Last modified: January 12, 2022

The landscape of autism research has changed dramatically since SFARI issued its first request for applications in 2007. It is now truly a multidisciplinary field, attracting top researchers from around the world. The Simons Foundation has committed more than $570 million in external research support to more than 600 investigators in the United States and abroad in service of SFARI’s mission: to improve the understanding, diagnosis and treatment of autism spectrum disorders (ASDs) by funding innovative research of the highest quality and relevance.

The SFARI science team often gets asked some version of the question, “What kind of science is SFARI likely to support in its requests for applications?” Unfortunately, this is an impossible question to answer given the complexities and multidisciplinary nature of the field and our inherent uncertainties about where the next major advance may come from. That said, we want to be as transparent as possible with researchers, whom we view as partners in this quickly moving and challenging field.

Below are our views on various scientific topics, many of which we’ve expressed in previous blog posts. Given the importance of these views in guiding our funding processes, we feel these perspectives deserve a more lasting place on our website. We view this page as a living document, one that we plan to update as the science and our viewpoints evolve.

As an overarching principle, we are particularly interested in projects that try to bridge different levels of understanding, especially by connecting insights from genes to molecular mechanisms to neural circuits to behavior. The causes of autism are almost always multifactorial but given the recent advances in the understanding of genetic risk for autism, we feel that working within a ‘genes to biology to behavior to therapeutics’ framework provides a rigorous and tractable way forward for now. For a brief overview of why genetics is the bedrock and how it can be leveraged to understand the biology of autism, see a recent review from SFARI Investigators Devanand Manoli and Matthew State discussing the current state of autism genetics¹.

The significant advances in understanding the genetics of ASD have served to highlight the heterogeneity of the condition. The next steps in building an effective ‘genes to biology to behavior to therapeutics’ framework will require innovative approaches to the quantitative analyses of ASD behavioral phenotypes. Quantitative phenotypic studies are necessary to develop an accurate nosology of ASD, which is critical for linking genes to biology to behavior as well as to develop future therapeutics.

As a first step, when preparing a proposal, we strongly recommend that applicants familiarize themselves with SFARI’s current and past grant portfolio, as well as SFARI-generated resources. We have put tremendous effort into the development of these resources, and we hope you will take full advantage of the knowledge gained in thinking about how your work might complement and take advantage of, but not duplicate, existing efforts.

Regardless of the exact science proposed, SFARI is deeply committed to producing rigorous, reproducible data that are readily shared with the scientific community. The apparent lack of reproducibility in biomedical science has become a widely discussed topic², so in support of this important issue, SFARI has created a list of methodological and statistical considerations for potential SFARI grant applicants.

The most current estimates of autism risk indicate that approximately 80 percent of the risk results from genetic alterations³. More than 100 genes now have strong evidence implicating them as risk factors for ASD⁴, with studies of ever-increasing sample sizes set to boost this number considerably^5,6.

Applicants can find more information about autism candidate genes and evolving community-based gene scores at SFARI Gene, an online database providing a convenient and comprehensive way to become familiar with the genetic landscape of autism. SFARI Gene lists hundreds of genes that have been implicated in ASD by various means but, importantly, also provides a scoring system to rate the strength of the evidence based on a range of criteria. We generally consider strong candidate risk genes (i.e., a false discovery probability under 10 percent) to be those with scores of 1 or S (genes underlying syndromes that are frequently accompanied by an autism diagnosis). You can also find a list of autism-associated genes that SPARK analyzes here, which are genes deemed sufficiently likely to be involved in autism risk that results are returned to the research participants (these genes have now been incorporated into the SFARI Gene lists).

With such large numbers of candidate genes, the research community will need to replicate results from the Simons Simplex Collection (SSC) and other collections in larger populations. To this end, SFARI has sponsored SPARK, a program with the goal of recruiting and generating exome sequences for 50,000 families with autism⁷. We anticipate that SPARK will continue to drive risk gene discovery in autism^5,6 and will also enable the development of robust polygenic risk scores for the first time. While an exhaustive characterization of the genetic landscape of autism is probably neither feasible nor necessary in the short term, a better understanding of each class of genetic risk variant — from small to large and from common to rare — is an important goal, keeping in mind that de novo and familial influences likely make an additive contribution in many cases⁸.

Given SFARI’s extensive investments in the genetics of ASD to date, prospective applicants are strongly encouraged to familiarize themselves with the data available from SFARI-supported cohorts, past genomics-focused requests for applications (RFAs) (here, here, and here) and related informatic tools to think carefully about how their research would complement and leverage SFARI’s ongoing efforts. Examples of well-characterized cohorts include the SFARI-supported SSC, Simons Searchlight, SPARK, and the Autism Inpatient Collection (AIC), which have been at the heart of SFARI’s research efforts in recent years. Each cohort offers a wealth of genetic data (genotypes and exome and genome sequences), phenotypic data (medical histories, psychometric testing, and brain imaging), and biospecimens (cell lines) for many of the participants.

Genetic and phenotypic data collected for some of the SFARI-supported cohorts can be requested through SFARI’s central database system, SFARI Base (see below “Research studies with human participants”). Researchers planning genetic studies should also be cognizant of other autism gene discovery efforts and be prepared to justify the uniqueness of their proposed studies. We welcome novel and complementary efforts to identify risk variants of any sort and are particularly interested in innovative applications that combine analyses of variants across the allele frequency spectrum.

Given that a clearer picture of the landscape of autism genetics is now emerging, we prioritize science that increases our understanding of how changes in certain ASD risk genes affect cells and circuits, especially pathways and circuits that are likely to be evolutionarily conserved in humans. Understanding these pathways and circuits is important to the development of a variety of therapeutic approaches.

Published network analyses^4,9 have reached a consensus that most (though certainly not all) ASD risk genes cluster broadly into the categories of regulators of gene expression (transcription factors, chromatin modulators, RNA-binding proteins, genes involved in protein modification) and regulators of synaptic function. Other smaller clusters of genes seem to have important roles in cytoskeletal biology and cell migration. In addition, several groups have reported enrichment of ASD risk genes in particular intracellular signaling pathways^10-12, including Wnt, Notch, PI3K/AKT, ERK and mTOR.

The first network analyses incorporating brain gene expression data^13,14 suggested that many of these risk genes converge on midfetal glutamatergic neurons. Subsequent analyses based on larger data sets and orthogonal methods have confirmed and deepened this finding: specifically, that disruption of many ASD risk genes is likely to have very early developmental consequences for neurogenesis.

As it happens, studies of any number of mouse lines carrying mutations in ASD risk genes have likewise identified early disruption in the timing and execution of neuronal differentiation from the proliferating population of neural progenitors^15-22. Intriguing findings have also extended these phenotypes to the study of autism risk genes in Xenopus tropicalis²³. Moreover, there is accumulating evidence that these findings are likely to extend to the human condition as well. For example, human induced pluripotent stem cell (iPSC) lines derived from individuals with idiopathic ASD and macrocephaly have a common phenotype: the premature appearance of a gene expression program that promotes neuronal differentiation²⁴. A range of other recent studies has supported a convergent role for autism risk genes in human neurogenesis^25-32.

Disruption of the orderly progression of neuronal differentiation therefore emerges as a potential point of convergence across multiple ASD risk genes as well as idiopathic ASD and deserves to be investigated in more detail. Of course, many questions remain: is it the same types of neurons that show changes in their proliferative progression in different genetic mouse models? Disruption of which signaling pathways and cellular mechanisms contribute to the observed changes in neuronal differentiation? And what are the consequences of early disruption of timing and execution of neuronal proliferation for neural circuits function later in life? The range of other ASD risk genes with acute effects on synaptic biology, dendritic spine development, axon guidance^33-35 or other core aspects of neuronal function are of equal interest to SFARI, and we also encourage applications that explore how mutations in this set of genes leads to changes in circuitry and behavior that are characteristic of ASD.

Given that many of these biological effects occur early in development, at prenatal or neonatal stages, when intervention options are limited, it will be important to determine whether there are downstream phenotypes that may be amenable for intervention. These potentially malleable phenotypes may come in the form of convergent molecular, circuit and systems-level effects. We welcome applications that address potential therapeutic mechanisms and their developmental windows of opportunity.

Our hope is that an understanding of the basic biological mechanisms through which variants in some genes confer ASD risk will eventually lead to the discovery of molecular and cellular mechanisms that are suited to be targeted therapeutically. However, the path along this more classical route to drug discovery is long. In recent years, particularly due to the success in treating spinal muscular atrophy (SMA)³⁶, the feasibility of using gene-targeted therapeutic approaches, such as antisense oligonucleotides (ASOs) or vector-based gene replacement therapies, has become tenable for neurodevelopmental disorders with a known risk gene.

The development of additional molecular strategies suited to manipulate gene expression in a targeted manner (e.g., approaches using CRISPR/Cas9) in humans are underway and make this a thriving and fast-moving area of investigation. The clear advantage of these types of therapies is that one may not have to decipher all the detailed molecular, cellular and circuit functions that an ASD risk gene may be involved in, therefore moving much faster towards the implementation of a treatment. In addition, addressing the problem at its core (the causative mutation)—possibly early in life—has not only the promise of mitigating features of the condition, but also of potentially preventing their onset in the first place. SFARI is currently funding multiple investigators who are developing novel gene-targeting approaches and SFARI is actively exploring what additional roles we may play moving forward.

SFARI recognizes the heightened interest among researchers, clinicians, and autism families in understanding the role that the gut-brain axis (GBA), including the microbiome, might play in modulating autism features. A recent systematic and integrated re-analysis of human studies in ASD along the GBA that was sponsored by SFARI shows a very strong association among several ‘omic’ levels along the GBA (microbiome, metabolome, immunome, brain transcriptome) and of each of those levels with ASD. However, existing studies lack the necessary standardization and time resolution to draw causal links and derive mechanistic insights (see a SFARI Conversation that describes this project to date). SFARI is now organizing a community effort to design human longitudinal intervention studies leveraging SFARI-sponsored cohorts, including SSC, Simons Searchlight, SPARK and the AIC to advance our understanding of the interplay between the human genome, the metagenome encoded by the microbiome, and phenotypes in individuals with ASD.

Experimental systems — such as rodents, Drosophila, C. elegans, zebrafish, nonhuman primates, postmortem tissue, iPSCs— provide critical platforms to explore the molecular, cellular and circuit mechanisms underlying ASD. SFARI is open to using these and other compelling organisms/systems for autism-relevant studies. As illustrated in a recent SFARI workshop on rat models, the choice of experimental system should be driven by the biological questions that can most appropriately addressed in each system.

SFARI emphasizes construct validity over face validity when choosing an experimental system; we prioritize proposals that start with an experimental system that recapitulates a mutation in a risk gene or an epidemiological factor that can be linked to ASD with high confidence. For rodent models in particular, behavioral resemblance to the human condition (e.g., in the BTBR mouse strain) — such as social interaction deficits or repetitive behaviors — can be a useful, functional readout of the underlying circuits in that species, but such behavioral phenotypes on their own do not have sufficient etiological validity to constitute a strong autism model. As discussed in a NIMH Council Workgroup on Genomics report, it may be superficial and misleading to accept phenocopies of human characteristics as predictive endpoints for translation. For an additional nuanced discussion of the uses of animal models in autism research, please read this recent SFARI Conversation with Steven Hyman.

SFARI is continuing its efforts to make mouse, rat, zebrafish and iPSC models of high-risk autism genes and copy number variants identified in human genetic studies available to researchers. Lists of mouse, rat and zebrafish models currently available because of SFARI efforts can be found on their respective pages on SFARI.org. For more information on available iPSC lines, how to request them and our perspectives on experimental considerations, please visit our iPSC models page.

In addition to animal and cellular models, SFARI makes postmortem human tissue available through the SFARI-funded Autism BrainNet, a collaborative network for the acquisition and distribution of postmortem brain tissue for research.

For clinically relevant studies, SFARI prioritizes research that is grounded in biology. Although we recognize the value of other types of research, such as optimizing behavioral interventions, we hope that, over the long term, focusing on biological mechanisms will lead to particularly effective interventions.

As exemplified by the focus of our Human Cognitive and Behavioral Science RFA, we encourage studies that utilize objective, quantitative behavioral methods, as well as noninvasive neurobiological methods, such as magnetic resonance imaging (MRI), electroencephalography (EEG) and magnetoencephalography (MEG). Such approaches can help advance ‘forward’ translation to biomarkers and objective outcome measures as well as ‘back’ translation to studies of neural mechanisms in experimental systems.

It should be noted, however, that given the heterogeneity of ASD, we place a premium on the use of sufficiently powered and well-characterized cohorts. We are also strongly supportive of efforts to increase scalability and accessibility of research studies through online platforms.

SPARK and Simons Searchlight have robust research matching programs (SPARK research match, Simons Searchlight research match) that allow researchers to apply to recruit from more than 100,000 SPARK participants with ASD and almost 1,500 Simons Searchlight participants with genetic variants in ~175 high risk autism genes and copy number variants (CNVs). We encourage researchers interested in recruiting SFARI cohort participants for their own studies to familiarize themselves with the research matching process and to contact [email protected] to learn about the availability of individuals suitable for the proposed study.

We hope this webpage provides the community with some insight on our evolving scientific perspectives and priorities. We welcome constructive feedback ([email protected]), and we will continue to update this page as new information and additional resources become available.

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