Posted by Autism Speaks staffers Simon Wallace, Ph.D., director of scientific development for Europe; Dana Marnane, vice president of awareness and events; and Daniel Lightfoot, Ph.D., director of the Autism Tissue Program
Over the last week, we visited three European countries to explore partnerships with researchers and autism organizations. In particular we’ve been discussing Autism Speaks’ efforts in the areas of awareness, communication, our Global Autism Public Health (GAPH) initiative and the Autism Tissue Program (ATP).
Pulling our suitcases behind us, our first stop was in Stockholm, Sweden, where we met with Prof. Sven Bölte, of the Karolinska Institute for Neurodevelopmental Disorders, to discuss establishing an autism brain bank in Sweden.
As highlighted in a recent Nature article, one of the best ways for scientists to understand how autism affects brain development is by looking directly at the tissue. Just as diabetes researchers must study the pancreas, scientists studying developmental neurological conditions such as autism must study brain tissue. Already, research has revealed altered cell organization in brains affected by autism. This research can continue and progress only by increasing donations of this precious resource. Autism Speaks is working with its partnering brain bank in the UK to expand collections into other European countries.
From Sweden, we traveled to London and shifted our focus from scientific research to autism awareness. In recent years, Autism Speaks has led global awareness efforts through initiatives such as our Ad Council campaigns, World Autism Awareness Day, GAPH and Light it up Blue. The measurable success of these efforts has led to expanded partnerships with European organizations. During our London visit, this crystallized in a meeting with European parent organizations and other autism advocates.
Present at the meeting were representatives of Autism Europe (which includes over 80 member associations), Autistica, Autism France, the Celtic Nations Autism Partnership, London’s Centre for Research in Autism and Education, the Hungarian Autism Society and Irish Autism Action. We spent the day learning about each other’s campaigns and brainstorming ways to increase global autism awareness. Everyone was familiar with our Light it Up Blue initiative and were actively planning their increased participation in the year ahead. The overall feeling was that, together, we can accomplish so much more. We will continue exploring this fruitful partnership in the months ahead.
Next it was a short hop to Utrecht, in the Netherlands, at the invitation of Nederlandse Vereniging voor Autisme (NVA), the country’s national autism organization. Its staff and members were eager to learn more about GAPH and our international awareness initiatives. Our team also took this opportunity to explore the development of a brain tissue bank in the Netherlands, to match our efforts in the UK and Sweden.
A highlight from this visit was the Netherlands National Autism meeting, the first national meeting of Dutch autism families and their research community. As special guests, we heard about Dutch research examining the relationship between genes and behavior, autism prevalence, nutrition, the elderly and autism, enabling technology and an intervention for young people with autism to help them understand sexuality. Over the next few weeks we will be inviting some of these researchers to describe their studies on our science blog.
There is much we can learn by working together with our European partners, and our visit was an important step in forging closer collaborations involving science and awareness. Goodbye for now; hejdå and dag to our Swedish and Dutch friends!
A major roadblock to our understanding of autism is our lack of known biological markers for this condition. Biological markers for a condition such as autism can include gene alterations and other measurable biochemical changes in the cells and tissue of those affected. The discovery of such markers is a tremendous boon as they can guide research into the causes and treatments of autism. Indeed, these markers can themselves become targets for interventions.
In the search for autism biological markers, there is an exciting lead in a small duplication of a DNA segment associated with a rare neurodevelopmental condition with similarities to autism. Chromosome 15q duplication syndrome (“dup15q,” for short) demonstrates symptoms similar to that of autism, including developmental delays in speech, language and thinking, as well as challenges in behavior and sensory processing. At present, around 3% to 5% of individuals with autism spectrum disorder (ASD) have dup15q. In other words, they display a “linkage” between these two distinct conditions. By studying the biomarker for dup15q syndrome—that is, the duplicated segment of chromosome 15—researchers can gain key insights into both conditions.
Last month, the Chromosome 15q Duplication Syndrome Advocacy group (IDEAS) (http://www.dup15q.org/) held its annual meeting in Philadelphia. Of particular focus was the frequency with which dup15q patients also experience seizures. This co-diagnosis of epilepsy is of keen interest to autism researchers because the prevalence of epilepsy is likewise elevated among people with autism.
Among the presenters at the conference, Dr. Jerzy Weigel, of the New York State Institute for Basic Research in Developmental Disabilities, discussed neurological structural changes found in dup15q brains. This unique and important research was accomplished through the donation of post-mortem brains of dup15q individuals by the Autism Tissue Program (ATP). By studying brain tissue directly, Dr. Weigel has shown that there are many specific microscopic changes within the brain of these individuals. The next exciting step is for researchers to discover how these tissue changes affect an individual with dup15q and how they may contribute to epilepsy. Such findings can further our understating of not only dup15q syndrome but also autism and epilepsy.
Autism Speaks and the Autism Tissue Program recognize the strong scientific links between autism and autism-associated disorders such as dup15q and epilepsy. As such, your donations (of time, funding, and participation) are supporting efforts to foster promising collaboration between disciplines that, in turn, can increase our understanding of autism and speed the discovery of new avenues for its prevention and treatment. A sincere thanks for your support. We’d love to hear your thoughts.
Fifty years ago, researchers discovered elevated levels of serotonin in the blood of children with autism. What would it mean to our understanding of autism if serotonin—a highly active neurochemical—was also increased in the brain?
In 1961, Schain and Freedman reported that about 40% of autistic children are born with high circulating blood levels of serotonin. This finding has been repeated many times by other researchers. What are the implications? Despite around 600 published research papers looking at autism and serotonin, we’re not really sure. But we’re getting closer to providing answers thanks to crucial help from Autism Speaks.
In the young, developing brain, serotonin stimulates the growth of neurons, or nerve cells. So it follows logically that if serotonin levels are increased in the brains of autistic children, then their brains should be larger. In fact, macrocephaly (big heads) in young children with autism is common. Not only are the brains larger, but certain sensory responses appear earlier in children with autism.
But these findings raise new questions: What do serotonin-producing neurons look like in the brains of children with autism? Would the size and number of serotonin-producing neurons suggest that these cells function earlier in children with autism than in children whose brains develop typically?
The best way to answer such questions is to examine brains of individuals with autism after death. Autism Speaks supports the Autism Tissue Program (ATP), which provides researchers such as myself with access to a the precious resource of brains from autism donors (whose identities are always kept confidential). For instance, ATP records have already confirmed that the brain weights of donors between the ages of 3 and 18 years who had autism are significantly heavier the brains of donors without autism.
To examine the details of serotonin-producing neurons, I and my colleagues prepare and stain slices of brain tissue to reveal the presence of proteins that distinguish serotonin neurons. This procedure allow us to follow how the branches, or axons, of these cells reach out and connect with neighboring cells. Such studies have shown a stark increase in the number of serotonin axons in the brains of children with autism, with these changes appearing in the youngest brains studied (age 3 years) and peaking at around 18 year so of age. Analyses of axon size and branching pattern confirm this increase in an area of the brain associated with auditory sensation and language—the superior temporal cortex. It is hypothesized that the earlier maturation of cortical neurons in this primary auditory area may hinder their incorporation into complex circuits underlying speech.
Of particular interest, my lab has found increased serotonin neuron connections that, on first impression, seem inconsistent with observations widely reported in the scientific literature. Let’s examine them:
First, imaging studies show a decreased rate of serotonin creation and use in the brains of children with autism following administration of tryptophan, a chemical that the body needs to make serotonin. Second, many of the behaviors associated with autism suggest a decrease in serotonin activity. In fact, doctors typically treat hyperactivity, repetitive behavior, and insomnia in adults with drugs that increase serotonin. Paradoxically, recent clinical studies show that drugs that increase serotonin (e.g., selective serotonin re-uptake inhibitors) actually worsen symptoms in children with autism.
The observation that serotonin axons are increased in the brains of people with autism may provide answers to these inconsistencies. Much work needs to done, and the availability of valuable postmortem tissue should be used to its greatest advantage to study not only serotonin neurons, but also other types of brain cells that can affect neurological development. Using the precious resource of donated brain tissue, scientists are able to perform the detailed analyses necessary to see which cells have problems, when and where those problems begin, and what mechanisms may be involved.
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 http://www.autismtissueprogram.org or call 877-333-0999 for information or to initiate a brain donation.
2. Azmitia EC, Singh JS, Whitaker-Azmitia PM. (2011) Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharmacology. 2011 Jun;60(7-8):1347-54.
Standing before the audience at the New York State Autism Consortium Meeting for Proposed Tissue Collaboration in March, Judith Omidvaran relayed the events that changed her life nearly four years ago. Judith and her husband were the parents of Sina, a 29 year old young man with high functioning autism and epilepsy. Sina had endured previous seizures, but this one took him from his loving parents forever. Reflecting back on that day, now seared into her memory, Judith recalled making a very important and lasting choice. Sina was gone from their everyday lives but she and her husband could donate his brain tissue. In that moment the grieving parents chose to make a lasting contribution to autism research and provide hope for a greater understanding of the lives and all too often untimely deaths of individuals with ASD.
Sudden, unexplained death related to epilepsy (SUDEP) is a most uncomfortable topic, but also a very important one. A new study led by members of Autism Speaks’ staff and published in the Journal of Child Neurology revealed that individuals with ASD who also have a seizure disorder have a risk of death that is eight times greater those with ASD and no seizure disorder. Seizures are not always evident at the time of diagnosis of ASD, and often begin to manifest in adolescence. The difficulties of living with a chronic developmental disorder would seem to be enough, without the weight of worry that these statistics convey. However, one cannot be forearmed if not forewarned.
The release of these data may have been disturbing to some members of the autism community.
Roger Dunlap III was diagnosed with autism at three, and his parents went through the all preparations of caring for the lifelong needs of a child with special needs. Young Roger’s parents, Roger and Heather, began an organization to support the long term care of Roger and others who shared his challenges when these children would need support after their parents had passed. In a twist of cruel irony, young Roger died unexpectedly in his sleep at 9 years old. He was never diagnosed with epilepsy and the exact cause of death remains unknown. The Dunlaps also made an important choice at a difficult time. Their involvement in the autism community connected them with the Autism Tissue Program and they got a call about donation soon after young Roger’s passing. They have continued their remarkable support for the autism community both through their own organization and Autism Speaks.
At this point, however, our understanding of sudden death in autism and epilepsy is poor. An analysis of data on deaths from the California Department of Developmental Services reveal that the cause of death is unknown in 40% of cases. This particular area is one that the Autism Tissue Program is working to improve through detailed analyses of all donated tissue and also though a survey of ASD families who experienced a sudden death of their loved one with ASD .
Autism Speaks, in partnership with the International League Against Epilepsy (ILAE) and Citizens United for Research in Epilepsy (CURE), hosted a meeting in December 2010. The meeting brought together experts in epilepsy research and autism to discuss areas of greatest need and priority in research. The seven key points they developed include:
1) Identifying infants with seizures at risk for autism and those with autism at risk for epilepsy.
2) Identifying risk factors common to autism and epilepsy.
3) Developing new tools to effectively evaluate data specific to epilepsy and autism.
4) Identify and develop animal models, biomarkers and assessment tools that inform outcome in infants with epilepsy that go on to develop autism and infants with autism that go on to develop epilepsy.
5) Explore the underlying mechanisms of convergence between autism and epilepsy.
6) Coordinate tissue and brain banking efforts in epilepsy and autism.
7) Develop behavioral and pharmacological treatment models and methods in infants with epilepsy and autism (or with one and at risk for the other).
These aims are indeed important for taking the next research steps, however, the fortitude of parents in a time of crisis may be the greatest contribution toward advancing our understanding of sudden death in epilepsy and autism. If you wish to learn more about the Autism Tissue Program, or want to share a story and participate in a survey about sudden unexpected death of a family member with ASD, please go to their website for more information or email email@example.com.
Read the press release on the Journal of Child Neurology publication here.
We still know very little about the human brain. With an estimated 100 billion neurons (nerve cells) in the human brain, scientists grapple to understand what these neurons do, how they interact with one another and how they make us who we are. It is therefore not surprising that we are still some way from fully understanding the human brain, and more significantly the autistic brain and why its development is altered. There are many scientific approaches that can be used to visually inspect the human brain, such as magnetic resonance imaging (MRI), but only one way of directly studying the human brain – and that is by looking at post-mortem brain tissue. For this very reason, brain tissue is a critical element in the process of neurological scientific discovery. Unfortunately, tissue donation remains rare, hindering the very research that will help us to understand autism.
The Autism Tissue Program (ATP), a Scientific Program of Autism Speaks, is dedicated to supporting scientists worldwide in their efforts to understand autism, autism related disorders and the human brain. The ATP is a tissue based repository (bio-bank), among only a few worldwide, that makes brain tissue available to qualified scientists in order to advance autism research.
In an effort to improve the worldwide availability of tissue-based resources in autism research, Autism Speaks has been seeking to expand its efforts by establishing sister programs in other countries. In 2009, Autism Speaks partnered with UK charity Autistica in creating a 2nd bio-repository based at the University of Oxford in the United Kingdom (UK). There are already 15 brains that have been donated to this tissue bank and, in addition, awareness of the importance of brain donation for autism research within the British autism stakeholder community and general public has increased enormously.
The Medical Research Council (MRC) – the UK’s equivalent of the NIH – has recently formed a network of UK brain banks, including the Oxford autism bank as a key member. This new infrastructure will be a vehicle for facilitating the awareness of the need for autism tissue collection as well as the donation of tissue from controls (individuals who have no underlying neurological or psychiatric disorder) and related neurodevelopmental disorders (e.g. Fragile X syndrome). By encouraging international collaboration and the establishment of a bio-bank network, we can increase the numbers of donations of this precious resource and build the capacity needed for research in this field.
Autism Speaks’ staff recently visited the brain bank in the Netherlands to explore new collaborative opportunities. Due to their geographical size and national organization, the Netherlands have a unique resource in that all brain donations are sent to a single bank based in Amsterdam. This streamlined system enables a higher rate of tissue donations and the administration is relatively straight forward. With the support of the Dutch autism research community and our partners at the Netherlands Autism Society we are hoping that the Netherlands Brain Bank could soon begin collecting autism tissue. Similar opportunities are also being explored in Sweden and Canada.
We are making great strides in scientific discovery and the last few years have seen significant advances in the genetics of autism. More than ever this highlights the importance of using autism tissue collections to explore how genetic differences in people with autism affect the cellular and molecular development of the brain. In turn, these research investments will guide the development of new pharmacological treatments for people with autism to alleviate some of the core and secondary symptoms. With more than 100 research publications resulting from the efforts of Autism Speaks, The Autism Tissue Program, Autistica, and most significantly the brains generously donated by families, we are off to a promising start.
To learn more about brain donation please visit the ATP at www.autismspeaks.org (1-877-333-0999) and UK Brain Bank for Autism & Related Developmental Research at www.brainbankforautism.org.uk (44 0800 089 0707).
A journal article published this week studying sex-linked hormones in brain is the 100th paper describing results from brain tissue provided by the Autism Tissue Program. Taken together, the 100 papers, all published in peer-reviewed scientific journals, represent a huge advance in our understanding of the brains of individuals with autism.
The first publications were released in 2001 and built on existing evidence of developmental changes in the brain of those with autism. The increase to 100 papers in 10 years mirrors the growth of the brain tissue resource from about 20 brains at the start to currently over 100 brains from individuals with a clear diagnosis of autism, ranging in age from 3 to 60. The papers also show the use of a wide range of specialized resources developed by the Autism Tissue Program including MRI, brain tissue biopsies, genetic material from brain tissue and a large permanent brain library of slides all derived from post mortem brains.
The 100th publication is by Valerie Hu, Ph.D. and colleagues at the George Washington University Medical Center titled: ‘Sex hormones in autism: Androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism’. The aim of the research, funded in part by Autism Speaks, was to examine a particular sex-linked candidate gene found throughout the human body, including brain tissue. This line of research could provide some rationale for the fact that four times more males are affected with autism than females. Dr. Hu’s research shows that both male and female hormones have varying and significant effects on the activity of the RORA gene product. The RORA gene product regulates an enzyme (aromatase) that converts testosterone into estrogen.
This study offers a molecular mechanism for understanding the sex bias towards males by increasing levels of testosterone. This paper is the first report a sex hormone-responsive candidate gene for ASD. RORA is important for the development of a part of the brain called the cerebellum. The cerebellum is involved in controlling some types of movement, but also plays a role in cognitive tasks such as redirecting attention. RORA also serves to protect neurons against inflammation and oxidative stress.
Dr. Hu and colleagues showed that the female hormone estrogen increases the expression of RORA, while the male hormone androgen (dihydrotestosterone) decreases it. Interestingly, the interaction is somewhat circular as RORA regulates the expression of aromatase, an enzyme that converts testosterone to estrogen. According to Dr. Hu, “We observed in the brains of individuals with autism a link between decreased in activity of RORA and a reduction of aromatase activity. This reduced activity would lead to build up of testosterone and a decrease in estrogen.”
This study provides a molecular explanation for the higher levels of testosterone observed in some individuals with autism. These findings also suggest a mechanism for the male bias in ASD because female brain tissue may benefit from the protective effects of naturally higher levels of estrogen In addition, the estrogen receptor shares some of the same target genes as RORA, thus compensating for RORA deficiency, which the research team has also observed in some individuals with ASD.
Zeroing in on specific gene effects in the brain is one of several research avenues undertaken by scientists that can only be done through the direct examination of human brain tissue. The value of the study of human brain tissue is the interpretation of the data in the context of the current knowledge about autism. Combined with post mortem imaging and genetic analysis scientists can gain a broader and more thorough understanding of ASD.
Scientists studying brain tissue today need to consider disorders that can co-exist with autism. The Autism Tissue Program takes great care to fully document medical conditions of brain donors. The informatics portal catalogs over sixty disorders or conditions occurring in those with a diagnosis of autism including epilepsy, Fragile X, Tuberous Sclerosis Complex, Duschenne Muscular Dystrophy, Angleman, Rett and Asperger Syndromes and partial duplications or deletions of several chromosomes.
The Autism Tissue Program has emerged as an important resource of not only brain tissue but also as in informational hub of research results from an international group of scientists. None of this work would be possible without the dedication of the families who chose to donate brain tissue of loved ones to the Autism Tissue Program. To register you or your family in the brain donor program, please visit www.autismtissueprogram.org for information and online registration, or call 877-333-0999 for information or to initiate a brain donation.
Click here to view the full list of 100 papers the Autism Tissue Program has made possible.
This Science post is by staff blogger Jane Pickett, Ph.D.
Researchers have several ways to peer into the human brain. A commonly-used tool is magnetic resonance imaging (MRI) and unlike the two-dimensional pixels in photography, voxels are used to describe the volume of brain measured by MRI. Currently, the standard voxel is a of ~1mm, about the size of coarse sea salt. Combining millions of voxels produces the 3D image of the brain you see in the figure. The view of the brain at this high resolution has led to some common ideas about the ‘autism’ brain.
Cynthia Schumann, Ph.D. and Christine Nordahl, Ph.D. of the MIND Institute at UC Davis, show how imaging, when paired with the microscopic inspection of the post mortem human brain, can help answer questions about typical and disordered brain development. MRI studies of autism have revealed an atypical trajectory of brain growth during early childhood, characterized by brain overgrowth, that is present especially in the frontal cortex (involved in higher mental functions) and also in specific structures such as the amygdala (involved in memory functions, particularly of emotional experiences).
Why are these areas growing larger than normal in young children? One way to answer this question is to look at the cells in these enlarged areas. That solution requires samples of donated postmortem brain tissue.
To give an idea of what’s in a voxel in a typical 3 year old child’s brain: there are an estimated 40,000 neurons in the space of a voxel in the cortex and 7000 in each voxel in the amygdala. The pictures in row C show just a portion of cells in a single voxel in the brain areas indicated. Some evidence indicates that neurons and another cell type called glia are more abundant in the brains of individuals with autism. Connections between cells need space and the more numerous brain cell branching that has been found can also lead to a size increase of a given area.
In addition to counting cells and their connections, fine-scale anatomy allows us to examine the layered organization of cells in the cerebral cortex and other local relationships in different brain areas. When researchers observe cells that are “out of place”, this suggests differences in the functioning of that local network of cells.
Researchers can also use antibodies to localize various molecules in post-mortem brain tissue. With these techniques scientists can identify cells that carry a particular type of neurotransmitter, or other cellular signals. One can also extract and analyze the building blocks for proteins in RNA and DNA and look for regions where a certain gene may have been “turned on” or off more than expected.
Given the coarse resolution of MRI, the field must look towards post-mortem human brain research to help us understand the neurobiological underpinnings of the difference in brain growth patterns that have been found in MRI studies. MRI studies are very helpful in targeting which brain regions should be explored further in post-mortem studies.
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.
Brain Research will be publishing a special issue of articles that feature presentations at the 2010 Brain Research meeting. Dr. Schumann’s paper is currently available online with appropriate institutional access or for purchase.
Schumann, CM and CW Nordahl. Bridging the gap between MRI and postmortem research in autism. Brain Res. (2010), doi:10.1016/j.brainres.2010.09.061.
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.