Biology

Overview: Homeostasis & Resilience

Homeostasis is the ability of biological systems – ranging from cells to entire organisms – to maintain their physiological function over time in response to changing conditions. Different homeostatic mechanisms operate at these different levels of biological organization, as well as in different types of cells and tissues. Although such mechanisms have been described at the level of entire organisms since the mid 19th century, the specific physiological circuits that maintain cellular and tissue homeostasis in many organs remain unclear.

We aim to map and understand the fundamental mechanisms that allow different tissues to establish and maintain their function over an animal’s lifespan, as well as how these homeostatic circuits malfunction in disease – particularly those associated with aging, such as chronic inflammation and neurodegeneration. We ultimately intend to apply this knowledge to engineer cells in living animals to promote resilience in the face of cellular stress, replace lost functionality, or even rejuvenate aged or damaged tissues. 

Brain Development, Homeostasis, & Degeneration

We focus on the mammalian brain, which is composed of post-mitotic neurons that must survive the lifetime of an animal in order to store memories, regulate behavior, and support cognition. Although neurons generally cannot be replaced, interactions between neurons and non-neuronal cells enable neural plasticity and maintain tissue homeostasis, allowing the brain to dynamically respond to stressors, compensate for damage, and learn new skills and information. Our goal is to understand the mechanisms underlying these homeostatic and plasticity processes at multiple scales – bridging the molecular, cellular, and systems levels of analysis – as well as how they change over an animal’s lifetime.

  • How does the mammalian brain mature?

    Mammalian brains undergo an extended period of maturation, during which time they are intrinsically plastic and can compensate for large amounts of damage. 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 does the adult mammalian brain engage plasticity 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 adult neuroplasticity.

  • 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

We apply a variety of tools and approaches to answer these questions, as well as developing new molecular technology, computational methods, or instrumentation where needed to open up new areas or scale our research.

Through these methods, we aim to quantitatively characterize and mechanistically understand physiological processes in complex biological systems, at high resolution and in their intact configuration. We then apply techniques from AI and machine learning to model and interpret high-dimensional biological data, to address specific hypotheses, make experimentally testable predictions, or discover unexpected phenomena. 

These approaches come from a variety of fields, including several within biology (molecular genetics, systems neuroscience, synthetic biology, functional genomics) as well as the physical and computational sciences (imaging, machine learning, chemistry). Although we primarily focus on the brain, the tools we develop aim to be broadly applicable to a variety of biological systems and processes.

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.