed scientists to specific signaling pathways; for example, a pathway involving two neurotransmitters: GABA and glutamate. These chemicals are crucial for neurons (brain cells) to establish a communication network through the formation of synapses (connections between neurons). Specifically, the genetic mutation alters the amount of these chemicals released in the brain (i.e., too much glutamate), resulting in over-excitation of the neural circuits. This disrupts learning.
Interestingly, at the same time these discoveries were being made, other scientists discovered that many of the genetic mutations that result in autism also disrupt the functioning of the synapse (view a recently funded study of synapse function). The strategy here is to look for common signaling pathways that are disrupted by different risk genes. These pathways offer the best hope for developing a medication that can be helpful not just with one genetic subtype of ASD, but more generally for many individuals who have ASD (even those where an environmental trigger might have been involved).
The process of drug target identification
Once a disrupted pathway or pathways contributing to a condition is discovered, scientists can start testing (“validating”) whether certain medications can restore the functioning of that pathway and improve behavioral functioning in animal models and humans. Another strategy for testing different medications is to examine the effects of the medication on cells (neurons) derived from freshly isolated post-mortem brain tissue that was donated by individuals with autism through Autism Speaks’ Autism Tissue Program.
Currently, several medications that are designed to improve behavioral functioning in autism are being tested in persons with associated genetic disorders such as Rett syndrome, Tuberous Sclerosis, and Fragile X syndrome (view two recently funded human clinical trials of medications for Rett syndrome and Tuberous Sclerosis ). If these medications are found to improve behavioral functioning in individuals with these conditions, plans to study some of these medications with people with ASD will follow. The hope is that because these conditions share some biological and behavioral similarities, these same medications will be more widely effective. At the same time, drawing from what we have learned about the role of glutamate from studies of Fragile X syndrome, Autism Speaks is currently funding a “phase one” or “proof of concept” clinical trial of memantine, a medication that reduces the availability of glutamate, for persons with ASD. As we understand more about the underlying biology of ASD using the strategies described above, there will be more promising leads for new medications that can improve the lives of persons with ASD.
The process from target identification to FDA approval of a new medication is arduous. Animal and human studies are needed to examine safety, side effects, optimal dosing, and other factors (these are referred to as Phase I, II, and III clinical trials). This “drug development pipeline” involves the collaboration among agencies such as the NIH and Autism Speaks that provide research funding; academic scientists who often conduct the high risk research that leads to target identification and validation; pharmaceutical companies who, once a target is validated, have the capability and resources of conducting the larger Phase II and III trials; and the FDA who is responsible for approving the medication for wide usage. This collaboration is essential for drug discovery and development.
Translational research moves findings from the lab to the families. It is one of many diverse areas of research emphasis at Autism Speaks. This type of research provides hope for the future. But, at the same time, we are funding studies that have more immediate impact on people lives. These include studies of novel behavioral and other types of interventions that can be quickly implemented by parents, therapists, and teachers, as well as many others (see examples of recently funded studies on Pivotal Response Training and Cognitive Enhancement Therapy that can have immediate impact. This balance between short- and long-term research is a key part of Autism Speaks’ overall funding strategy.
This is a guest blog by Jane Pickett, Ph.D. Dr. Pickett has been a pinnacle and founding member of the Autism Tissue Program (ATP), with an unparalleled experience in the field of autism tissue research and brain banking. Among her duties, Jane stewards the ATP’s vast tissue resources and accumulated data through the ATP Portal, manages the ATP’s large tissue grant portfolio, oversees the TAB and is the direct contact for our supported scientists. Jane has over 10 years experience serving as coordinator of the Developmental Disability services in Oregon where she participated on the Early Intervention Team, developed and monitored state funded programs for all age groups, provided crisis management for families and facilitated parent support groups. Her research background includes published studies in molecular and behavioral genetics, neuropeptide biosynthesis, cellular and developmental processes and the role of stress, gender and hormones at Princeton University. Jane also holds a staff position at the Harvard Brain and Tissue Research Center (HBTRC).
Biologists often try to understand a particular disorder from the perspective of a particular cell, or cell structure. This was an idea behind a recent public talk, “The Autism Spectrum: Recent Scientific Advances”, by UC Irvine (UCI) medical geneticist Dr. John Jay Gargus. The link between autism and mitochondria is also the subject of a number of research projects supported by post-mortem brain tissue donated by families to the Autism Tissue Program (ATP).
A mitochondrion is an energy-producing organelle found in cells in the body. Cells that require a lot of energy (like brain, muscle and liver) have 1000s of mitochondria and others with low energy demand have just a few. Mitochondria float in the cytoplasm of the cell, outside of the nucleus where the cell’s chromosomes reside. Each mitochondrion has its own set of 37 genes in a small circular ring of DNA that encode proteins integral for mitochondrial function. However, the mitochondria cannot act entirely alone, depending in part on the production of proteins from some of the genes in the nucleus for full functionality.
Mitochondria combine the fats and sugars we eat with the oxygen we breathe to produce energy for almost all of our cellular needs. If mitochondria are not functioning properly, cells are affected too. Consider brain cells, highly specialized cells with high energy requirements during their development, migration, maturation and function. Brain cells called neurons develop processes in order to deliver chemical messages over long distances; sometimes these processes, called axons, are several inches long for a neuron in one side (hemisphere) of the brain to communicate with cells on the other side of the brain. Mitochondria must provide the energy to ‘build’ these processes, be transported along the axons and once at the junction with other cells (synapses) their functions are necessary to keep up with the demands of brain circuits performing such roles as sensory processing, attention, learning and memory.
The donor, age 25, had autism and a chromosome duplication called IDIC15q. The pathology observed may be linked to a problem with the system of electron carriers that are needed to make energy rich molecules from metabolism in the mitochonrida. A partial block in the electron-transport chain (respiratory chain) was observed in living persons with autism and IDIC15q by a team working with Dr. Jay Gargus and reported in the journal Mitochrondrion (2).
Muscle hypotonia is common in autism and IDIC15q patients. The energy made by mitochondria provides the main source of power for muscle cell contraction and nerve cell firing so that muscle cells and nerve cells are especially sensitive to mitochondrial defects. The combined effects of energy deprivation contributes to the main symptoms of mitochondrial myopathies and encephalopathies (muscle and brain disorders). The link between autism and mitochondrial disease is the focus of rigorous study and the subject of one of the top ten research achievements in 2009 (3).
Other mitochondrial abnormalities have been described in brain tissue of individuals with autism. A molecular survey of the tissues of the cortex and cerebellum of brains of individuals with autism showed a change in the function of a gene, SLC25A12, a key element in mitochondrial energy production and cell metabolism (4). This gene is important in neurodevelopment and ‘turns on’ early in fetal brain tissue giving rise to a select region associated with early exaggerated postnatal brain growth in children with autism. A second report on brain genetics from the same French-US group explored another susceptibility locus for autism, a gene called MARK1 (5). The MARK1 gene product is an enzyme that regulates mitochondrial trafficking along microtubules in neurons: a process which serves as a sort of “highway” within a cell. Without the right amount of MARK1 produced, mitochondria are likely to be stuck in a “traffic jam” and impair cellular function. In both studies, the authors discovered an over expression of the two genes in the prefrontal cortex but not in the cerebellum.
So, what is autism to a mitochondrion? The significance of these findings is that cellular and molecular changes found in the brains of persons with autism are linked to mitochondrial function and are thought to compromise a host of physical and cognitive problems seen in the disorder. Continued research on the state of mitochondria in autism increases the potential for new diagnostics and therapies. Brain tissue is important to be able to visualize structural changes as well as to document molecular changes within the cell.
Acknowledgement: We wish to gratefully recognize the gifts of hope by the families of brain donors. Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. Anyone can register to be a future brain tissue donor. Information can be found at www.autismtissueprogram.org or call toll-free 877-333-0999 for a packet of information, with questions or to initiate a brain donation. Without this partnership between families and scientists, our progress in understanding the underlying biology of autism so effective treatments can be discovered would be much slower.
1. ATP Informatics Portal, ATP Documents, www.atpportal.org
2. Filipek, Pauline A. et al. (2008) Mitochondrial Dysfunction in Autistic Patients with 15q Inverted Duplication. Mitochondrion 8: 136–145.
3. Shoffner J, et al. (2009) Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression J Child Neurol. Sep 22. [Epub ahead of print]
4. Lepagnol-Bestel AM, et al. (2008) SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal
cortex of autistic subjects. Molecular Psychiatry. 13(4):385-97.
5. Maussion G, et al. (2008) Convergent evidence identifying MAP/microtubule affinity regulating kinase 1 (MARK1) as a susceptibility gene for autism. Human Molecular Genetics 17:1-11