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