Research Program

The Allen Lab develops innovative new approaches to understand how living systems establish and maintain physiological function, and how this can fail in aging and disease. We aim to understand the mechanisms by which cells and tissues sense, adapt to, and recover from perturbations like stress and damage. By uncovering the fundamental principles underlying how different cell types and tissues preserve their function, we aim to develop interventions that enhance their natural capacity for repair and adaptation.

Biology

Homeostasis, Resilience, & Aging

Biological systems maintain function despite changing conditions through resilience mechanisms that operate across scales, from molecules to organisms. While these processes have been recognized since the 19th century, the specific circuits that preserve cellular and tissue function remain largely unknown.

We map the fundamental mechanisms that maintain tissue function throughout life and identify how they fail in aging and disease. Our goal is to engineer cells in living animals to enhance resilience, restore lost function, and reverse age-related decline.

We initially focus on the mammalian brain, whose neurons must survive an entire lifetime to store memories, regulate behavior, and support cognition. While neurons cannot be replaced, the brain has remarkable abilities to adapt to stress, compensate for damage, and learn continuously. We study these resilience and plasticity mechanisms across scales — from molecules to circuits to behavior — and track how they change from development through aging.

  • How does the mammalian brain establish its mature function?

    Mammalian brains undergo an extended period of maturation, during which time they are intrinsically plastic and can compensate for large amounts of damage. Yet, stress and damage at this stage can also have lifelong effects. We want to understand at both the molecular/cellular and circuit level this process of maturation, and how it allows the loss of neurons and synapses to be functionally compensated. By comparing animals of different ages, we aim to understand how these plasticity processes change over time, causing the same perturbations in adults can have devastating effects.

    How is the adult mammalian brain resilient in the face of damage?

    Although the adult brain is less plastic than during development, lesion studies have revealed an enormous latent ability for adult circuits to rewire and functionally compensate for damage. Leveraging tools from genomics and systems neuroscience, we aim to set up model systems that will allow us to pinpoint, mechanistically dissect, and ultimately control the specific cellular and circuit changes that underly neural circuit resilience.

  • How do brains maintain their function for long periods of time, even under changing physiological conditions and external perturbations?

    We aim to systematically map and understand the cellular and molecular pathways that act both cell autonomously and cell-non-autonomously to maintain brain function and respond to damage and stressors. To do so, we aim to develop new tools to precisely control different stress response pathways in vivo and measure their effects on tissue function.

    How does the brain sense and respond to disruptions to cellular and tissue homeostasis throughout the body?

    Diverse populations of neurons in the brain sense different physiological variable in order to maintain a constant internal environment. We previously mapped the circuits underlying thirst, the control of water balance. Now, we aim to more generally understand the ability of the brain to sense and respond to cellular and tissue stress responses signals that may occur across different organs during damage and aging.

  • What are the causes of decline of function with age?

    We are interested in understanding the fundamental mechanisms of brain aging and neurodegenerative disease. These processes have been challenging to study in the past due to the complexity of the mammalian brain and the long timescales on which aging and neurodegenerative disease occur. We aim to overcome these limitations through the development and application of new tools that allow us to map multiple interacting components of the mammalian brain at high resolution across multiple spatial and temporal scales.

    To what extent is this decline repairable or reversible?

    We aim to develop interventions to engineer living cells in the brain to promote resilience during aging. Our long term aims are to repair, replace, or rejuvenate aged or damaged cells and tissues.

Technology

Mapping & Manipulating Biology

We develop technologies across scales—from molecular tools to computational methods—to answer important questions and open new research areas. Our approaches integrate biology, engineering, and physical sciences, from molecular genetics and neuroscience to AI and advanced imaging

Through these methods, we quantitatively characterize physiological processes at high resolution in intact living systems. We apply AI and machine learning to model complex biological data, generate testable predictions, and make unexpected discoveries. The tools we develop are designed to be broadly applicable across biological systems.

Our ultimate goal is to make resilience programmable, enhancing the natural capacity of cells and tissues to adapt and repair. This convergence of tools for measurement, modeling, and manipulation opens new possibilities for preventing decline and restoring function in aging and disease.

If any of these questions or approaches interest you, please contact us.

  • All tissues function through the coordinated activity of many different types of principal and support cells arranged in a precise organization. The brain in particular operates through the coordinated activity of millions of neurons, of thousands of types, as well as multiple types of non-neuronal cells. The complexity of tissues poses a measurement challenge: to work out physiological circuits, ideally one would like to resolve the state, type, and activity of every cell in a tissue under a variety of physiological processes. We have developed approaches for highly multiplex molecular phenotyping of cells in intact tissue, as well as large-scale measurements of brain activity using both neurophysiology and molecular genetic tools.

  • Unbiased genetic screens in invertebrate model organisms such as flies and worms have been an enormously powerful tool to uncover the molecular regulators of physiological processes ranging from development to inflammation to behavior. These screens typically relied on complex phenotypes visible by eye. Although performing unbiased genetic screens in cultured mammalian cells is now routine thanks to the advent of CRISPR, applying these approaches in tissues of vertebrates has proven challenging: typically single genes are knocked out, one at a time, and then animals are phenotypes manually. We are developing approaches to make the process of understanding and controlling gene function in living animals radically more efficient, by virally delivering genetic perturbations in a mosaic to different tissues and measuring high-dimensional cellular phenotypes in intact tissue at a scale of millions of cells.

  • Rapid advances in generative AI have already revolutionized structural biology and are poised to transform our ability to understand physiological processes in complex biological systems. By training generative models on large-scale, high-dimensional data of both cells’ state both under homeostatic conditions and in response to large-scale genetic perturbations and complex physiological states such as disease, we hope to build predictive models of tissue function that reveal new mechanisms of cellular function, allow us to perform virtual experiments that make experimentally testable predictions, and dramatically accelerate in vivo cellular engineering.