OVERVIEW
Our lab seeks to define the molecular logic of complex cell behaviors— how cells go from sets of interacting molecules to the emergent properties of living systems.
We currently focus on three questions:
- How do individual cells control their shape and movement?
- How do groups of cells share information to make collective decisions?
- How are signaling and mechanics integrated to guide cell fate decisions during pre-implantation mammalian development?
We study a diversity of cell types and behaviors. We believe that this makes it easier to identify the general principles of cellular decision-making. We often pair biosensors to visualize a quantitative dynamic of choice inside living cells with precision tools to control the regulators of these behaviors. We also leverage synthetic approaches like optogenetics and de novo protein design to sharpen our understanding of cellular self-organization. This approach reveals the molecular logic of these complex cell decisions.
Transformative science often happens at interfaces. We seek to borrow tools and concepts from other fields to address open questions in cell biology and frequently develop new tools when they are needed to accelerate progress.
Our approach opens up opportunities for cross pollination between different projects in the lab and frequently leverages collaborations with other labs in the field.
Cell polarity, shape, and movement
For proper function, many cells direct their migration in response to cues from their environment. This process underlies the functioning of the immune system, the wiring of the nervous system, and the healing of wounds. At a fundamental level, we don’t yet understand the molecular logic that cells use to control their movement. We primarily study migration in neutrophils– innate immune cells that migrate to sites of injury and infection. This behavior requires a seamless integration of many cellular sub-routines. The cell has to decide when and where to make a protrusion. The protrusion is a self-organizing structure that is guided by soluble as well as mechanical guidance cues. What are the rules of this self-organization? Each protrusion competes with the rest of the cell to enable a winner-take-all, and the currency for global coordination is forces transmitted through the plasma membrane and cortex. How do biochemical signals and forces collaborate in this process? On the opposite side of the protrusion, cells generate contractions so the back of the cell can follow the front. How are these front and back programs appropriately positioned? We study the crosstalk of the many currencies (biochemical signals, physical forces, membrane geometry, electrical properties) that integrate these decisions.
Directional movement of white blood cells to a point source of attractant (center).
We are dissecting the molecular logic of how cells control their shape and movement during chemotaxis.
Neutrophils collectively migrating to sites of infection. These self-organizing swarming waves help cells coordinate where to go and how many get there.
Collective cell behaviors
In the previous section, we focus on how different parts of the cell talk to one another for cell-wide coordination of migration. Here we focus on a similar concept at a different scale– groups of cells that share information to make collective decisions. Multicellular coordination enables a dizzying array of cellular processes from the healing of our wounds to the beating of our hearts to the digestion of our meals. Just like flocks of birds and schools of fish and swarms of ants, collective decision-making enables better decisions than individuals acting alone. In these systems (as in cellular systems), no one is in charge, and everyone is only acting on local cues– so how do collective decisions arise? We are interested in defining the local rules of cellular interaction that generate emergent responses for groups of cells in the context of the immune response, vertebrate development, wound healing, the beating of hearts, and digestion of meals. We are actively developing model systems, molecular tools, and theoretical frameworks that will advance our ability to manipulate, quantify, and engineer emergent physiological behavior to better understand the general principles of multicellular signal integration.
Pre-implantation embryo development
During mammalian pre-implantation development, cells must make their first critical fate choice to specify the lineages that form the placenta or the embryo proper. This bifurcation results in two spatially distinct cell populations with limited interconversion between cell fates. To achieve this lineage commitment, the embryo coordinates major mechanical changes with critical signaling programs that drive cell fate. This makes the mouse embryo a tractable model system to study the integration of signaling and mechanics that guides polarity establishment, symmetry breaking, and self-organization during development. We initially studied embryonic development in fish and birds and currently focus on the early mouse embryo. We leverage classical embryology with advances in light-sheet microscopy, novel biosensors, optogenetic tools, and biophysical approaches to disentangle the signaling circuit underlying normal and defective embryogenesis. Understanding the mechanisms through which the embryo balances and commits cell fates needed for uterine implantation will be critical for future studies that aim to improve Assisted Reproductive Technologies.
Visualization of a pre-implantation mouse embryo development. The embryo integrates signaling and mechanics to robustly guide morphogenesis.
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Webpage & Illustration by www.oliverhoeller.com.