Geert W. Schmid-Schoenbein, Ph.D.
Distinguished Professor
Shu Chien-Gene Ley Department of Bioengineering
University of California, San Diego
Seminar Information
How is it possible that during eating, for example, a tasty sausage, you digest an intestine inside your intestine but not your own intestine? The answer to this question turns out to be a key to understanding the fundamental mechanisms for aging as well as the organ failures at the end of life.
At a meal, the pancreatic digestive enzymes in one’s small intestine degrade the biomolecules we require for nutrition. Essential to this process, digestive enzymes are highly concentrated in the small intestine. They are catalytically active and almost completely compartmentalized within the intestinal lumen by a mucin/epithelium/goblet cell barrier. When intact, this barrier is impermeable to pancreatic digestive enzymes.
However, when the intestinal barrier is compromised, digestive enzymes are able to escape out of the small intestine. For example, during a meal, goblet cells in the barrier release their mucin, which becomes the site where digestive proteases escape through the intestinal barrier and into the central circulation. This process repeats itself daily, allowing digestive enzymes to accumulate in all organs, resulting in eventual degradation of organ function. Pancreatic digestive enzymes, including the serine proteases, activate secondary tissue proteases, cleave plasma and extracellular matrix proteins, cleave cell membrane receptors, and cause loss of cellular functions. This is the definition of autodigestion and are the typical signs of aging.
Leakage of digestive enzymes into the circulation exists on a continuum: chronic low-level degradation of bowel integrity with subclinical leak of digestive enzymes into the systemic circulation can become catastrophic in the event of overt small intestinal failure, such as occurs in shock and sepsis. In this condition, the epithelial/mucin barrier becomes markedly
compromised, allowing concentrated digestive enzymes to escape into the circulation. All organs become infiltrated by high concentrations of pancreatic digestive enzymes, leading to multiple organ dysfunctions and mortality.
Deliberate blockade in the intestinal lumen itself of pancreatic digestive proteases with small-molecular-weight inhibitors matched to the high concentrations of pancreatic proteases reduces mortality in acute shock and sepsis. For interventions against aging, we are developing nuanced methods to block digestive enzymes in peripheral tissues, minimizing autodigestion while preserving digestion.
Geert W. Schmid-Schoenbein, Distinguished Professor in the Shu Chien-Gene Ley Department of Bioengineering, is a former Chair of the Department and teaches cell and molecular biomechanics and bioengineering of living tissues, with applications to diseases.
He is a Founding Member of the American Institute for Medical and Biological Engineering, and was President of the Biomedical Engineering Society, the Microcirculatory Society, and the North American Society of Biorheology. He is a
Fellow of the American Physiological Society, the American Heart Association, the International Federation for Medical and Biological Engineering, and a Member of the National Academy of Engineering. He was Chair of the US National Committee on Biomechanics and the World Council for Biomechanics.
His team develops fundamental models of the microcirculation. They discovered the mechanisms for the obstruction and loss of capillaries, the fluid shear stress sensor in immune cells, the shear stress shelters on endothelium, and a second valve system in lymphatics. They apply bioengineering analyses to inflammation, metabolic disease, shock and sepsis, and develop new interventional approaches. The team discovered a mechanism for cell/tissue/organ degradation due to digestive enzymes, designated “Autodigestion”.