Integrative Approaches to Molecular Biology edited by Julio Collado-Vides, Boris Magasanik, and Temple F. Smith huangzhiman 200212.26 www.dnathink.org CONTENTS Preface vii 1 1 Evolution as Engineering Richard C. Lewontin I 11 Computational Biology 2 13 Analysis of Bacteriophage T4 Based on the Completed DNA Sequence Elizabeth Kutter 3 29 The Identification of Protein Functional Patterns Temple F. Smith, Richard Lathrop, and Fred E. Cohen 4 63 Comparative Genomics: A New Integrative Biology Robert J. Robbins 5 91 On Genomes and Cosmologies Antoine Danchin II 113 Regulation, Metabolism, and Differentiation: Experimental and Theoretical Integration 6 115 A Kinetic Formalism for Integrative Molecular Biology: Manifestation in Biochemical Systems Theory and Use in Elucidating Design Principles for Gene Circuits Michael A. Savageau 7 147 Genome Analysis and Global Regulation in Escherichia coli Frederick C. Neidhardt 8 167 Feedback Loops: The Wheels of Regulatory Networks Ren¨¦ Thomas ¡¡ 9 179 Integrative Representations of the Regulation of Gene Expression Julio Collado-Vides 10 205 Eukaryotic Transcription Thomas Oehler and Leonard Guarente 11 211 Analysis of Complex Metabolic Pathways Michael L. Mavrovouniotis 12 239 Where Do Biochemical Pathways Lead? Jack Cohen and Sean H. Rice 13 253 Gene Circuits and Their Uses John Reinitz and David H. Sharp 14 273 Fallback Positions and Fossils in Gene Regulation Boris Magasanik 15 281 The Language of the Genes Robert C. Berwick Glossary 297 References 303 Contributors 331 Index 335 Page iii Integrative Approaches to Molecular Biology edited by Julio Collado-Vides, Boris Magasanik, and Temple F. Smith Page iv © 1996 Massachusetts Institute of Technology All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher. This book was set in Palatino by Asco Trade Typesetting Ltd., Hong Kong and was printed and bound in the United States of America. Library of Congress Cataloging-in-Publication Data Integrative approaches to molecular biology / edited by Julio Collado-Vides, Boris Magasanik, and Temple F. Smith. p. cm. Consequence of a meeting held at the Center for Nitrogen Fixation, National Autonomous University of Mexico, Cuernavaca, in Feb. 1994. Includes bibliographical references and index. ISBN 0-262-03239-2 (hc : alk. paper) 1. Molecular biology¡ªCongresses. I. Collado-Vides, Julio. II. Magasanik, Boris. III. Smith, Temple F. QH506.1483 1996 574.8'8¡ªdc20 95-46156 CIP Page vii PREFACE There are several quite distinct levels of integration essential to modern molecular biology. First, the field of molecular biology itself developed from the integration of methods and approaches drawn from traditional biochemistry, genetics, and physics. Today the methodologies employed encompass those drawn from the additional disciplines of mathematics, computer science, engineering, and even linguistics. There is little doubt that a discipline that employs such a range of methodologies, to say nothing of the range and complexity of the biological systems under study, will require new means of integration and synthesis. The need for synthesis is particularly true if the wealth of data being generated by modern molecular biology is to be exploited fully. Few, if any, would claim that a complete description of all the individual molecular components of a living cell will allow one to understand the complete life cycle and environmental interactions of the organism containing that cell. On the other hand, without the near-complete molecular level description, is there any chance of understanding those higher-level behaviors at more than a purely descriptive level? Probably not, if molecular biology's mentor discipline of (classical) physics is a reasonable analog. Note that our current views of cosmology are built on a detailed knowledge of fundamental particle physics, including the details of the interaction of the smallest constituents of matter with light. The latter provided insight into the origin of the 2.7-degree background cosmological microwave radiation, which in turn provides one of the major supporting arguments for the so-called big bang theory. Similarly, our current views of the major biological theories of the evolutionary relatedness of all terrestrial life and its origins have been greatly enhanced by the growing wealth of molecular data. One has only to recall the introduction of the notion of neutral mutation or the RNA enzyme, the first notion leading to the concept of neutral evolution and, indirectly, to that of "punctuated equilibrium," and the second to that of the "RNA-world" origin. Even such classic biological areas as taxonomy have been greatly enhanced by our new molecular data. It is difficult to envision the future integration of our new wealth of information but, in the best sense of the word reduce, biology may well become a simpler, reduced set of ideas and Page viii concepts, integrating many of the emergent properties of living systems into understandable and analyzable units. Undoubtedly, integration of biology must ultimately involve an evolutionary perspective. However, evolutionary theory does not yet provide an explicit conceptual system strong enough to explain the biological organization at the level of detail common in molecular biology¡ªprotein and DNA structure, gene regulation and organization, metabolism, cellular structure¡ªbriefly, the structure of organisms at the molecular level. This reveals another area from which the required integration clearly is missing¡ªthat of molecular biology as a discipline wherein theories have been rather limited in their effectiveness. What makes biological systems so impenetrable to theories? Nobody doubts that organisms obey the laws of physics. This truism is, nonetheless, a source of misunderstanding: A rather naive attitude will demand that biology become a science similar to physics¡ªthat is, a science wherein theory plays an important role in shaping experiments, wherein predictions at one level have been shown to fit adequately with a large body of observations at a higher level¡ªthe successful natural science. But surely biology is limited in what it can achieve in this direction when faced with the task of providing an understanding of complex and historical systems such as cells, organs, organisms, or ecological communities. To begin, physics itself struggles to explain physical phenomena that occur embedded within biological organisms. Such physical phenomena encompass a vast array of problems¡ªfor example, turbulence inside small elastic tubules (blood vessels); temperature transference; laws of motion of middle-size objects at the surface of the planet; chemical behavior of highly heterogeneous low-ionic-strength solutions; evaluation of activity coefficients of molecules in a heterogeneous mixture; interactions involving molecules with atoms numbering in the thousands and at concentrations of some few molecules per cell; and finding the energy landscape for protein folding. These phenomena are difficult problems for classical physics and have contributed to the development of new descriptive tools such as fractal geometries and chaos theory. In fact, they have little to do with the boundaries within which classical physics works best: ensembles with few interacting objects and very large numbers of identical objects. Biological processes occur within physical systems with which simple predictive physics has trouble, processes that no doubt obey the laws of quantum and statistical physics but wherein prediction is not yet as simple as predicting the clockwise movement of stars. It is within such highly heterogeneous, rather compartmentalized, semiliquid systems that processes of interest to the biologist occur. As complex as they are, however, they are not at the core of what constitute the biological properties that help better to identify an organism as a biological entity¡ªreproduction and differentiation, transference of information through generations; informational molecule processing, editing, and proofreading; and ordered chemical reactions in the form of metabolic pathways and regulatory networks. Page ix This underlying physical complexity makes the analysis of biological organisms difficult. Perhaps a mathematical system to name and reveal plausible universal biological principles has not yet been invented. It also is plausible that a single formal method will not be devised to describe biological organisms, as is the aim of much of modern physics. The various contributions to this book illustrate how rich and diverse are the methods currently being developed and tested in pursuit of a better understanding and integration of biology at the molecular level. Important difficulties also exist at the level of the main concepts that build the dominant framework of theory within biology. Recall, for instance, how important problems have been raised regarding the structure of evolutionary theory (Sober, 1984). In the first chapter of this book, Richard Lewontin offers a critique of the evolutionary process as one of engineering design. The idea that organs and biological structures have clearly identifiable functions¡ªhands are made to hold, the Krebs cycle is made to degrade carbon sources¡ªis already a questionable beginning for theory construction and has important consequences, as Lewontin shows. Much later in this book, Boris