New three-tiered computational pipeline discovers dysregulation in innate immunity pathways that can be used for treatment repurposing.
By Sumaiya Nazeen
As crucial as the brain is in defining our own existence, we have a very limited understanding of how it actually works. Without a comprehensive understanding of the brain, our understanding of disorders that are related to the brain is also very limited. One such disorder is Autism Spectrum Disorder, aka ASD.
ASD is a developmental disorder that impairs how a person interacts socially, such as their ability to communicate and make sense of the world, and gives rise to stereotypic and repetitive behaviors. It is a lifelong disability, which possibly develops within the first three years of life. One in every 68 individuals in the US suffers from ASD and it costs the U.S. economy about $236 billion a year. The prevalence rate is similar (~1%) in several other countries in Asia, Europe, and North America (Figure 1). But this statistic could be just a tip of the iceberg. It is believed there could be many more individuals who remain undiagnosed. This fact makes it an invisible disability.
After the 1980s, scientists became certain that there is a strong genetic component behind ASD. This conclusion is based on the observations that ASD is more frequent in identical twins than non-identical twins, and also more frequent in families with history of neuropsychiatric diseases. However, ASD is still baffling. Not only does ASD have a diverse range of symptoms, but it can also be accompanied by many seemingly unrelated diseases.
In a recent study, we have finally managed to shed some light into the underlying biology that contributes to the co-occurrence of these diseases in ASD patients. This joint work from the Computation and Biology Group led by Prof. Bonnie Berger and the Kohane lab led by Prof. Isaac Kohane, appears in the Genome Biology special issue on “The Biology of Human Diseases, as Revealed Through Genomics”, and opens up new avenues for treatment.
We computationally analyzed genomic data from a huge body of patients suffering from ASD and eleven of its frequently co-occurring diseases. These diseases are: asthma, bacterial and viral infection, chronic kidney disease, cerebral palsy, dilated cardiomyopathy, ear infection, epilepsy, inflammatory bowel disease (IBD), muscular dystrophy, schizophrenia, and upper respiratory infection. This analysis was conducted through a three-tiered lens of genes, pathways, and diseases.
Three-tiered computational approach
For complex diseases, finding a guilty party is a formidable task. The tactic that is commonly used by researchers is guilt by association. It states that, genes with similar functions interact with each other in a network following a series of actions, i.e. pathways which involve genes and other molecules in a cell. Successful execution of pathways gives rise to different biological functions. When a gene is mutated, its effect ripples through the network affecting other genes. This disrupts normal execution of pathways downstream, which in turn gives rise to different diseases. Often seemingly unrelated diseases share some commonalities at the pathway/function level because of this phenomenon.
We used this knowledge to look at ASD and its co-occurring diseases at all three levels: genes, pathways, and diseases. We first analyze the gene expression data from patients with each disease separately to find the disrupted genes. Then we move to the pathway level to identify which pathways are disrupted in each disease due to the disrupted genes. Finally, we find the disrupted pathways that have statistically significant impact on multiple diseases. Our computational approach is general and can be used as template for studying any group of diseases that need to be studied together.
The role of innate immunity
We found that Toll-like receptor signaling and Chemokine signaling pathways are significantly disrupted in ASD and several of its co-occurring diseases. These pathways play a key role in the innate immune response. Also, the disruptions in both pathways occur regardless of whether those diseases are immune related. A less than normal immune system has been suspected to increase the risk of ASD for quite some time now, but there has been no strong genetic evidence supporting this claim.
In humans, the innate immune system is the first line of defense against infections and environmental exposures. The innate immunity cells include: natural killer cells, mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. These cells identify and eliminate pathogens (e.g., viruses, bacteria, allergens etc.) that might cause infection. Toll-like receptors and chemokine receptors play an important role in initiating this defense mechanism. Toll-like receptors recognize pathogens that have breached physical defenses, and activate immune cell responses. Similarly, chemokine receptors are also activated by pathogen breaches, and they in turn activate other genes and pathways directing immune cells to the target pathogen.
Toll-like signaling and chemokine signaling pathways don’t work solely for innate immune response; they also overlap significantly with the pathways that control synaptic plasticity. Synaptic plasticity is the ability of brain cells to form connections of varying strength over time, in response to increases or decreases in their activity. This function is one of the basic foundations of learning and memory in humans and disruption of it can affect behavior, feelings, and thoughts. Thus, a disruption of these pathways may be part of the reason why patients who suffer from ASD (a behavioral disorder), also tend to have other diseases simultaneously.
The results from our study raise the possibility of using the existing treatments for innate immunity disorders for treating ASD patients. Drug compounds targeting Toll-like receptors are currently under development and have shown promise in clinical trials for treating bacterial and viral infections, asthma, allergies, and autoimmunity. Drug compounds targeting chemokine signaling pathway have shown potential in treating rheumatoid arthritis (RA) and other inflammatory rheumatic diseases in animal models. These treatments, when available, can be repurposed for treating ASD as highlighted by our multi-level cross-sectional computational method, which gives a holistic understanding of ASD.
This research was funded by the grants from the National Institute of Health (NIH), the Simons Foundation, International Fulbright Science and Technology Fellowship, and MIT School of Science Ludwig Center Fellowship.
Sumaiya Nazeen is a 2012 International Fulbright Science & Technology fellow from Bangladesh, and a PhD student in the Department of Electrical Engineering and Computer Science at Massachusetts Institute of Technology.