Encyclopedia of Bioprocess Technology.pdf

ENCYCLOPEDIA OF

BIOPROCESS TECHNOLOGY:

FE RM ENTATION, BIOCATALYSIS,

AND

BIOSEPARATION

VOLUMES 1 - 5

Michael C. Flickinger

University of Minnesota

St. Paul, Minnesota

Stephen W. Drew

Merck and Co., Inc.

Rahway, New Jersey

A Wiley-Interscience Publication

John Wiley & Sons, Inc.

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

This book is printed on acid-free paper. A

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Flickinger, Michael C.

The encyclopedia of bioprocess technology : fermentation,

biocatalysis, and bioseparation / Michael C. Flickinger, Stephen W.

Drew.

p. cm.

Includes index.

ISBN 0-471-13822-3 (alk. paper)

1. Biochemical engineering--Encyclopedias. I. Drew, Stephen W.,

1945- . II. Title.

TP248.3.F57 1999

660.6 03--dc21

99-11576

CIP

Printed in the United States of America.

10987654321

WILEY BIOTECHNOLOGY ENCYCLOPEDIAS

Encyclopedia of Bioprocess Technology: Fermentation, Biocatalysis, and Bioseparation

Edited by Michael C. Flickinger and Stephen W. Drew

Encyclopedia of Molecular Biology

Edited by Thomas E. Creighton

Encyclopedia of Cell Technology

Edited by Raymond E. Spier

Encyclopedia of Ethical, Legal, and Policy Issues in Biotechnology

Edited by Thomas J. Murray and Maxwell J. Mehlman

ENCYCLOPEDIA OF BIOPROCESS TECHNOLOGY:

FERMENTATION, BIOCATALYSIS, AND BIOSEPARATION

EDITORIAL BOARD

Chairman

Elmer Gaden, Jr.

University of Virginia, Charlottesville

Edward L. Cussler

University of Minnesota

Jonathan S. Dordick

Rensselaer Polytechnic Institute

Bryan Grifﬁths

Centre for Applied Microbiology and Research

Lars Hagel

Amersham Pharmacia

Zhao Kai

National Vaccine and Serum Institute

Subash B. Karkare

AMGEN

Murry Moo-Young

University of Waterloo

Tetsuo Oka

Kyowa Hakko Kogyo Co., Ltd.

Karl Schugerl

University of Hannover

Atsuo Tanaka

Kyoto University

Kathryn Zoon

U.S. Food and Drug Administration

Associate Editors

H.W. Blanch

University of California, Berkeley

Yusuf Chisti

University of Almer´a

Arnold Demain

Massachusetts Institute of Technology

Peter Dunnill

Advanced Centre for Biochemical Engineering

David Estell

Khepri Pharmaceuticals

Csaba Horvath

Yale University

Arthur E. Humphrey

Pennsylvania State University

Bjorn K. Lydersen

Irvine Scientiﬁc

Poul B. Poulson

Novo Nordisk

Dane Zabriskie

Biogen, Inc.

Series Editor

Leroy Hood

University of Washington

Editorial Board

Stuart E. Builder

Strategic Biodevelopment

John R. Birch

Lonza Biologics

Charles L. Cooney

Massachusetts Institute of Technology

Editorial Staff

Publisher: Jacqueline I. Kroschwitz

Managing Editor: Camille Pecoul Carter

Editor: Glenn Collins

Editorial Assistant: Hugh Kelly

PREFACE

The Wiley Biotechnology Encyclopedias, composed of

the Encyclopedia 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 para-

digm changes.

Biotechnology is now beginning to be viewed as an in-

formational science. In a simplistic sense there are three

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

linear information 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 chromo-

somes or our expressed genes (or mRNAs) generates infor-

mation of several distinct types: genes, regulatorymachin-

ery, and information that enables chromosomes to carry

out their tasks as informational organelles (e.g., centrom-

eric 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. Pro-

teins pose four technical challenges: ( 1 ) Proteins are syn-

thesized as linear strings and fold into precise three-di-

mensional structures as dictated by the order of amino acid

residues in the string. Can we formulate the rules for pro-

tein folding to predict three-dimensional structure from

primary amino acid sequence? The identiﬁcation and com-

parative analysis of all human and model organism (bac-

teria, yeast, nematode, ﬂy, mouse, etc.) genes and proteins

will eventually lead to a lexicon of motifs that are the build-

ing block components of genes and proteins. These motifs

will greatly constrain the shape space that computational

algorithms 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 10–15 years. ( 2 ) Can we predict pro-

tein function from knowledge of the three-dimensional

structure? Once again the lexicon of motifs with their func-

tional as well as structural correlations will play a critical

role in solving this problem. ( 3 ) How do the myriad of

chemical modiﬁcations of proteins (e.g., phosphorylation,

acetylation, etc.) alter their structures and modify their

functions? The mass spectrometer will play a key role in

identifying secondary modiﬁcations. ( 4 ) How do proteins

interact with one another and/or with other macromole-

cules to form complex molecular machines (e.g., the ribo-

somal subunits)? If these functional complexes can be iso-

lated, the mass spectrometer, coupled with a knowledge of

all protein sequences that can be derived from the com-

plete genomic sequence of the organism, will serve as a

powerful tool for identifying all the components of complex

molecular machines.

The third type of biological information arises fromcom-

plex biological systems and networks. Systems informa-

tion is four dimensional because it varies with time. For

example, the human brain has 1,012 neurons making ap-

proximately 1,015 connections. From this network arise

systems properties such as memory, consciousness, and

the ability to learn. The important point is that systems

properties cannot be understood from studying the net-

work elements (e.g., neurons) one at a time; rather the col-

lective behavior of the elements needs to be studied. To

study most biological systems, three issues need to be

stressed. First, most biological systems are too complex to

study directly, therefore they must be divided into tracta-

ble subsystems whose properties in part reﬂect those of the

system. These subsystems must be sufﬁciently small to an-

alyze all their elements and connections. Second, high-

throughput analytic or global tools are required for study-

ing many systems elements at one time (see later). Finally,

the systems information needs to be modeled mathemati-

cally before systems properties can be predicted and ulti-

mately understood. This will require recruiting computer

scientists and applied mathematicians into biology—just

as the attempts to decipher the information of complete

genomes and the protein folding and structure/function

problems have required the recruitment of computational

scientists.

I would be remiss not to point out that there are many

other molecules that generate biological information:

amino acids, carbohydrates, lipids, and so forth. These too

must be studied in the context of their speciﬁc structures

and speciﬁc functions.

The deciphering and manipulation of these various

types of biological information represent an enormous

technical challenge for biotechnology. Yet major new and

powerful tools for doing so are emerging.

One class of tools for deciphering biological information

is termed high-throughput analytic or global tools. These

tools can be used to study many genes or chromosome fea-

tures (genomics), many proteins (proteomics), or many

cells rapidly: large-scale DNA sequencing, genomewide

genetic mapping, cDNA or oligonucleotide arrays, two-

dimensional gel electrophoresis and other global protein

separation technologies, mass spectrometric analysis of

proteins and protein fragments, multiparameter, high-

throughput cell and chromosome sorting, and high-

throughput phenotypic assays.

A second approach to the deciphering andmanipulation

of biological information centers around combinatorial

strategies. The basic idea is to synthesize an informational

string (DNA fragments, RNA fragments, protein frag-

ments, antibody combining sites, etc.) using all combina-

tions of the basic letters of the corresponding alphabet,

thus creating many different shapes that can be used to

activate, inhibit, or complement the biological functions of

designated three-dimensional shapes (e.g., a molecule in a

signal transduction pathway). The power of combinational

chemistry is just beginning to be appreciated.

PREFACE

A critical approach to deciphering biological informa-

tion will ultimately be the ability to visualize the function-

ing of genes, proteins, cells, and other informational ele-

ments within living organisms (in vivo informational

imaging).

Finally, there are the computational tools required to

collect, store, analyze, model, and ultimately distribute the

various types of biological information. The creation pres-

ents a challenge comparable to that of developing new in-

strumentation and new chemistries. Once again this

means recruiting computer scientists and applied mathe-

maticians to biology. The biggest challenge in this regard

is the language barriers that separate different scientiﬁc

disciplines. Teaching biology as an informational science

has been a very effective means for breeching these bar-

riers.

The challenge is, of course, to decipher various types of

biological information and then be able to use this infor-

mation to manipulate genes, proteins, cells, and informa-

tional pathways in living organisms to eliminate or pre-

vent disease, produce higher-yield crops, or increase the

productivity of animals for meat and other foods.

Biotechnology and its applications raise a host of social,

ethical, and legal questions, for example, genetic privacy,

germline genetic engineering, cloning of animals, genes

that inﬂuence behavior, cost of therapeutic drugs gener-

ated by biotechnology, animal rights, and the nature and

control of intellectual property.

Clearly, the challenge is to educate society so that each

citizen can thoughtfully and rationally deal with these is-

sues, for ultimately society dictates the resources and reg-

ulations that circumscribe the development and practice of

biotechnology. Ultimately, I feel enormous responsibility

rests with scientists 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 detail in the Encyclopedia of Ethical,

Legal, and Policy Issues 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 emerg-

ing informational paradigm change that is powerfully po-

sitioning science as we move into the twenty-ﬁrst century

to more effectively decipher and manipulate for human-

kind’s beneﬁt the biological information of relevant living

organisms.

Leroy Hood

University of Washington

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