#1 complex Systems and Hypoth Testing_Hypoth testing - and DM (3-23)

#1 complex Systems and Hypoth Testing_Hypoth testing - and DM (3-23)

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Unformatted text preview: 1.Control of Complex Systems and Networks: Some Principles of Metabolic Integration in the Whole Organism 2. Evidence and Hypothesis Testing in Medicine Marc K. Hellerstein, M.D., Ph.D. Professor of Human Nutrition (D.H. Calloway Chair), University of California Berkeley; Professor of Endocrinology, Metabolism and Nutrition, Dept. of Medicine, University of California at San Francisco NST 160: Introductory Lecture Human Nutrition: Focusing on the Human (I.e., whole organismal) aspect Focus in nutrition has changed: from foods to how body metabolizes nutrients Students here have learned much about the individual components of these systems (genes, mRNAs, proteins, intermediary metabolites, signaling molecules, nutrients, etc.) But the principles of metabolic control and integration within these complex systems are not often taught This will be the focus of some of my classes in the present course Organization of First Part of Course: Human Nutrition Dissonance between our understanding of the parts and the whole in complex biological systems The radically uneven development in knowledge about components (reductionist understanding) vs intact assemblages (integrated understanding) tends to be taken for granted Paradox is that the former has not led to parralel ability to control the latter, especially when things go wrong, as in disease The Central Paradox of Contemporary Biology and Medicine The Modern Drug Discovery and Development (DDD) Paradigm Modern drug discovery was expected to lead to a renaissance of new cures The system works as follows:- A molecule (protein or gene) is identified as a potential target for treating disease- Libraries of chemicals are screened for interaction with the target (high-throughput screening)- Hits are discovered; modified to be more effective (combinatorial chemistry)- These hits are tested for safety and efficacy as drugs The Modern Drug Discovery and Development (DDD) Paradigm Has Disappointed Contrary to expectations, the rate of new drug approvals is at an historical low Attrition ( >98% failure rate) has resulted in a clogged pipeline, inability to prosecute leads and unrecognized actions of drugs Primary reason: Current tools do not predict success or failure of agents Outputs of Complex Biochemical Networks are the True Outcome Measures Gene, Drug, Nutrient Output Whole does not equal the sum of the parts. New levels of control (emergent properties) Non-linearity and unpredictability of response Individual components have little control strength (capacity to control output of fully assembled system) This is even true in simplest systems (e.g., bacteria- see example of metabolic engineers) And what is controlled is flow (flux), not the level of any component part Systems may exhibit internal principle of flux control (network architecture; defense of fluxes) How does complexity change things? It is essentially impossible to just step in and fix a...
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#1 complex Systems and Hypoth Testing_Hypoth testing - and DM (3-23)

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