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Fundamental Questions

Hypotheses

Approach

FUNDAMENTAL QUESTIONS

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?

HYPOTHESES

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.

We take an interdisciplinary approach based on the following set of hypotheses that are all now supported by experimental results:

Cellular Tensegrity Theory. Cells and tissues are organized as discrete network structures, and they use tensegrity architecture to mechanically stabilize themselves. In the cellular tensegrity theory, complex mechanical behaviors in cells and tissues emerge through establishment of a mechanical force balance between different molecular elements in the cytoskeleton and ECM that maintains the cell in a state of isometric tension.

Solid-State Biochemistry. Many of the biochemical events that mediate cell metabolism and signal transduction proceed using solid-state biochemistry. The enzymes and substrates that mediate these biochemical reactions are physically immobilized on insoluble molecular scaffolds within the cytoskeleton, nucleus and ECM.

Integrins as Mechanotransducers. Mechanical forces impact cellular signal transduction and influence cell decision making based on their transmission across cell surface adhesion receptors, such as integrins, that mechanically couple extracellular molecular scaffolds to the internal cytoskeleton. Mechanical forces are converted into chemical and electrical signals through stress-dependent distortion of molecules that associate with load-bearing elements of the cytoskeleton.

Cell Fates as Attractor States. Stable cell phenotypes, such as growth, differentiation, and apoptosis represent preprogrammed stable states or high dimensional “attractors?that emerge as a result of distributed information processing in genome-wide gene and protein regulatory networks. In this paradigm, cell fate switching may proceed via multiple pathways and require changes in many different proteins and genes; yet the process results in the same common end phenotype because they are selected from a set of common “default?states.

Linkage between Structural and Information Processing Networks. Mechanical distortion of cells influences their behavior based on structural changes in the cytoskeleton and associated transmembrane linkages that impact multiple solid-state signaling activities. Because of the attractor states in the genome-wide regulatory network, these signaling activities self-organize to produce concerted phenotypes, such as the switch between different cell fates.

APPROACH

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. More detailed information regarding our current experimental and theoretical efforts may be found under the following topic headings:

 Tissue Morphogenesis

 Cellular Mechanotransduction

  Cell Engineering

 Tensegrity and Complex Systems Biology




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