Encyclopedia of Molecular Biology.pdf

ENCYCLOPEDIA

MOLECULAR

BIOLOGY

VOLUMES 1 - 4

European' Molecular Biology Laboratory

London, England

A Wiley-lnterscience

Publication

John Wiley

& Sons, Inc.

New York / Chichester / Weinheim / Brisbane / Singapore / Toronto

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Library of Congress Cataloging-in-Publication Data:

Creighton, Thomas E., 1940-

The encyclopedia of molecular biology I Thomas E. Creighton.

p. cm.

Includes index.

ISBN 0-471-15302-8 (alk. paper)

I. Molecular biology-Encyclopedias.

I. Title.

QH506.C74 1999

572.8'03-dc21

99-11575

CIP

Printed in the United States of America.

10 9 8 7 6 5 4 3 2 1

PREFACE

The Wiley Biotechnology Encyclopedias, composedof the Ency-

clopedia of Molecular Biology, the Encyclopedia of Bioprocess

Technology: Fermentation, Biocatalysis, and Bioseparation,

the Encyclopedia of Cell Technology, and the Encyclopedia of

Ethical, Legal, and Policy Issues in Biotechnology, cover very

broadly four major contemporary themes in biotechnology.

The series comes at a fascinating time in that as we move into

the twenty-first century, the discipline of biotechnology is

undergoing striking paradigm changes.

Biotechnology is now beginning to be viewed as an i~-

formational ~.clence.In a simplistic sense, there are three

types of biological information. First, there is the digital or

linear inf9rmation of our chromosomes and genes, with the

four-letter alphabet composed of G, C, A, and T (the bases

Guanine, Cytosine, Adenine, and Thymine). Variation in the

order of these letters in the digital strings of our chromosomes

or our expressed genes (or mRNAs) generates information

of several distinct types: genes, regulatory machinery, and

information that enables chromosomes to carry out their tasks

as informational organelles (eg, centromeric and telomeric

sequences).

Second, there is the three-dimensional information of

proteins, the molecular machines of life. Proteins are strings

of amino acids employing a 20-letter alphabet. Proteins pose

four technical challenges: (i) Proteins are synthesized as linear

strings and fold into precise three-dimensional structures as

dictated by the order of amino acid residues in the string. Can

we formulate the rules for protein folding to predict three-

dimensional structure from primary amino acid sequence?The

identification and comparative analysis of all human and model

organism (bacteria, yeast, nematode, fly, mouse, etc.) genes

and proteins will eventually lead to a lexicon of motifs that are

the building block components of genes and proteins. These

motifs will greatly constrain the shape spacecomputational al-

gorithms must search to successfully correlate primary amino

acid sequence with the correct three-dimensional shapes. The

protein-folding problem will probably be solved within the

next 10 to 15 years. (ii) Can we predict protein function from

knowledge of the three-dimensional structure? Once again the

lexicon of motifs with their functional as well as structural

correlations will playa critical role in solving this problem. (iii)

How do the myriad of chemical modifications of proteins (eg,

phosphorylation, acetylation) alter their structures and modify

their functions? The mass spectrometer will playa key role

in identifying secondary modifications. (iv) How do proteins

interact with one another and/or with other macromolecules

to form complex molecular machines (eg, the ribosomal sub-

units)? If these functional complexes can be isolated, the mass

it varies with time. For example,the

human brain has 1012neurons making approximately 1015

connections.From this network arises systems properties

such a memory, consciousness,and the ability to learn. The

important point is that systemsproperties cannot be under-

stoodfrom studying the network elements(eg,neurons)oneat

a time; rather, the collectivebehaviorof the elementsneedsto

be studied together. To study most biological systems,three

issuesneedto be stressed.First, most biological systemsare

too complexto study directly; therefore they must be divided

into tractable subsystemswhose properties in part reflect

those of the system. These subsystemsmust be sufficiently

small to analyze all their elementsand connections.Second,

high-throughput analytic or globaltoolsare requiredfor study-

ing many systemselementsat one time (seebelow).Finally,

the systemsinformation needsto be modeledmathematically

before systems properties can be predicted and ultimately

understood.This will require recruiting computer scientists

and appliedmathematicsinto biology-just asthe attemptsto

decipherthe information of completegenomesand the protein

folding and structure/function problems have required the

recruitment of comput~tionalscientists.

I would beremissnot to point out that there are many other

moleculesthat generatebiological information-amino acids,

carbohydrates,lipids, etc. These too must be studied in the

contextof their specificstructures and specificfunctions.

The decipheringand manipulation of thesevarious typesof

biological information represent an enormoustechnical chal-

lengefor biotechnology.Yet major new and powerful tools for

doingsoare emerging.

One classof tools for decipheringbiological information is

termed high-throughput analytic or global tools. Thesetools

can study many genes or chromosomefeatures (genomics),

many proteins (proteomics),or many cells rapidly: large-scale

DNA sequencing;genome-widegenetic mapping; cDNA or

oligonucleotidearrays;two-dimensionalgelelectrophoresisand

other globalprotein separationtechnologies;massspectromet-

ric analysisofproteinsandprotein fragments;multiparameter,

high-throughput cell and chromosomesorting; and high-

throughput phenotypicassays.

A secondapproachto the decipheringand manipulation of

biological information centers around combinatorial strate-

spectrometer,coupledwith aknowledgeof all protein sequences

that canbederivedfrom the completegenomicsequenceof the

organism,will serve as a powerful tool for identifying all the

componentsof complexmolecularmachines.

The third type of biological information arises from com-

plex biological systemsand networks.Systemsinformation is

four-dimensionalbecause

gies. The basic idea is to synthesizean informational string

(DNA fragments,RNA fragments,protein fragments,antibody

combiningsites,etc.)using all combinationsof the basicletters

of the correspondingalphabet-thus creating many different

shapesthat canbeusedto activate,inhibit, or complementthe

biological functions of designated three-dimensionalshapes

(eg,a moleculein a signal transductionpathway).Thepowerof

combinationalchemistry is just beginningto beappreciated.

A critical approachto deciphering biological information

will ultimately be the ability to visualize the functioning of

genes,proteins,cells,and other informational elementswithin

living organisms(in vivoinformational imaging).

Finally, there are the computationaltools required to col-

lect, store, analyze,model,and ultimately distribute the var-

ious types of biological information. The creation presents a

challengecomparableto that of developingof new instrumen-

tation and new chemistries. Onceagain, this meansrecruit-

ing computerscientistsandappliedmathematiciansto biology.

The biggestchallengein this regard is the languagebarriers

that separatedifferent scientific disciplines.Teachingbiology

asan informational sciencehasbeena very effectivemeansfor

breechingtheselanguagebarriers.

The challengeis, of course,to decipherthesevarious types

of biological information and then be able to use this infor-

mation to manipulate genes,proteins,cells,and informational

pathwaysin living organismsto eliminate or prevent disease,

producehigher yield crops,or increasethe productivity of ani-

mal productsandmeat.

Biotechnology and its applications raise a host of social, eth-

ical, and legal questions; for example, genetic privacy, germline

genetic engineering, cloning animals, genes that influence

behavior, cost of therapeutic drugs generated by biotechnol-

ogy, animal rights, and the nature and control of intellectual

property.

The challenge clearly is to educate society so that each cit-

izen can thoughtfully and rationally deal with these issues,

for ultimately society dictates the resources and regulations

that circumscribe the development and practice of biotechnol-

ogy. mtimately, I feel enormous responsibility rests with sci-

entists to inform and educate society about the challenges as

well as the opportunities arising from biotechnology. These

are critical issues for biotechnology that are developed in de-

tail in the Encyclopedia of Ethical, Legal, and Policy ]ssues in

Biotechnology.

The view that biotechnology is an informational science

pervades virtually every aspect of this science-including

discovery, reduction to practice, and societal concerns. These

Encyclopedias of Biotechnology reinforce the emerging in-

formational paradigm change that is powerfully positioning

science as we move into the twenty-first century to more

effectively decipher and manipulate for humankind's benefit

the biological information of relevant living organisms.

LEROYHOOD

UniversityofWashington

CONTRIBUTORS

Hanna E.Abboud, University of Texas, Health Science Center, San Antonio,

Sankar Adhya, National Cancer Institute, National Institutes of Health,

Bethesda, MD

Hiroji Aiba, Nagoya University, Chikusa, Nagoya, Japan

Philip Aisen, Albert Einstein College of Medicine, Bronx, NY

Rudolf K. Allemann, University of Birmingham, Birmingham, United

Kingdom

Nicholas Allen, The Babraham Institute, Cambridge, United Kingdom

Suresh Ambudkar, National Cancer Institute, National Institutes of Health,

Bethesda, MD

Vernon E. Anderson, Case Western Reserve University, Cleveland, OH

Berlil Andersson, Stockholm University, Stockholm, Sweden

Ruth Hogue Angeletti, Albert Einstein College of Medicine, Bronx, NY

Rodolfo Aramayo, schering-Plough Research Institute, Kenilworth, NJ

Yari Argon, University of Chicago, Chicago, IL

K. Arora, University of California, Irvine, CA

leonie K. Ashman, Hanson Center for Cancer Research, Adeleide, Australia

John F. Atkins, University of Utah, Salt Lake City, UT

William M. Atkins, University of Washington, Seattle, WA

Daniel Atkinson, UCLA, Los Angeles, CA

David Auld, Harvard Medical School, Boston, MA

Paul Babitzke, Pennsylvania State University, University Park, PA

Andrew Baird, Prizm Pharmaceuticals, San Diego, CA

Stacey JoBaker, Temple University School of Medicine, Philadelphia, PA

Tom Baldwin, Texas A&M University, College Station, TX

Michael Bamshad, University of Utah Health Sciences Center, Salt Lake

City, UT

Probal Banerjee, College of Staten Island, New York, NY

Ruma Banerjee, University of Nebraska, Lincoln, NE

William RoBauer, University of California, San Francisco, CA

Christopher Baum, Heinrich-Pette Institut, Hamburg, Germany

Edward A. Bayer, Weizmann Institute of Science, Rehovot, Israel

Miguel Beato, Philipps-Universitaet Marburg, Institut fuer Molekularbiolo-

gie, Marburg, Germany

Dorothy Beckett, University of Maryland, Baltimore, MD

Samuel Benchimol, University of Toronto, Toronto, Ontario, Canada

Steven JoBenkovic, Pennsylvania State University, University Park, PA

Tomas Bergman, Karolinska Institutet, Stockholm, Sweden

Gerald Bergtrom, University of Wisconsin, Milwaukee, WI

Alan Bernstein, Mount Sinai Hospital, Toronto, Ontario, Canada

Harris Do Bernstein, NIDDKD, National Institutes of Health, Bethesda, MD

Sophie Bertrand, Universiteit Gent, Gent, Belgium

D. M. Bethea, Thomas Jefferson University, Philadelphia, PA

Dieter Beyer, Rhone Poulenc Rorer Recherche Developpement, Vitry-sur-

Seine, France

Timothy R. Billiar, University of Pittsburgh Medical Center, Pittsburgh, PA

Asgeir Bjornsson, University of Aarhus, Aarhus, Denmark

Colin C. FoBlake, Norfolk, United Kingdom

F. Bonomi, Universita Degli Studi Di Milano, Milano, Italy

Ralph A. Bradshaw, University of California, Irvine, CA

Bertram Brenig, Georg-August University, Gottingen, Germany

Kenneth J. Breslauer, Rutgers University, Piscataway, NJ

Roy J. Britten, California Institute of Technology, Corona del Mar, CA

Maurizio Brunori, University of Rome, "La Sapienza, " Rome, Italy

Bernd Bukau, Albert-Ludwigs Universitat Freiburg, Freiburg, Germany

Jens R. Bundgaard, University of Copenhagen, Copenhagen, Denmark

Arsene Burny, Universite Libre de Bruxelles, Rhode Saint Genese, Belgium

Kenneth Burtis, University of California, Davis, CA

Ana Busturia, Universidad Aut noma de Madrid, Madrid, Spain

Giulio L. Cantoni, NIMH, National Institutes of Health, Bethesda, Ma

M. Stella Carlomango, Universita Degli Studi Di Napoli Federico II, Napoli,

Italy

Gerald M. Carlson, University of Missouri, Kansas City, MO

Graham Carpenter, Vanderbilt University, Nashville, TN

Robin W. Carrell, University of Cambridge, Cambridge, United Kingdom

James Castelli-Gair, University of Cambridge, Cambridge, United Kingdom

Enrique Cerda-Olmedo, Universidad de Sevilla, Sevilla, Spain

Jonathan Chaires, University of Mississippi Medical Center, Jackson, MS

Kung-Yao Chang, MRC Laboratory of Molecular Biology, Cambridge,

United Kingdom

Lee Chao, Medical University of South Carolina, Charleston, SC

Ansuman Chattopadhyay, Vanderbilt University School of Medicine,

Nashville, TN

Walter Chazin, Scripps Research Institute, La Jolla, CA

Elizabeth H. Chen, University of Texas, Southwestern Medical Center,

Dallas, TX

Donald P. Cheney, Northeastern University, Boston, MA

Andreas Chrambach, National Institutes of Health, Bethesda, Ma

Jason Christiansen, Virginia Polytechnic Institute, Blacksburg, VA

Jon A. Christopher, Texas A&M University, College Station, TX

Brian F. C. Clark, Aarhus University, Aarhus, Denmark

Dennis Clegg, University of California, Santa Barbara, CA

F. Cliften, University of Colorado Health Sciences Center, Denver, CO

Georges N. Cohen, Institut Pasteur, Paris, France

Roberta Colman, University of Delaware, Newark, DE

Orla M. Conneely, Baylor College of Medicine, Houston, TX

Barry S. Cooperman, University of Pennsylvania, Philadelphia, PA

Pamela Correll, The Pennsylvania State University, University Park, PA

Pascale Cossart, Institut Pasteur, Paris, France

Nancy Craig, Johns Hopkins University, Baltimore, Ma

Elliott Crooke, Georgetown University, Washington, DC

Stanley T. Crooke, 1515Pharmaceuticals, Inc., Carlsbad, CA

Richard D. Cummings, University of Oklahoma, Oklahoma City, OK

James Curran, Wake Forest University, Winston-Salem, NC

Michael A. Cusanovich, University of Arizona, Tucson, AZ

Giuseppe D'Alessio, Universita di Napoli Federico II, Napoli, Italy

Antoine Danchin, Institut Pasteur, Paris, France

vii

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