TL Liu et al., 2018
Credit: TL Liu et al., 2018

Physiology encompasses the functions carried out by different organs and tissues in the body that allow an organism to eat, breathe, reproduce, and continuously adapt to changing conditions to ensure survival. Fundamentally, these functions are produced through the collective actions of cells, thousands and trillions of which comprise a simple worm and a human body, respectively. We still have a poor understanding of how cellular processes − which cell biologists seek to explain at the level of molecules, organelles, and cell-cell interactions − give rise to the systems-level phenomena that are described by physiologists.

4D Cellular Physiology at Janelia aims to fundamentally alter this landscape by establishing strong technical, biological, and conceptual bridges that bring physiology within reach of mechanistic cell biology. We feel that this problem is now at a turning point with tools, existing or within reach, for measuring dynamics of heterogeneous cells within tissue environments and harnessing computation and theory to understand how communities of cells self-organize and communicate to create functional organs and organisms.

4D Cellular Physiology is a grand challenge, one that will excite current and future generations. Janelia certainly cannot do it alone, nor would we want to. We want to engage with others around the world, and have 4DCP at Janelia aid your work, whether through in-person or virtual conferences, our visitor’s program, the Advanced Imaging Center, collaborations, tools that we develop, or data that we share. We are all part of one big network of science, and only through that network can we hope to understand the network of cells that make us who we are.

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  • 4D Cellular Physiology encompasses several elements of the challenge and the aspirations of the research at Janelia, including: studying the dynamics of cell behavior and communications in 3D multi-cellular systems over time, and not just snapshots; recognizing the need to make measurements of individual cells, and not just as averaged populations; and framing questions about phenomena that need cellular and molecular explanations at the macro-level.

  • Progress in 4D Cellular Physiology will require a suite of new tools for investigating and conceptualizing the connection between cell behavior and physiology. The core tool research areas of Janelia (Computation & Theory and Molecular Tools & Imaging) are well-suited to connect and bootstrap between the different length (nanometers to meters) and time scales (milliseconds to days) that connect the worlds of cell biology and physiology. Janelia is a special environment that supports tool builders, technology developers, and computer scientists who can push their talents and work in close collaboration with biology-focused tool users. We welcome new tool builders as well as biologists to join us at Janelia and propel the emerging field of 4D Cellular Physiology.

  • 4D Cellular Physiology synergizes well with our current research area, Mechanistic Cognitive Neuroscience. Just as 4DCP aspires to bridge the fields of cell biology and physiology, MCN aims to connect the fields of cognitive psychology to mechanistic cellular and systems neuroscience. Both programs have a shared goal of understanding how animals behave and coordinate their responses at different biological scales (i.e., molecules, cells, organs, and whole body) to promote survival under a broad range of conditions. Both use technologies to study cells in their native tissue environments. The peripheral nervous system, which links the body and the brain, also will comprise one element of the 4DCP program.

We aim to create a unique and interactive community at Janelia that can stimulate us individually and collectively to think about the overarching problems facing the field − understanding the general principles of how cells self-organize and how information flows across scales to create multicellular life.

  • 4D Cellular Physiology is a new research area at Janelia that is fully internally funded for 15 years. Currently, 3 Senior Group Leaders and 6 Group Leaders comprise 4DCP research team. We will hire more lab heads in Fall 2022, aiming for a total of 15 4DCP labs. In addition, we will hire new Group Leaders and Senior Group Leaders in the core areas of Molecular Tools and Imaging and Computation & Theory whose work will be related to 4DCP. We also will launch Project Teams that will tackle problems in 4DCP (see CellMap). Many of our current scientists also are interested in working on 4DCP.

  • With a critical mass of current scientists and those who will come to join us, we will create a unique intellectual community of scientists who are dedicated to a mechanistic cellular-level understanding of physiological problems and can collectively think about and interrogate these problems across scales. Within this large undertaking, we have begun to identify sub-areas of focus based upon scientific synergies emerging among our newly recruited Group Leaders. These sub-areas include:

    1. Brain-body communication and interoception- how nerves sense the status of organs and tissues and relay this information between organ systems and the brain. Several 4DCP labs (Misha Ahrens, Isabel Espinosa Medina, Anoj Ilanges, and Yin Liu) are interested in this problem, which is fundamental for homeostasis and long-range communication in animals. We envision many connections between this effort and Mechanistic Cognitive Neuroscience. Initial studies will focus on zebrafish and mouse animal models. 

    2. Mechanistic tissue biology- how communities of different cell types form, self-organize, and communicate to govern the functions and shapes of organs and tissues. Initial studies will focus on C. elegans (with Meng Wang and Hari Shroff joining Janelia), multi-cellular slime molds, zebrafish, and mice will be a focus of our initial efforts. Over time, we hope that these efforts will converge on the elucidation of general principles that underlie multi-cellular life and the cooperation that underlies cellular ecosystems.

  • The true scope of 4D Cellular Physiology will require decades of work from scientists around the world. We are excited to make Janelia an engine that drives progress for the entire field and look forward to the many interactions and collaborations that we form over the coming years.