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OCR for page R1
Mathematics and 21st Century Biology
MATHEMATICS AND 21ST CENTURY BIOLOGY
Committee on Mathematical Sciences Research for DOE’s Computational Biology
Board on Mathematical Sciences and Their Applications
Division on Engineering and Physical Sciences
NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C. www.nap.edu
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Mathematics and 21st Century Biology
THE NATIONAL ACADEMIES PRESS
500 Fifth Street, N.W. Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This study was supported by Contract No. DE-AT01-03ER25552 between the National Academy of Sciences and the Department of Energy. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project.
International Standard Book Number 0-309-09584-0 (Book)
International Standard Book Number 0-309-54856-X (PDF)
Library of Congress Catalog Card Number 2005024164
Additional copies of this report are available from the
National Academies Press,
500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu
Copyright 2005 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
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Mathematics and 21st Century Biology
THE NATIONAL ACADEMIES
Adviser to the Nation on Science, Engineering, and Medicine
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council.
www.national-academies.org
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Mathematics and 21st Century Biology
COMMITTEE ON MATHEMATICAL SCIENCES RESEARCH FOR DOE’S COMPUTATIONAL BIOLOGY
MAYNARD V. OLSON,
University of Washington,
Chair
PETER J. BICKEL,
University of California at Berkeley
JACK D. COWAN,
University of Chicago
NINA FEDOROFF,
Pennsylvania State University
LESLIE GREENGARD,
New York University
RICHARD HUDSON,
University of Chicago
JAMES KEENER,
University of Utah
ROBERT LIPSHUTZ,
Affymetrix, Inc.
JILL P. MESIROV,
Massachusetts Institute of Technology
CLAUDIA NEUHAUSER,
University of Minnesota
STANISLAV Y. SHVARTSMAN,
Princeton University
GARY D. STORMO,
Washington University
MICHAEL S. WATERMAN,
University of Southern California
PETER G. WOLYNES,
University of California at San Diego
WING H. WONG,
Stanford University
JOHN WOOLEY,
University of California at San Diego
Staff
SCOTT WEIDMAN, Director,
Board on Mathematical Sciences and Their Applications
JENNIFER SLIMOWITZ, Program Officer (through February 18, 2005)
BARBARA WRIGHT, Administrative Assistant
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Mathematics and 21st Century Biology
BOARD ON MATHEMATICAL SCIENCES AND THEIR APPLICATIONS
DAVID W. McLAUGHLIN,
New York University,
Chair
TANYA STYBLO BEDER,
Tribeca Investments, LLC
PATRICK L. BROCKETT,
University of Texas at Austin
ARAVINDA CHAKRAVARTI,
Johns Hopkins University School of Medicine
PHILLIP COLELLA,
Lawrence Berkeley National Laboratory
LAWRENCE CRAIG EVANS,
University of California at Berkeley
JOHN E. HOPCROFT,
Cornell University
ROBERT KASS,
Carnegie Mellon University
KATHRYN B. LASKEY,
George Mason University
C. DAVID LEVERMORE,
University of Maryland
ROBERT LIPSHUTZ,
Affymetrix, Inc.
CHARLES M. LUCAS,
AIG
CHARLES MANSKI,
Northwestern University
JOYCE McLAUGHLIN,
Rensselaer Polytechnic Institute
PRABHAKAR RAGHAVAN,
Verity, Inc.
STEPHEN M. ROBINSON,
University of Wisconsin-Madison
EDWARD WEGMAN,
George Mason University
DETLOF VON WINTERFELDT,
University of Southern California
Staff
SCOTT WEIDMAN, Director,
Board on Mathematical Sciences and Their Applications
JENNIFER SLIMOWITZ, Program Officer (through February 18, 2005)
BARBARA WRIGHT, Administrative Assistant
For more information on BMSA, see its Web site at http://www7.nationalacademies.org/bms
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Mathematics and 21st Century Biology
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Mathematics and 21st Century Biology
Preface
This report was commissioned by the Office of Advanced Scientific Computing Research (OASCR) at the Department of Energy (DOE). This office, which has broad responsibilities for applications of mathematics and computing to all fields of science of importance to DOE, sought advice as specified in the charge to the committee:
The study will recommend mathematical sciences research activities to the Department of Energy that will enable science to make effective use of the large amount of existing genomic information and the much larger and more diverse collections of structural and functional genomic information that are being created. The recommended activities should cover both current research needs and also include some higher-risk research that might lead to innovative approaches for the future.
In discussions with OASCR officials, it became apparent that the intent was to sponsor a broad, scientifically based view of the opportunities that now lie at the interface between the mathematical sciences and biology. “The mathematical sciences” was to be broadly defined to include statistics, computational science, and all areas of applied mathematics.1 Although the Department of Energy is an agency with deep roots in applying the mathematical sciences to the physical sciences—as well as a pioneer in selected biological applications such as protein-structure de-
1
An upcoming National Academies report from the Computer Science and Telecommunications Board will address the interface between computer science and biology.
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Mathematics and 21st Century Biology
termination and genome sequencing—there was no intent that the committee analyze specific DOE programs or restrict itself to DOE’s existing programmatic boundaries. Hence, the recommendations are stated in general terms and are applicable to programs at any of the funding organizations whose missions encompass the mathematical sciences, biology, and the interactions between these fields, including but not limited to DOE. The committee has worked very hard to provide substantiated guidance about the scientific opportunities that these organizations are poised to support.
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report:
James Collins, Boston University,
Terry Gaasterland, Rockefeller University,
David Haussler, University of California at Santa Cruz,
Douglas Lauffenburger, Massachusetts Institute of Technology, and
Simon Levin, Princeton University.
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Ronald Douglas, Texas A&M University. Appointed by the National Research Council, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
In addition, the committee thanks Mark Daly, Avner Friedman, and Alan Perelson for their remarks and suggestions during the study process.
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Mathematics and 21st Century Biology
Contents
EXECUTIVE SUMMARY
1
1
THE NATURE OF THE FIELD
12
Introduction,
12
The Mathematics-Biology Interface,
12
What Has Changed in Recent Years?,
15
What Makes Computational Biology Problems Hard?,
19
Factors Common to Successful Interactions Between the Mathematical Sciences and the Biosciences,
20
Preparing the Ground for Improved Synergies of Benefit to Both Fields,
22
Structure of This Report,
27
References,
27
2
HISTORICAL SUCCESSES
29
The Beginnings of Population Biology,
29
Inference of Gene Function by Homology,
30
Evolutionary Processes in Populations,
32
Modeling,
33
Medical and Biological Imaging,
34
Summary,
35
References,
36
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3
UNDERSTANDING MOLECULES
38
Introduction,
38
The Mathematics-Biology Connection,
39
Areas of Mathematical Applications for Molecules,
41
Sequence Analysis,
41
Structure Analysis,
43
Dynamics,
45
Interactions,
47
Future Directions,
48
References,
49
4
UNDERSTANDING CELLS
51
Introduction,
51
Exemplification of These Issues,
52
Cellular Structures,
55
Discovery of Cellular Networks and Their Functions,
57
From Networks to Cellular Functions,
60
From Cells to Tissues,
66
Data Integration,
68
Biological Considerations,
70
Future Directions,
72
References.
73
5
UNDERSTANDING ORGANISMS
80
Cardiac Physiology,
81
Circulatory Physiology,
84
Respiratory Physiology,
85
Information Processing,
86
Endocrine Physiology,
87
Morphogenesis and Pattern Formation,
88
Locomotion,
90
Cancer,
91
Delivery of Therapy to Target Tumor Cells,
91
Mechanisms of Drug Action,
92
Growth and Differentiation of Cell Populations,
92
Development of Resistance,
92
In Vivo Dynamics of the HIV-1 Infection,
93
Future Directions,
94
References,
95
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Mathematics and 21st Century Biology
6
UNDERSTANDING POPULATIONS
99
Population Genetics,
99
Ecological Aspects of Populations,
104
A Synthesis of Ecology and Evolution,
106
References,
108
7
UNDERSTANDING COMMUNITIES AND ECOSYSTEMS
110
Computation,
116
Future Directions,
117
References,
122
8
CROSSCUTTING THEMES
127
The “Small n, Large P“ Problem,
127
Finding Patterns in Gene-Expression Data,
128
Supervised Learning,
131
Unsupervised Learning,
132
Analysis of Ordered Systems,
134
Applications of Hidden Markov Models to the Analysis of DNA, RNA, and Protein Sequences,
134
Profile HMMs,
135
HMMs in Gene Finding,
136
Applications of Monte Carlo Methods in Computational Biology,
138
Gibbs Sampling in Motif Finding,
139
Inference of Regulatory Networks,
139
Sampling Protein Conformations,
140
Lessons from Mathematical Themes of Current Import,
140
Processing of Low-Level Data,
142
Epilogue,
144
References,
145
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