Abstract
Obtaining knowledge requires, at its base, information and appropriate means by which to gain the raw data. Ultimately, generating data requires methods. Such is the nature of scientific investigation—the demand for new techniques is driven by questions that cannot be addressed with the tools at hand. As noted in “Negative Consequences of the Central Dogma,” 1 the simple tools of nucleic acid biochemistry have diverted efforts to understanding cellular processes. Even today, most research is limited to the narrow space defined by lipid bilayer and the proteins embedded in it.
The view of histopathology is entirely cell-centric. The term extracellular matrix is functionally dismissive for everything else. One consequence of this perspective is the limited focus on the tools to explore the extracellular matrix. Studies of extracellular matrix are more chemistry-focused—depending on histochemical techniques—contrast agents that bind biomolecules and chemical imaging method based on general properties of biochemistry, rather than with the molecular specificity of immunohistochemistry. The primary tools of the extracellular matrix remain the H&E, Masson trichrome, reticulin, and Sirius red stains. Powerful, yes, but limited.
Proteoglycans are prominent in developmental biology and biomedicine before the advent of PCR, as they could be dissected by precise biochemical methods. The concept of a morphogen gradient remains central to developmental biology. The techniques are complex and require substantial starting material and exquisite technical attention, but the rewards are high. The knowledge obtained from molecular biology revolutionized our understanding of organism; however, it has left enormous gaps in our knowledge of the extracellular matrix and a substantial gap in mechanism.
As research was reduced to in vitro and in silico investigations, with confirmation in vivo based on end point assays, the tools to understand long-distance cellular signaling and concepts of gradients in development, endocrinology, and immunology have suffered. However, with the advent of cell and tissue-focused “atlases” that characterize cells and tissues beyond the cell surface, and incorporate the dynamics of time at the cell and organism level, investigation of the extracellular matrix has assumed a new importance as we attempt to develop a more holistic approach to biology. Biochemistry described the molecular interactions of the cell components, and physiology described the interactions of the organs. Now is the opportunity to expand our approach to cellular physiology to encompass the interaction of cells, their matrix, and how they come together to form tissues and organs at the biomolecular level.