Yale School of Medicine (YSM) has been awarded a grant of nearly $25 million by the Aligning Research to Impact Autism (ARIA) initiative. The award, which is part of ARIA’s Human Developmental Neurobiology Research Hub, focuses on building foundational maps and models of the developing human brain and clarifying how and when autism diverges from typical development.

“We are very grateful to ARIA for their investment in Yale,” says Nancy J. Brown, MD, the Jean and David W. Wallace Dean of Yale School of Medicine. “Their philanthropy is advancing a new era of autism research, which we hope will lead to an understanding of its earliest beginning in the developing brain. The impact of their grant will extend well beyond Yale School of Medicine, creating knowledge that can guide earlier detection, clearer biomarkers, and more precise interventions for individuals with autism and their families.”

Co-led by Nenad Sestan, MD, PhD, Harvey and Kate Cushing Professor of Neuroscience, and professor of comparative medicine, of genetics, and of psychiatry at YSM, and Paola Arlotta, PhD, the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University, this grant is designed to meet the scientific challenge at its origin point—early brain development—by building the foundational models needed to detect, interpret, and address developmental differences.

“My colleagues and I are profoundly grateful for ARIA’s visionary support,” says Sestan. “This award enables us to advance our research into the development of the human brain’s neural circuits. By bringing together experts across disciplines and institutions, we aim to better understand how brain development unfolds and how autism emerges. Ultimately, we hope this work accelerates discovery, improves early detection, and informs more effective interventions.”

Autism is a neurodevelopmental condition that affects communication, social interaction, and behavior, and often includes differences in learning, attention, sensory processing, sleep, or motor skills. According to the Centers for Disease Control, 1 in 31 children in the United States has autism. The World Health Organization estimates that approximately 1 in 100 children worldwide is affected.

Despite decades of neuroscience progress, researchers lack a high-resolution, time-lapse “map” of the developing human brain. “We have detailed maps of our planet, yet our map of the brain, especially the developing brain, remains incomplete,” says Sestan.

The brain’s earliest developmental stages are difficult to study directly because brain maturation unfolds over nearly two decades and research access to developing human tissue is limited. At the same time, the period when autism-related differences first manifest is also the period when the brain is most rapidly changing. Many neurons and most synaptic circuits form in the first years of life, meaning adult brain models cannot simply be scaled down to understand an infant or toddler.

Without a precise developmental reference, scientists strive to pinpoint mechanisms, identify early-life deviations, or design interventions that reflect the biology of a particular person at a particular time. ARIA’s grant supports a coordinated approach by integrating experiments, imaging, computation, and clinical partnerships to build that reference and translate it into discovery.

ARIA’s investment supports four complementary projects that work together as a single engine of discovery. Each is designed to deliver concrete tools and resources—validated assays, model systems, datasets, and computational models—while continuously feeding insights back into the whole program.

1) A high-resolution map of the developing brain’s wiring

One major focus is creating the first high-resolution connectome model of the developing human brain, spanning prenatal life through adolescence. In collaboration with Hao Huang, PhD, professor of radiology at the University of Pennsylvania, and the faculty director of Small Animal Imaging Facility at Children’s Hospital of Philadelphia, Sestan’s lab will build an atlas of how brain “highways” (long-range connections between distant regions) and “streets” (local cellular circuits and synapses) emerge and mature over time.

This effort matters because modern neuromodulation and neurostimulation treatments in adults, such as those used in Parkinson’s disease, depression, and obsessive-compulsive disorder, have advanced by targeting specific circuits. But in neurodevelopmental conditions like autism, the challenge is different: Symptoms and connectivity differences can arise in infancy, and the adult brain’s wiring diagram offers limited guidance for the rapidly shifting landscape of early development.

A developmental connectome built at unprecedented resolution could help researchers define which pathways are changing, when those changes occur, and how early-life neuroplasticity might be leveraged to design more targeted interventions.

2) A cellular and molecular model of where autism diverges from typical development

A second pillar of Sestan’s work will build a foundational model of cell types and gene regulatory programs across key brain regions and developmental stages, establishing a rigorous baseline for typical development and then mapping divergence associated with autism.

Because many autism-associated genes influence how other genes are turned on and off, identifying gene regulatory networks and the developmental windows in which they shift is central to translating genetics into biology, and biology into therapeutic hypotheses. This work integrates single-cell multi-omics approaches (including gene expression and chromatin regulation) with spatial data, allowing researchers to link molecular signatures to specific cell populations, brain regions, and time points.

3) Patient-derived brain organoids to connect genetics, development, and clinical features

Arlotta’s lab will use patient-derived brain organoids, three-dimensional models grown from induced pluripotent stem cells, to study developmental processes that cannot be observed directly in living children.

Organoids make it possible to explore how autism-linked genetic states influence developmental timing, cell fate decisions, synapse formation, and network activity across large cohorts of individuals with and without autism, while connecting those biological readouts to deep clinical phenotyping through ARIA’s IMPACT (Innovative Medicine and Precision Approaches to Clinical Trials) Network and other collaborating hubs. The result may reveal a powerful bridge between human genetics and measurable changes in developing neural circuits.

4) Generative AI to predict interventions and prioritize therapeutic targets

The fourth pillar, led by Marinka Zitnik, PhD, associate professor of biomedical informatics at Harvard Medical School and associate faculty at the Kempner Institute for the Study of Natural and Artificial Intelligence at Harvard University, will develop generative, multimodal AI models operating at cellular resolution, tools designed to learn from complex datasets and produce mechanistically grounded predictions.

By integrating data across genes, proteins, pathways, cell types, brain regions, circuits, and patient-level phenotypes, the models aim to identify biomarkers, prioritize therapeutic targets, and simulate how candidate interventions might shift development toward typical trajectories. The long-term vision is a “virtual cell” platform that can forecast outcomes, including the critical role of dose and timing, and help the field move more efficiently from discovery to validation.

The award builds collaboratively on ARIA’s $27.7 million grant to YSM in July 2025 and the research led by Murat Günel, MD, chair of the Department of Neurosurgery, Sterling Professor of Neurosurgery, and professor of genetics and of neuroscience at YSM. Günel’s program leverages state-of-the-art technologies and cross-departmental expertise to develop large brain models that will serve as the basis for personalized, circuit-based therapies.

Sestan’s work to define the cellular, molecular, and circuit architecture of the developing human brain provides a critical developmental framework for these efforts. Built on years of close scientific collaboration, the two ARIA-supported projects are organically connected through Yale’s uniquely collaborative environment, which brings together developmental biology, human genetics, neural recording, clinical phenotyping, AI, and engineering in a unified effort to understand autism and translate discovery into meaningful benefits for patients and families.

Brown reinforces the impact of the award: “This additional grant from ARIA will support YSM researchers and collaborators at other institutions in generating shared datasets, experimental models, and AI-enabled tools aimed at speeding biomarker discovery and the identification of novel therapeutic targets. It will help build an integrated, developmental understanding of autism, opening new paths for earlier, more personalized approaches.”