Ingber Laboratory

The Ingber laboratory is interested in the general mechanism of cell and developmental regulation: how cells respond to signals and coordinate their behaviors to produce tissues with specialized form and function. The specific focus is on control of angiogenesis and vascular development. Our approach has been driven by our hypothesis that the process of tissue construction may be regulated mechanically. We introduced the concept that living cells stabilize their internal cytoskeleton, and control their shape and mechanics, using an architectural system first described by Buckminster Fuller, known as "tensegrity" To approach questions relating to how mechanical distortion of the cell and cytoskeleton influence intracellular biochemistry and pattern formation, we have combined the use of techniques from various fields, including molecular cell biology, mechanical engineering, physics, chemistry, and computer science. This work has led to the identification of mechanical forces and the cytoskeleton as critical cell and developmental regulators, and the discovery that transmembrane integrin receptors which anchor cells to extracellular matrix also mediate mechanotransduction. The process by mechanical signals are converted into an intracellular biochemical response. The lab also has shown that extracellular matrix and cell shape distortion play central roles in control of angiogenesis that is required for tumor growth and expansion, and has developed numerous novel microtechnologies, nanotechnologies, magnetic control systems and computational models in the course of pursuing these studies. Their potential applications are currently being explored in areas ranging from ultra-sensitive clinical diagnostics to nanoscale medical devices, engineered tissues, and biologically-inspired materials for tissue repair and reconstruction.

The Ingber laboratory is interested in the fundamental problem of how cells decide whether to move, grow, contract, differentiate, or die during tissue development. We specifically focus on angiogenesis - the growth of blood capillaries - a process that is critical for the growth of cancer and many other debilitating diseases. In more general terms, the challenge is to understand how the information encoded within genes and biochemical reactions maps into the observable “systems-level?properties of whole living cells and tissues. Our approach is novel in that we combine approaches from molecular cell biology, biophysics, chemistry, engineering and computer science to address how higher level, hierarchical behaviors emerge in context of both the hardware (structure) and the software (information processing systems) of the cell. We are asking three major questions:

(1) How do interactions between chemicals and molecules lead to the production of living cells and tissues with characteristic shapes and mechanical properties?

(2) How do dynamic network interactions among genes and regulatory molecules produce a coherent information processing machinery that enables cells to sense multiple simultaneous inputs and orchestrate a single concerted response?

(3) How do changes in structural networks within living cells impact these information processing networks, and vice versa?

Current understanding of cell and tissue regulation is explained largely in terms of changes in individual molecules, intermolecular binding interactions, and signal transduction modules. We strive to understand how this molecular information can be placed in context of the highly complex structural and biochemical networks that we know exist in living cells and tissues. In particular, we want to understand how the mechanical force balance that cells establish between their contractile cytoskeleton and resisting extracellular matrix (ECM) adhesions govern whether mammalian cells will move, grow, differentiate or die, and thereby control pattern formation during tissue development.

To explore the role of biological structure in cell regulation and to test these hypotheses, we combine methods and tools from molecular cell biology, chemistry, physics, engineering, and computer science, as well as new approaches from microfabrication, microfluidics and nanotechnology. We commonly study angiogenesis and use capillary endothelial cells as a model system because new insights into this mechanism of morphogenetic control may potentially impact development of new therapeutics for treatment of cancer and other angiogenesis-dependent diseases. One angiogenesis inhibitor compound (TNP-470) discovered in this laboratory has already entered clinical trials for treatment of human cancer. However, our interests are broad, and include, for example: application of femtosecond lasers in cell biology; development of new visualization tools for functional genomics; engineering of magnetic cellular switches; and, even creation of a new theory for the origin of life that incorpor ates tensegrity as a central guiding principle.