Table Of Content30 Advances in Biochemical Engineering/
Biotechnology
Managing Editor: A. Fiechter
ssecorpoiB
retemaraP Control
With Contributions yb
R ,lawargA .A Fiechter, .C ,reuertsnielK
.H .C Lim, .T ,ahgiewoP .S Shimizu,
.H Ursprung, .T 6namaY
With 88 Figures and 28 Tables
Springer-Verlag
Berlin Heidelberg New York Tokyo
4891
ISBN 3-540-13539-1 Springer-Verlag Berlin Heidelberg New York Tokyo
ISBN 0-387-13539-1 Springer-Verlag New York Heidelberg Berlin Tokyo
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2152/3020-543210
Managing Editor
Professor Dr. A. Fiechter
Institut ffir Biotechnologie
Eidgen6ssische Technische Hochschule,
H6nggerberg,
CH-8093 Zfirich
Editorial Board
Prof. Dr. S. Aiba Department of Fermentation Technology, Faculty of
Engineering, Osaka University. Yamada-Kami, Suita-
Shi, Osaka 565, Japan
Prof. Dr. B. Atkinson University of Manchester, Dept. Chemical Engineering,
Manchester;England
Prof. Dr. E. Bylink#~a Head of Technology Dept., National Institute of
Antibiotika. 3a Nagatinska Str., Moscow M-105/USSR
Prof. Dr. Ch. L. Coo~tey Massachusetts Institute of Technology.
Department of Chemical Engineering,
Cambridge. Massachusetts 02139~USA
Prof. Dr. H. Dellweg Techn. Universit/~t Berlin, Lehrstuhl fox
Biotechnologie, Seestral3e ,31 D-1000 Berlin 65
Prof. Dr. ,4. L. Dema#~ Massachusetts Institute of Technology, Dept. of
Nutrition & Food So., Room 56-125,
Cambridge, Mass. 02139:'USA
Prof. Dr. S. Fukui Dept. of Industrial Chemistry. Faculty of
Engineering, Sakyo-Ku, Kyoto 606, Japan
Prof. Dr. K. Kieslieh Wissenschaftl. Direktor, Ges. fiir Biotechnolog.
Forschung mbH. Mascheroder Weg ,1
D-3300 Braunschweig
Prof. Dr. R. M. Lafferty Techn. Hochschule Graz, Institut for
Biochem. Technol., Schl6gelgasse 9, A-8010 Graz
Prof. Dr. K. Mosbach Biochemical Div., Chemical Center. University of kund,
S-22007 Lund/Sweden
Prof. Dr. H. J. Rehm Westf. Wilhelms Universit/it, Institut ffir
Mikrobiologie. Tibusstrage 7 ,51 D-4400 Mfinster
Prof. Dr. P. L. Rogers School of Biological Technology. The University
of New South Wales. PO Box .1
Kensington, New South Wales, Australia 2033
Prof. Dr. H. Sahm Institut ffir Biotechnologie, Kernforschungsanlage
Jfilich, D-5170 Jfilich
Prof. Dr. K. Schiigerl Institut f/.ir Technische Chemic, Universit/it Hannover,
CallinstraBe 3, D-3000 Hannover
Prof. Dr. H. Suomalainen Director, The Finnish State Alcohol Monopoly, Ako,
P.O.B. 350, 00101 Helsinki I0.,Finland
Prof. Dr. S. Suzuki Tokyo Institute of Technology,
Nagatsuta Campus. Research Laboratory of Resources
Utilization
4259, Nagatsuta, Midori-ku, Yokohama 227/Japan
Prof. Dr. H. Taguchi Faculty of Engineering. Osaka University, Yamada-kami,
Suita-shi, Osaka 565/Japan
Prof. Dr. G. 27 Tsao Director. Lab. of Renewable Resources Eng., A. A. Potter
Eng. Center, Purdue University, West Lafayette,
IN 47907/USA
Table of Contents
Editorial
A. Fiechter . . . . . . . . . . . . . . . . . . . . . .
Biotechnology: The New Chance for Industry
H. Ursprung . . . . . . . . . . . . . . . . . . . . .
Physical and Chemical Parameters of Microbial Growth
A. Fiechter . . . . . . . . . . . . . . . . . . . . . .
Analyses of Various Control Schemes for Continuous
Bioreactors
P. Agrawal, H. C. Lira . . . . . . . . . . . . . . . . . 61
Modeling and Simulation of Bioreactor Process Dynamics
C. Kleinstreuer, T. Poweigha . . . . . . . . . . . . . . 91
Fed-batch Techniques in Microbial Processes . . . . . . . . 147
T. Yamaha, S. Shimizu
Author Index Volumes 1-30 . . . . . . . . . . . . . . . 195
Editorial
Prof. Dr. Heinrich Ursprung is president of the Swiss Federal Institute of Technology
in Zurich (ETHZ). In this position, he is responsible for maintaining and developing
the standards of this educational and research institution.
Along with the departments of engineering, chemistry, pharmacy, forestry, agri-
culture, mathematics and physics, a faculty of sciences is also a part of the ETHZ.
The foresighted view of President Ursprung made it possible to develop within this
latter department, a special curriculum and thusa n additional degree in biotechnology.
Accordingly, a new institute for biotechnology was implemented at the satellite
campus H6nggerberg, as a neighbor to the already existing Institute of Cell Biology
and Institute of Molecular Biology.
2 lairotidE
The rearrangement of the existing faculties of an academic instituion is generally
not easy to perform, especially in biology where scientific progress is quite rapid
and modifications can be effected only with some delay. Also, situations at most
universities are usually not financially favorable to the promotion of quickly develop-
ing areas.
As a former cell biologist, Prof. Ursprung very early recognized when molecular
sciences had grown to a level for potential application in industry and the environ-
ment. He sees that engineering elements have to join the biological components in
order to furnish a sound basis for the applied area of biotechnology. Using his vast
experience as an academic leader, he has expressed his views in numerous lectures,
conversations, and article publications, thus becoming one of the most renowned
leaders of science policy.
A. Fiechter
Biotechnology: The New Chance for Industry
Heinrich Ursprung
President, Swiss Federal Institute of Technology (ETH) Z/irich, Switzerland
Generous support has been pouring into research on basic biology for decades.
It is not surprising that the question of its pay-off is asked with increasing insistence.
In other fields it has been customary to relate important technological breakthroughs
to cognate discoveries in basic science: this or that discovery, it is said, ,,was valorized'.
When will this happen in the Life Sciences? When and how will the epoch-making
discoveries of molecular, or "new" biology be valorized?
When we call interfer, ons as witnesses, we are just scratching the surface of a valoriz-
ing potential of unprecedented dimensions. One must realize what all has become
feasible by the discoveries of New Biology. (This term refers not only to the double
helix, gene-splicing, and monoclonal antibodies. It refers to the very introduction
of quantitative, molecular, and physical thinking into the Life Sciences; to our vast
knowledge of enzymology and more generally speaking, protein chemistry; to
the spectacular advances in immunology). The key to valorizing these discoveries
and insights is biotechnology. Its basic strategy is to scale up biological processes to
industrial dimensions, by adapting methods borrowed from process and control
engineering to biological processes. In this sense, biotechnology is not a natural
science, but an engineering science. Its finality lies not primarily in explaining and
understanding phenomena, but in producing things. A biotechnologist working on the
synthesis of insulin from human genes that were incorporated into bacteria is not
primarily interested in DNA surgery, but in industrial scale production of a better
insulin without having to rely on pancreas glands. He may want to scale up the
manufacturing process to the dimension of a 10'000 gallon fermenter. It should be
noted that in the process as a whole, the costs at the DNA surgery end amount to
perhaps 5 %. The subsequent steps of scaling-up and purification devour 95 % of
the financial effort. From the economical viewpoint it is therefore imperative to keep
improving the methodology of the latter.
It is true that the cases developed in recent years are relatively few: insulin, inter-
ferons, vaccines, growth hormones, to mention four. But our knowledge of metabolism
is vast, and there is no a priori reason to believe that all enzyme (and therefore, gene)
mediated reactions could not be scaled up by fermentation technology, enzyme
immobilization, and related techniques. Using enzymes derived from thermostable
organisms, heat denaturation problems encountered e.g. in the application for waste-
water treatment, can be overcome. By protein engineering, including the chemical
synthesis of novel genes, custom tailored enzymes with novel properties can be
constructed. There appears to be no theoretical limit. Protein engineering may also
lead to new approaches in extreme miniaturization, in a yet ill-defined area of so-
4 .H Ursprung
called biochips. In fact, chemistry-derived biology and physics-derived electronics-
may converge into bioelectronics, opening new markets for electronic devices carrying
biological specifity, as bioelectrodes or biosensors. The potential application in bio-
medical technology is vast.
It is self-evident that biotechnology is important for the fine-chemical industry.
It is also important for the pharmaceutical industry, not only in view of novepla thways
of synthesis, but of novel strategies for drug administration. Liposomes with built-in
antibodies against surfaces of target cells can carry their drugs to the right cells when
introduced into the bloodstream of a patient. The obvious advantage of this strategy
lies in the lower doses of drugs needed, and the concomitant lowering of unwanted
side effects.
Biotechnology will have an increasing impact on agrochemistry, too. Plant cell
culture techniques have been improved, and mass production of genetically defined
plantlets is becoming feasible; it will interest the seed industry. If crop plants resistant
to drought or disease can be produced in large quantities cheaply, their impact on
agriculture can be substantial. Other developments in crop science concern nitrogen
fixation by grasses including wheat and corn. Hopes are high that plant physiologists
and geneticists will succeed in enabling the roots of such crop plants to form symbioses
with soil bacteria, making them autonomous for nitrogen fixation, imitating legume
plants.
Biotechnological thinking has also entered the field of fuels. Will fuels be produced
by converting biomass on a large scale? Recent improvements in the degradation
rate of lignin look encouraging, as does the conversion of organic waste into precious
oxychemicals. Moreover, biotechnology is useful for a more efficient exploitation
of conventional fuel sources. Microorganisms that release surfactants are being used
for altering the adhesion between sand grains and oil droplets. This example, too,
shows that biotechnology is, because of its finality, an engineering science: the
objective in this case is not to understand the physiology of surfactant release, but to
exploit the biological phenomenon for large scale technical application.
In parallel to the development of techniques for scaling up, an instrumentation
industry is growing. Companies with expertise in chemical plant layout or the con-
struction of process equipment are diversifying their efforts into bioreactor design;
among the difficulties encountered are problems of sterilization. But the opportunities
are large, and they include not only reactor vessels, but entire control systems with
intricate sensors measuring those parameters that are crucial for optimizing the
process for high yields.
New scientific approaches of the dimension of biotechnology inevitably raise
questions of policy. While professors of chemistry or electrical engineering have a
long record of fruitful interactions with industry, for many biology professors the
opportunity is only recent. Old questions arisea new. Should biotechnology professors
serve as consultants to industry? Or does this constitute treason against acadelnia?
Should they found companies of their own ? Who provides the capital? Shouldi ndustry,
or should the University, create an '~ between the two? On or off campus,
as Science Parks or Research Parks? If a state-operated University enters the field:
is it distorting competition? Should it? What becomes of the potential income from
such activities? Does it go into the pocket of the professor, his University, the State,
or industry? What in biotechnology may be patented? Organism? Genomes?
:ygolonhcetoiB The weN Chance for Industry 5
Whatever the questions, the answers should come quickly. Delays could be very
costly to the economy. In several countries, particularly Japan and the United States,
hundreds of new companies have been created in recent years in the area of bio-
technology. Many of them enjoy the expertise of scientists who left their Universities.
In other countries this approach has not been chosen to any extent thus far. There,
the problems of transferring biotechnological know-how from Universities to practice
remain to be solved. Of course, the normal way of this transfer is to train students
and release them from the University. This is a slow process, however, and it functions
only if Universities are sufficiently quick in establishing the necessary curricula.
Those that have done this may expedite the transfer by offering training courses for
staff now employed in industry. This requires decisions on the part of industry to
move in the direction of biotechnology. My observations indicate that this, too,
is less the case in Europe than in Japan and the United States.
It is nevertheless encouraging to note that in Europe, both science promotion
agencies and University authorities are increasingly aware of the vast potential of
biotechnology. Some of them have begun to support it substantially. Supporting
biotechnology in itself means making an early pay-off more likely. Support bio-
technology !
