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The roots - A short history of industrial microbiology and biotechnology
Article in Applied Microbiology and Biotechnology · March 2013

DOI: 10.1007/s00253-013-4768-2 · Source: PubMed
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AUTHOR'S PROOF!
Metadata of the article that will be visualized in OnlineFirst
1 Article Title The roots—a short history of industrial microbiology and

biotechnology
2 Article Sub- Title
3 Article Copyright - Springer-Verlag Berlin Heidelberg 2013
Year (This w ill be the copyright line in the final PDF)
4 Journal Name Applied Microbiology and Biotechnology
5 Family Name Buchholz
6 Particle
7 Given Name Klaus
8 Suffix
Corresponding
9 Organization Technical University of Braunschweig
Author
10 Division Institute for Chemical Engineering
11 Address Hans-Sommer Str. 10, Braunschweig 38106,
Germany
12 e-mail k.buchholz@tu-bs.de
13 Family Name Collins
14 Particle
15 Given Name John
16 Suffix
17 Author Organization Technical University of Braunschweig
18 Division Life Science Faculty, c/o Helmholtz Centre for
InfectionResearch - HZI, AG Directed Evolution
19 Address Inhoffenstr. 7, Braunschweig 38124, Germany
20 e-mail tojohncollins@gmail.com
21 Received 20 December 2012
22 Schedule Revised 8 February 2013
23 Accepted 9 February 2013
24 Abstract Early biotechnology (BT) had its roots in fascinating discoveries,
such as yeast as living matter being responsible for the
fermentation of beer and wine. Serious controversies arose between
vitalists and chemists, resulting in the reversal of theories and
paradigms, but prompting continuing research and progress.
Pasteur’s work led to the establishment of the science of
microbiology by developing pure monoculture in sterile medium,
AUTHOR'S PROOF!
and together with the work of Robert Koch to the recognition that a
single pathogenic organism is the causative agent for a particular
disease. Pasteur also achieved innovations for industrial processes
of high economic relevance, including beer, wine and alcohol.
Several decades later Buchner, disproved the hypothesis that
processes in living cells required a metaphysical ‘vis vitalis’ in
addition to pure chemical laws. Enzymes were shown to be the
chemical basis of bioconversions. Studies on the formation of
products in microbial fermentations, resulted in the manufacture of
citric acid, and chemical components required for explosives
particularly in war time, acetone and butanol, and further products
through fermentation. The requirements for penicillin during the
Second World War lead to the industrial manufacture of penicillin,
and to the era of antibiotics with further antibiotics, like
streptomycin, becoming available. This was followed by a new
class of high value-added products, mainly secondary metabolites,
e.g. steroids obtained by biotransformation. By the mid-twentieth
century, biotechnology was becoming an accepted specialty with
courses being established in the life sciences departments of
several universities. Starting in the 1970s and 1980s, BT gained
the attention of governmental agencies in Germany, the UK,
Japan, the USA, and others as a field of innovative potential and
economic growth, leading to expansion of the field. Basic research
in Biochemistry and Molecular Biology dramatically widened the
field of life sciences and at the same time unified them
considerably by the study of genes and their relatedness throughout
the evolutionary process. The scope of accessible products and
services expanded significantly. Economic input accelerated
research and development, by encouraging and financing the
development of new methods, tools, machines and the foundation
of new companies. The discipline of ‘New Biotechnology’ became
one of the lead sciences. Although biotechnology has historical
roots, it continues to influence diverse industrial fields of activity,
including food, feed and other commodities, for example polymer
manufacture, biofuels and energy production, providing services
such as environmental protection, and the development and
production of many of the most effective drugs. The understanding
of biology down to the molecular level opens the way to create
novel products and efficient environmentally acceptable methods
for their production.
25 Keywords Biotechnology - History - Fermentation theories - Industrial
separated by ' - ' microbiology - Genetic techniques - Biotech companies
26 Foot note
information
AUTHOR'S PROOF! JrnlID 253_ArtID 4768_Proof# 1 - 19/02/2013
Appl Microbiol Biotechnol

DOI 10.1007/s00253-013-4768-2
1
3 MINI-REVIEW
2
4 The roots—a short history of industrial microbiology

5 and biotechnology
7 Klaus Buchholz & John Collins
8 Received: 20 December 2012 / Revised: 8 February 2013 / Accepted: 9 February 2013
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9 # Springer-Verlag Berlin Heidelberg 2013
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10
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11 Abstract Early biotechnology (BT) had its roots in fasci- mainly secondary metabolites, e.g. steroids obtained by 36
12 nating discoveries, such as yeast as living matter being biotransformation. By the mid-twentieth century, biotech- 37
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13 responsible for the fermentation of beer and wine. Serious nology was becoming an accepted specialty with courses 38
14 controversies arose between vitalists and chemists, resulting being established in the life sciences departments of several 39
15 in the reversal of theories and paradigms, but prompting D universities. Starting in the 1970s and 1980s, BT gained the 40
16 continuing research and progress. Pasteur’s work led to the attention of governmental agencies in Germany, the UK, 41
17 42
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establishment of the science of microbiology by developing Japan, the USA, and others as a field of innovative potential
18 pure monoculture in sterile medium, and together with the and economic growth, leading to expansion of the field. 43
19 work of Robert Koch to the recognition that a single path- Basic research in Biochemistry and Molecular Biology dra- 44
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20 ogenic organism is the causative agent for a particular matically widened the field of life sciences and at the same 45
21 disease. Pasteur also achieved innovations for industrial time unified them considerably by the study of genes and 46
22 processes of high economic relevance, including beer, wine their relatedness throughout the evolutionary process. The 47
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23 and alcohol. Several decades later Buchner, disproved the scope of accessible products and services expanded signif- 48
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24 hypothesis that processes in living cells required a meta- icantly. Economic input accelerated research and develop- 49
25 physical ‘vis vitalis’ in addition to pure chemical laws. ment, by encouraging and financing the development of 50
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26 Enzymes were shown to be the chemical basis of biocon- new methods, tools, machines and the foundation of new 51
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27 versions. Studies on the formation of products in microbial companies. The discipline of ‘New Biotechnology’ became 52
28 fermentations, resulted in the manufacture of citric acid, and one of the lead sciences. Although biotechnology has histor- 53
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29 chemical components required for explosives particularly in ical roots, it continues to influence diverse industrial fields of 54
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30 war time, acetone and butanol, and further products through activity, including food, feed and other commodities, for 55
31 fermentation. The requirements for penicillin during the example polymer manufacture, biofuels and energy produc- 56
32 Second World War lead to the industrial manufacture of tion, providing services such as environmental protection, and 57
33 penicillin, and to the era of antibiotics with further antibi- the development and production of many of the most effective 58
34 otics, like streptomycin, becoming available. This was drugs. The understanding of biology down to the molecular 59
35 followed by a new class of high value-added products, level opens the way to create novel products and efficient 60
environmentally acceptable methods for their production. 61
K. Buchholz (*)
Q1 Institute for Chemical Engineering, Keywords Biotechnology . History . Fermentation theories . 62
Technical University of Braunschweig, Hans-Sommer Str. 10, Industrial microbiology . Genetic techniques . Biotech 63
38106 Braunschweig, Germany
companies 64
e-mail: k.buchholz@tu-bs.de
J. Collins
Life Science Faculty, c/o Helmholtz Centre Introduction 65
for InfectionResearch - HZI, AG Directed Evolution,
Technical University of Braunschweig, Inhoffenstr. 7,
38124 Braunschweig, Germany Fermentation has been of great practical and economic 66
e-mail: tojohncollins@gmail.com relevance as a handicraft for thousands of years, notably 67
AUTHOR'S PROOF!
JrnlID 253_ArtID 4768_Proof# 1 - 19/02/2013
68 the production of beer, wine and bread. The written first the fact that several compounds act in harmony with each 118
69 document was by the Sumerians 6,000 years ago and de- other, others in opposition to each other, so that the first 119
70 scribes the technique of brewing (Bud 1993). Beer and wine attract, the latter reject each other’. Kützing (1837, pp. 396, 120
71 manufacture was economically so important in ancient 397) believed that ‘… organic entities (living organisms) 121
72 Mesopotamia and Egypt that it became a major source of can form themselves by spontaneous generation …’, and he 122
73 tax revenue. Soya fermentation was established in China assumed two forces, the ‘organizing living force, and the 123
74 around 3500 BP. Due to its great practical relevance alco- chemical affinity, fighting each other …’, and Quevenne 124
75 holic fermentation was of major technical as well as scien- (1838, p.469) used the term ‘secret of life’. In contrast to 125
76 tific interest. Controversies over basic concepts, e.g. the vitalist school, Liebig, the head of the chemical school, 126
77 vitalism versus materialism in chemistry and biology, vigorously argued against the concept of living bodies being 127
78 resulted in the establishment, and reversal of theories and active in fermentation processes and advanced his erroneous 128
79 paradigms, but finally lead to scientific rationalisation of theory of ferments that supposed a body undergoing decom- 129
80 causality, and continuous technical progress, resulting in position which transfers its disturbed equilibrium onto other 130
81 the emergence of BT. metastable substances (Liebig 1839). In his book on chem- 131
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ical technology, Knapp (1847, p. 271) came to the conclu- 132
sion that ‘no one of the … hypotheses is up to now accepted 133
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82 The early period till 1850—fermentation mysteries as unequivocal truth’. 134
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The importance of fermentation processes corresponds 135
83 Leeuwenhook, about 1680, had observed, with the aid of his with the large sections that were devoted to the topic in 136
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84 microscope, tiny ‘animalcules’ in droplets of liquids, which the books on technology and chemical engineering of the 137
85 he, however, did not associate with fermentation. Then, in time (Otto 1838; Poppe 1842; Knapp 1847; Wagner 1857; 138
86 the second half of the eighteenth century Spallanzani under- Payen, 1874). Knapp (1847, p.367) reported that brewing
D 139
87 took microscopic investigations of many specimens, includ- was performed in Germany at the level of handicraft, esti- 140
88 141
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ing sperm and microbial growth. By the end of the mated at a volume of about 22.7 million hectolitres (2,27
89 eighteenth and beginning of the nineteenth centuries, re- million m3) in 1840, whereas in the UK it was carried out on 142
90 spectively, Lavoisier and Gay-Lussac had elaborated quan- an industrial scale in large factories with fermenters of up to 143
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91 titative correlations for alcoholic fermentation, without 240,000 L. Particularly beer, as well as wine, acetic and 144
92 giving explanations for the process underlying it. From the lactic acid production contributed significantly to the na- 145
93 mid-1830s evidence began to accumulate which pointed to tional economies. A ‘fast acetic acid manufacture’ 146
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94 the biological nature of fermentation. Based on well- (‘Schnellessigfabrikation’) was developed by Schützenbach 147
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95 designed experiments, Schwann (1837) and Cagniard- in 1823. It worked, remarkably, with active acetic acid bacte- 148
96 Latour (1838) independently showed that yeast is a micro- ria (of course not recognized at that time) immobilized on 149
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97 organism, an ‘organized’ body, and that alcoholic fermenta- beechwood chips (Ost 1900). 150
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98 tion is linked to living yeast. Both observed the yeast of beer Unformed, or unorganized ferments, obviously non- 151
99 being little globular bodies able to reproduce themselves, living matter, different from yeast, enzymes in today’s 152
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100 excluding spontaneous generation, and presenting a theory terms, were recognized and further characterized. Notably 153
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101 on fermentation corresponding in essential parts to that diastase, of which small amounts were able to liquify large 154
102 which Pasteur put forward about two decades later (for an amounts of starch was studied in detail (Payen 1874). 155 Q2
103 extended overview, see Buchholz and Collins 2010, part I). Further, enzymes described were, e.g. ‘emulsin’ (in Liebig 156 Q3
104 Many other scientists, including Kützing, Turpin and 1839) and pepsin (in Schwann 1836a, b) (see Buchholz and 157
105 Quevenne, contributed significant advances in understand- Poulson 2000). The first industrial processes that used 158
106 ing fermentation, confirming that living organisms were enzymes (diastase) to produce dextrins were established 159
107 involved in fermentation processes other than that leading from the 1830s onwards in France, based on Payen’s work 160
108 to alcohol, e.g., in acetic acid fermentation. However, their (Knapp 1847). 161
109 arguments were often confused by mystic concepts, in par- The most relevant events of this period are summarized 162
110 ticular that fermentation emerges from spontaneous genera- in Table 1. 163
111 tion, and is a consequence of a ‘secret living force’ (in
112 contrast to chemical forces), a that view promoted, e.g.
113 Gay-Lussac (Buchholz and Collins 2010, chapter 2). The The period from 1850 to 1890—the emergence 164
114 mysterious concepts are obvious from a textbook by Poppe of microbiology as a science 165
115 (1842, p. 229): ‘Fermentation is seen as a—at a time and
116 under circumstances spontaneous - occurring mighty move- It was only with Pasteur’s work that the scientific debate on 166
117 ment in a liquid of different compounds …, which is due to the nature of fermentation was settled in favor of the role of 167
Q5 t1:1 Table 1 Dates and events in early biotechnology
t1:2 Ancient handicraft
t1:3 6000 BC Beer fermentation

t1:4 3500 BC Wine fermentation
t1:5 3500 BC Soja fermentation
t1:6 Cheese and bread fermentation
t1:7 Fourteenth century Industrial acetic acid fermentation
t1:8 Early period up to 1850 Technical application
t1:9 Scientific events
t1:10 1680 Leeuwenhoek observes microorganisms
t1:11 1783 Spallanzani observed protease action
t1:12 1793 Lavoisier and
t1:13 1810 Gay-Lussac: quantitative chemistry of alcoholic fermentation Gay- Early eighteenth century: technical beer and wine fermentation;
Lussac: hypothesis of spontaneous generation also industrial beer fermentation
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t1:14 1833 Payen and Persoz: diastase (enzyme) characterization 1823 Immobilized bacteria used for acetic acid production
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t1:15 1836 Berzelius: catalysis (including enzymes) a
t1:16 1837, 1838 Schwann, Cagniard-Latour: living cells as fermentation agents
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t1:17 1834, 1838 Kützing, Quevenne: hypotheses of spontaneous generation, (see
also before, Gay- Lussac); vital factor
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t1:18 1839 Liebig: chemical decay hypothesis 1840s industrial enzymatic dextrin production (Payen)
t1:19 1830s Major controversy on fermentation theories
a
Berzelius (1836) D
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168 living microorganisms, starting from hypotheses based on must provide the nutrients for the microorganism; and (5) 197
169 empirical results provided by sophisticated experiments and specific chemical features characterized by the main fermen- 198
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170 ingenious theoretical conclusions. Pasteur’s outstanding ac- tation products and by products (Pasteur 1857a, b). 199
171 complishments have been documented in several biogra- One of the mysteries of fermentation had remained highly 200
172 phies, e.g. (Birch et al. 1990) and Geison (1995). The first controversial, the hypothesis of a ‘generatio spontanea’, spon- 201
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173 basic question which Pasteur definitively answered was that taneous generation of living organisms. Pasteur (1862) 202
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174 of the origin and character of fermentation: Was it brought addressed this basic and controversial question efficiently. 203
175 about by living microorganisms, or by pure chemical phe- He referred to Schwann and others whose ‘serious work’ he 204
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176 nomena, as Liebig, Berzelius and their school believed? In repeated and confirmed, with significant experimental modi- 205
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177 the 1850s, Pasteur had visited a factory for alcohol production fications (see also Geison 1995 p. 115). In addition to highly 206
178 on a nearly daily basis and took samples of the fermentation precise experiments using various methods, Pasteur undertook 207
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179 broth which he investigated in his laboratory. Losses in alco- something of a show in 1860 with expeditions to high altitude 208
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180 holic fermentation were an initial stimulus to work on a mountains, most spectacularly to the Alps and the glacier Mer 209
181 scientific explanation and on finding technical solutions. de Glace, to demonstrate the existence of germ free air, in 210
182 After numerous microscopical observations, he observed contrast to air under normal conditions carrying germs causing 211
183 yeast buds in normal fermentation runs, but rods that he soon infection in sugar juices (and in fermentation). The results of 212
184 identified as lactic acid ‘yeast’, when the fermentation ‘ran these experiments were presented by Pasteur first in a lecture 213
185 sour’ (due to the formation of acetic or lactic acid) (Pasteur to the Société Chimique de Paris in 1861 and then in a famous 214
186 1857b). He investigated lactic acid fermentation in detail. In lecture at the Sorbonne in 1864, a demonstrative performance 215
187 his paper on the topic, Pasteur (1857a) elaborated the essen- for ‘tout Paris’. ‘The finding of yeasts and their living nature, 216
188 tials of fermentation processes. He presented the means with as well as the knowledge of their origin, eliminates the mys- 217
189 which to isolate microorganisms in a pure culture. In his tery of the spontaneous occurence of fermentations of natural 218
190 discussion he introduced (1) the biological conception of sugar juices…’ (Pasteur 1876, pp. 229, 230). Pasteur made a 219
191 fermentation as the result of the activity of living microorgan- radical attack against the chemical school, with Liebig as the 220
192 isms; (2) he discussed the practice of inoculation for starting a head, this being the central arena of dispute on fermentation 221
193 reliable fermentation, that was also common practice in beer (Pasteur 1860; Geison 1995). 222
194 fermentation; (3) the notion of specificity, according to which Pasteur’s book Etudes sur la Bière (Pasteur 1876) gave a 223
195 each fermentation could be traced to a specific microbe; (4) thorough experimental, theoretical and scientific account of 224
196 the essential experimental factor that the fermentation medium his investigations, results, and conclusions. He developed 225
AUTHOR'S PROOF!
226 technical solutions to a number of practical problems, and Although the application of fermentation processes was 253
227 explained his motives in doing so. His findings, and their well established, there were still problems with the manu- 254
228 establishment, may be considered to be a new paradigm facture and quality of the most important products, alcohol, 255
229 guiding further research. Pasteur thus laid the foundations beer and wine. Considerable losses occurred in factories 256
230 of a new scientific discipline, microbiology, known as bac- producing alcohol from beet, when the juice was turning 257
231 teriology at the time (Delaunay 1951, Avant-propos, p. 22). sour. Early in his investigations on fermentation, Pasteur 258
232 Among others, Berthelot (1860, 1864) and Béchamp (1864) was engaged in several industrial problems. They were sub- 259
233 published a range of relevant papers on fermentation, e.g. of jects of highly accurate and meticulous scientific investiga- 260
234 substrates other than sugar. tions by Béchamp and Pasteur and led to the solution of the 261
235 However, one final mystery in fermentation remained: most urgent problems—an ingenious combination of scien- 262
236 the ‘vital force’ hypothesis linked all chemical transformations tific and technical progress with mutual interaction (Geison 263
237 in fermentations to a mysterious act depending on life, … 1995; Birch et al. 1990). Pasteur (1873; 1876, p. 328) 264
238 stating that the ‘chemical act of fermentation is essentially a patented his invention of a closed vessel for brewing to 265
239 phenomenon correspondent to a vital act, beginning and protect the fermentation process from air-borne infections 266
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240 ending with the latter’ (Pasteur 1876, pp. 229, 230, 306). (Fig. 1). 267
241 Several new active substances (enzymes) from different A range of fermentation products became an important 268
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242 sources (e.g. flowers and fruits, pancreas) were discovered, part of the overall economy in European, North American 269
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243 including invertase, lipase and fibrinolytic activities, and and Asian countries. At the end of the nineteenth century, 270
244 emulsin (Buchholz and Poulson 2000; Buchholz and Collins the fermentation industry was growing fast. It encompassed 271
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245 2010, chapter 3). By the 1870s, studies had established the the manufacture of beer and wine, industrial alcohol, yeast, 272
246 existence of two types of ferments. They became known as acetic and lactic acid, cheese, soy sauce and sake. Beer 273
247 unformed (unorganized) and formed (organized) ferments (the D manufacture represented one of the most important economic 274
248 latter referred to living bodies, such as yeast). The German activities. Thus in Germany, it had grown to 50 mn (million) 275
249 276
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physiologist, Willy Kühne (1877) referred to the pepsin type hL (hectoliter, 100 L) in 1890 (Ullmann 1915, p. 533). The
250 of unformed ferments as ‘enzymes’. production process was described in all technology text- 277
251 A summary of important scientific discoveries and appli- books of the nineteenth century. Wine was also an im- 278
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252 cations is given in Table 2. portant fermentation product, having a major economic 279
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Q4 t2:1 Table 2 The period from 1850 to 1890 (Scriban 1982, pp.13, 14; Buchholz and Collins 2010, chapters 3 and 4)
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t2:2 Time scientists Scientific findings, events Technical progress, industrial innovation
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t2:3 1837/1838 Schwann and Experimental demonstration of living yeast as agent in Growing importance of industrial fermentation of beer
Cagniard-Latour alcoholic fermentation (production 23 million hL in 1840, Germany) a
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t2:4 1850 Rayer and Davaine Detection of the origin of anthrax and the role of Technical-scale production of yeast, wine, soy sauce,
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microorganisms in diseases sake. Industrial-scale beer fermentation in GB

t2:5 1856–1877 Pasteur Investigations on fermentation (from 1856 on):
U
Investigations on alcohol fermentation (1858)

t2:6 Studies on spontaneous generation (1859–1862) 1870s: Hansen breeding pure yeast for commercial
application; 1874 Christian Hansen’s Laboratory
t2:7 Detection of anaerobic fermentation (1861) (Denmark): production of rennet (chymosin) for cheese
manufacture
t2:8 Studies on wine fermentation, invention of
t2:9 Pasteurisation (1864) Beer production: 36 million hectolitres in 1873, Germany
t2:10 Studies on beer fermentation (1871)
t2:11 Theory of fermentation (1876)
t2:12 Detection of facultative anaerobic fermentation of yeast New type of industrial beer fermenter (Pasteur; Fig. 1)
t2:13 1866 Mendel Heredity laws
t2:14 1876 Koch Work the bacterium leading to anthrax; agar plate method 1895 Wehmer: Lactic acid production
t2:15 1877-86 Pasteur Begin of investigations on anthrax (1877)
t2:16 1880 Winogradsky Soil microorganisms: the bacterial nature of nitrification
t2:17 1881 Pasteur Vaccination against anthrax and rabies
There are, of course, more scientists and events which have been relevant; however, inevitably, a selection must be made
a
1 hL corresponds to 100 L, or 0.1 m3
Fig. 1 Pasteur’s technical

fermenter (Pasteur 1876, p. 328)
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280 impact. The production around 1890 was estimated at 120 beginning of microbial diagnostics which involved specific 314
281 mn hL world wide, 113 mn hL in Europe, in France alone staining. 315
282 about 39 mn hL (Brockhaus 1895, vol. 16, pp. 591–595). D Ferments in terms of enzymes found application, diastase 316
283 Wine was attributed not only agreeable but also health on a major industrial scale, since the 1840s, a few others in 317
284 318
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effects when administered properly, e.g. a remarkable means the second half of the nineteenth century. The first company
285 for preserving the forces and improving the resistance to founded on an enzyme-based process was ‘Christian 319
286 infections. The physiology was described with ‘stimulation Hansen’s laboratory in Copenhagen (Denmark), so named 320
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287 of the nervous system and blood circulation, improving to this day. It pioneered the use of rennet (lab ferment, 321
288 or enhancing the subjective feeling and performance’ chymosin), for cheese manufacture (Brockhaus 1894b, vol. 322
289 (Brockhaus 1895, vol. 16, pp. 591–595). The alcohol pro- 10, p. 863; Poulson and Buchholz 2003). Further pancreas 323
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290 duction in Germany was estimated up to 3.7 million hL in enzymes, trypsin or pancreatin, and pepsin, isolated from 324
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291 1893/1894. An advanced technology had been developed pig or cow, were used as drugs, for example, as digestive 325
292 and applied in large factories: the process using starch as the aids. ‘Pepsin is a rational drug insofar… that a weekend 326
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293 raw material was operated at high pressure to ensure gelati- function of the stomach (dyspepsia) is enforced by little 327
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294 nization (Henzedämpfer.); hydrolysis was then achieved by doses of pepsin, and, in fact, numerous positive reports by 328
295 adding diastase (malt) to stirred tank reactors, followed by doctors are available’ (Brockhaus 1894b). 329
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296 fermentation for 72 h, using yeast that had been produced A wave of foundation of research institutions, mainly 330
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297 separately; distilleries were controlled automatically governmental institutes took place, devoted to research on 331
298 (Brockhaus 1895, vol. 15, p. 172–178). Yeast as a commer- beer, wine and food manufacture, hygiene, medical care, 332
299 cial product was mainly generated in high yield in distiller- and water, as well as laboratories of the brewing and bakery 333
300 ies (pressed yeast, Presshefe); it was then sold for use in industries, notably in Europe, and several in the USA. 334
301 other industrial processes, for example bread manufacture Institutions for brewing research and education were 335
302 (Payen 1874, Vol. 2, p. 403). In Denmark, Hansen made established in Weihenstephan near Munich (1872–1876), 336
303 major progress in breeding pure yeast by working with solid Berlin (‘Institut für Gärungsgewerbe,’ 1874), Hohenheim 337
304 culture media (e.g. agar plates, as did Koch) isolating colo- (1888) (all in Germany), in Copenhagen, and in Paris the 338
305 nies from single cells which he could then propagate. This famous ‘Institut Pasteur’ (1888). In Britain, the ‘British 339
306 became the basis for pure yeast fermentation and commer- School of Malting and Brewing’ was founded at the 340
307 cial applications which was adopted e.g. by the German University of Birmingham in 1899. In the USA, by states 341
308 brewing industry, where the Berlin Institute and its first decrees, agricultural research institutions were founded from 342
309 director Max Delbrück played a major role. The work 1863 on, that eventually became the origins of big universities 343
310 of Pasteur and Koch placed emphasis on the particular like MIT, Cornell, and Wisconsin (Bud 1993). 344
311 quality of individual pure cultures or clones. It was Following Pasteur and Koch’s success in identifying 345
312 realized that quality control and characterization of the causative agents of disease and establishing pure cultures, 346
313 organisms used were important. This accompanied the pharmaceutical companies also established bacteriology 347
AUTHOR'S PROOF!
348 departments which produced vaccines or tested substances fermentation, during the period up to 1930, stimulated the 398
349 for their antimicrobial properties (Metz 1997). J. E. Siebel in molecular approach to the study of the pathway of alcoholic 399
350 Chicago issued a journal ‘Zymotechnic Magazine: Zeitschrift fermentation, mainly the research on the successive inter- 400
351 für Gärungsgewerbe and Food and Beverage Critic.’ In mediates in metabolism. Buchner himself continued to 401
352 German-speaking countries, 10 journals on brewing were work on cell-free fermentation investigating intermediate 402
353 issued at that time (Brockhaus 1894a, b). Jörgensen, in compounds and activities both in cell-free press juice as 403
354 1885, founded the journal Zymotechnisk Tidende, and pub- well as in living yeast that would convert possible in- 404
355 lished a highly regarded book on Microorganisms and fer- termediates including trioses. By the end of the 1940s, 405
356 mentation. Several further books on mycology and/or bacteria the scheme of glycolysis and alcohol formation was 406
357 or microorganisms were issued. The terms Bacteriology or finally complete (Florkin 1975; Kohler 1975; Buchholz 407
358 Mycology, ‘Zymotechnologie’, or Microbiology denominated and Collins 2010, chapter 4). 408
359 the new research field. Of major impact on industrial microbiology were 409
360 Thus the ‘Age of Bacteriology’ began with a new para- Fernbach’s systematic investigations at the Institut Pasteur 410
361 digm, and a broadened industrial and economic base. in Paris on metabolic intermediates during alcoholic fermen- 411
F
tation (mainly of glycolysis) by various microorganisms, 412
e.g. yeast and Tyrothrix tenuis; this included the formation 413
O
362 The period from 1890 to 1940—The advent of acids, notably acetic, succinic and pyruvic acids. He 414
O
363 of biochemistry, and new products identified corresponding enzymatic activities: the begin- 415
nings of what we now call biochemistry research. This 416
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364 In 1891, Fischer established stereochemistry, illustrating his was not only important in elucidating the mechanism of 417
365 theory on specificity with the famous picture of a lock and fermentation but was also of practical relevance for acid 418
366 key: ‘To use a picture, I will say that enzyme and glucoside production. Fernbach obtained patents on the fermentation
D 419
367 must fit like lock and key in order to interact chemically. . .’ of starch for the production of acetone and higher alcohols 420
368 421
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(Fischer 1909). With the work of Emil Fischer (1852–1919) (Fernbach 1910; Fernbach and Strange 1911).
369 came the breakthrough in the development of structural Around 1907–1910, there was a shortage of rubber on the 422
370 biochemistry; in the course of his scientific career he world market. Perkin in the UK proposed an alliance, com- 423
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371 completely shifted the orientation of research in chemistry prising an extended list of chemists and bacteriologists, 424
372 towards the principal organic components of living matter: including Fernbach and Weizmann, with the aim to produce 425
373 sugars, fats, and proteins (Fruton and Simmonds 1953). butanol (butyl alcohol), which could be converted into bu- 426
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374 Buchner in the mid-1890s ended the hypothesis of tadiene. This in turn could be polymerized to yield synthetic 427
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375 vis vitalis, that still postulated hidden mysterious forces rubber (Perkin Jr. 1912). Shortly after this initiative, the First 428
376 in fermentation, when he published a series of papers World War created a demand that drove technical innovation 429
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377 (Buchner 1897, 1898; Buchner and Rapp 1898), which in the fermentation industries. The ‘acetone butanol’ fer- 430
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378 signaled a breakthrough in fermentation and enzymology. mentation process became a key technology for explosives 431
379 Buchner’s key experiment was to prepare a press juice from production since acetone was required as a solvent, in short 432
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380 yeast, which contained all the enzymes required for the supply in Britain. Chaim Weizmann, who had worked in 433
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381 transformation of sugar into alcohol and carbon dioxide, Fernbach’s laboratory, continued similar research in the 434
382 and to demonstrate that no living cells remained. He then Biochemical Department of Manchester University, and 435
383 could show that this solution could perform the same reac- made a new contribution using a more abundant source of 436
384 tion as did living yeast during fermentation, assuming one raw material, viz. maize, in 1915 (Speakman 1919). 437
385 enzyme, called zymase, being the catalyst. Buchner Weizmann brought his own laboratory experiments to the 438
386 presented the proof that (alcoholic) fermentation did not notice of the Admiralty, in the spring of 1915. He asked 439
387 require the presence of ‘. . .such a complex apparatus as is Winston Churchill, the first Lord of the Admiralty, to build a 440
388 the yeast cell’. The agent was in fact a soluble substance— plant, and in July, a pilot plant was erected in Nicholson’s 441
389 without doubt a protein body—which he called ‘zymase,’ London gin distillery. The process is usually referred to as 442
390 and what much later turned out to be the enzyme system the Weizmann process (Weizmann 1917; Nathan 1919; for 443
391 of the whole glycolytic pathway (Buchner 1897). With more details and the political background refer to, Bud 444
392 Buchner’s work the dogma of the ‘vis vitalis’ fell. It initiated 1993). The manufacture of acetone by the Weizmann pro- 445
393 a new paradigm, the biochemical paradigm, which, in con- cess attained the greatest success at the factory of British 446
394 trast to that of Pasteur, stated that enzyme catalysis, includ- Acetones, Toronto, Ltd., in Canada, on a large scale. 447
395 ing complex phenomena like that of alcoholic fermentation, Fourteen new fermenters were constructed, about 18 ft 448
396 was a chemical process not necessarily linked to the pres- (5.5 m) in diameter and 20 ft (6.1 m) high, holding 24,000 449
397 ence and action of living cells. The discovery of cell-free gallons (91 m3) of mash (Nathan 1919; Speakman 1919). In 450
451 Germany, war requirements concerned glycerol (glycerin) Enzyme technology rapidly expanded. A range of enzymes, 504
452 for the manufacture of explosives, when supplies of fat including diastase (amylolytic enzymes), proteases and 505
453 became enormously curtailed as a result of the imposition pectinases, were isolated from different organisms for com- 506
454 of the sea blockade. Investigations initiated by Lüdecke with mercial use, mainly from Bacillus subtilis and other species 507
455 the object of obtaining glycerol on an industrial scale by such as Aspergillus oryzae and A. niger (Tauber 1949, pp. 508
456 means of fermentation became of supreme importance. 396–494; Buchholz and Poulson 2000). Takamine began 509
457 The process was developed by the Protol Company. The isolating bacterial amylases in the 1890s in Japan. In 1894, 510
458 monthly output of glycerol was about 1,000 tons he obtained a patent for the production of a diastatic enzyme 511
459 (Connstein and Lüdecke 1919a, b). preparation from molds, which he called ‘Takadiastase’ for 512
460 The formation of oxalic and citric acids by Apergillus and the production of amylases for the hydrolysis of starches in 513
461 Penicillium species had been observed by Wehmer in the food manufacture (Tauber 1949). Major applications of en- 514
462 1890s. Citric acid fermentation became an object of study zymes were proteases in the chill-proofing of beer, and the 515
463 by several academic groups that were actively engaged in addition of malt extract in dough-making by American 516
464 optimizing the process and in elucidating the biochemical bakers in the USA. In 1922, they used 30 million pounds 517
F
465 mechanism leading from the sugar substrate to citric acid. (13,500 tons) of malt extract valued at $ 2.5 million. In 518
466 Currie undertook what came to be considered a classic 1907, Röhm patented the application of a mixture containing 519
O
467 investigation of the factors controlling the production of pancreatic extract as a bating agent, replacing the unpleasant 520
O
468 citric acid by a selected strain of Aspergillus niger; he use of dung, and he founded the Röhm and Haas Company 521
469 elaborated optimum conditions for the production of citric in the same year based on this application. From about 1930 522
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470 acid. Currie joined Chas. Pfizer in New York, where a plant onwards, the enzyme preparation was produced by fermen- 523
471 was established which went into production in 1923. By tation (Tauber 1949; Buchholz and Poulson 2000). For 524
472 1933, this industry already contributed 85 % (in Europe education the Institute in Berlin offered various courses from
D 525
473 5,100 tons and in the USA 3,500 tons) of the world’s 1888 (and later a curriculum for brewers), as did the ‘Institut 526
474 527
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citric acid production of 10,400 tons. Further products für Gärungsphysiologie und Bakteriologie’ that was
475 manufactured by fermentation were gluconic acid and lactic established at the Technical High School in Vienna in 528
476 acid (May and Herrick 1930; Frey 1930; Roehr 1996, 1998). 1897, as well as other institutions. Courses on fermentation 529
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477 Another important example of industrial research activity were offered by Bernhauer at the German University in 530
478 was the development of the oxidation of sorbitol to sorbose Prague in the 1930s (Bud 1993/1995, pp. 60, 61, 104, 531
479 by Acetobacter suboxydans as an intermediate for vitamin 132, 202, 203; Clifton 1966). 532
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480 C. The corresponding so-called Reichstein process was used Important scientific breakthroughs and applications are 533
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481 from the 1930s on a large industrial scale (Buchholz and summarized in Table 3. 534
482 Seibel 2008). Another process established in the 1930s was
O
483 the manufacture of L-ephedrine as a pharmaceutical using

C
484 the stereoselective condensation of benzaldehyde and The period from 1940 to 1970—the era of antibiotics, 535
485 acetaldehyde by yeast (Vasic-Racki 2000). Ethanol con- and the emergence of biotechnology 536
N
486 tinued to represent a major product of outstanding economic

U
487 importance. Florey, Heatley and Chain, towards the end of the 1930s, 537
488 A breakthrough event was in 1928 when Fleming ob- began to investigate penicillin in the course of their system- 538
489 served that a culture of a Penicillium notatum inhibited the atic study of antibacterial substances at Oxford University. 539
490 growth of bacteria. He demonstrated the production of an The credit for resurrecting penicillin, described at the time 540
491 antibacterial substance in the culture broth and named it ‘as unstable as an opera singer’, certainly goes to the Oxford 541
492 penicillin. However, there was rather a long delay before group. They developed an assay, found a way of producing 542
493 research and development aiming at production was un- penicillin in surface culture and demonstrated the marked 543
494 dertaken, finally stimulated by Florey, Heatley, and Chain activity and therapeutic value of penicillin in a clinical trial 544
495 who entered this field again toward the end of the 1930s in 1940 (Bud 2007; Coghill 1970; Demain 1981; Ohno et al. 545 Q6
496 (Bud 2007; see below). 2000). Early yields and recovery, however, were very 546
497 The nature of enzymes and the structure of proteins discouraging and the difficulties in wartime England led 547
498 required more than 40 years to be established, and it them to visit authorities, laboratories, and industrial compa- 548
499 remained controversial for decades (Sumner and Myrbäck nies in the USA for help in July, 1941. They were advised 549
500 1950). In the 1930s, Stanley successfully crystallized the by research authorities to visit Peoria, Illinois, USA, to talk 550
501 tobacco mosaic virus; it was the first time that any living form with officials of the Northern Regional Research Laboratory 551
502 had been crystallized, and it revolutionized thinking about (NRRL) because this institution had just organized a fer- 552
503 the chemical nature of life (VanDemark and Batzing 1987). mentation division. The representatives offered Florey all 553
AUTHOR'S PROOF!
t3:1 Table 3 The period from 1890 to 1940 (Buchholz and Collins 2010, chapter 4; Roehr 1996)
t3:2 Time scientistsa Scientific findings, events Technical progress, industrial innovation
t3:3 1894 E. Fischer Specificity of enzymes Enzyme technology expanding (Takadiastase)

t3:4 1897 Buchner Fermentation due to enzyme action only First waste disposal biogas reactor (Bombay)
t3:5 1900s Buchner Rersearch on fermentation intermediates
t3:6 1905 E. Fischer and others Research in the nature of proteins 1907 Enzyme technology: Röhm and Haas company
(Germany)
t3:7 1910f Fernbach Rersearch on fermentation intermediates
t3:8 1911f Fernbach and Strange; Microbial formation of acetone and butanol b
Fermentation technology expanding: Production of butanol
1912f Perkin for rubber manufacture b
t3:9 1915f Weizmann Finding of Clostridium acetobutylicum War requirements: acetone and butanol production
t3:10 1915f Connstein and Lüdecke Glycerol fermentation b Glycerol production for explosives
t3:11 1916 Thom and Currie Citric acid fermentation b
t3:12
F
1920s Pfizer: Industrial production of citric acid
t3:13 1920s and 1930s Embden, Research on glycolysis Large-scale industrial yeast production for bakeries
O
Meyerhoff and others
t3:14 1925, 1930s Sumner, Northrup Enzyme crystallization
O
t3:15 1928 Fleming Finding of penicillin action Large-scale waste water treatment (1928, Essen, Germany)
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t3:16 1933 Reichstein Sorbitol transformation into L-sorbose Reichstein process for vitamin C production
t3:17 End of 1930s Florey and Chain Resumed research on penicillin Sterile enzyme fermentation for detergents etc.
t3:18 1940 Protein structure solved Peak alcohol production
a
D
Selected scientists and events relevant for applied microbiology (see also first footnote in Table 2)
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b
Most intermediates mentioned here, butanol, acetone, citric acid, etc., have been observed before, but not developed further for industrial
production
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554 the help they could give. Biosynthesis work began on July unknown approach to interdisciplinary cooperation and pro- 581
555 15, 1941, at the NRRL under the general direction of Dr. ject organization (Coghill 1970). 582
556 Coghill (Greene and Schmitz Jr. 1970). Research studies Strain screening and development, including mutation 583
R
557 were also initiated at the Universities of Minnesota (on procedures, proved to be a key factor for success. From 584
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558 microbial strains), Wisconsin (on fermentation), Penn State many sources, including soil samples from around the 585
559 (on recovery), the Carnegie Institute, Wisconsin and world, collected by the US Army, many hundreds of strains 586
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560 Stanford (on mutation) and at MIT (on drying and packag- of penicillin-producers were isolated. The best producer of 587
C
561 ing) (Coghill 1970). By the fall of 1941, yields of penicillin all (labeled NRRL 1951), ironically, came from a moldy 588
562 began to climb to 6, 10, and to 24 Oxford units per mL, cantaloupe melon from a Peoria fruit market. Genetic 589
N
563 using an improved mould strain, as compared with about changes were undertaken at the Carnegie Institute and at 590
U
564 3 units/mL obtained by the Oxford group. the University of Wisconsin. Moyer’s (NRRL) medium 591
565 In December 1941, the US Government became interested. improvement and use of a better NRRL strain raised the 592
566 The US Department of Agriculture (USDA) called a meeting concentration of penicillin to 100 units/mL. Subsequent 593
567 in New York which included representatives from the improvements raised this by another order of magnitude to 594
568 National Research Council, and four companies, Merck, about 1,500 units/mL with the Wisconsin strain (Coghill 595
569 Squibb, Pfizer and Lederle, an event that was considered to 1970). ‘As a result, we began to get a trickle of a supply 596
570 represent the real turning point for penicillin production of penicillin during the early months of 1942’, as Richards 597
571 (Coghill 1970; Greene and Schmitz Jr. 1970) (some 18 more reported (Greene and Schmitz Jr. 1970; Silcox 1970). By 598
572 companies became involved subsequently; Elder 1970). June 1942, enough penicillin to treat 10 patients had been 599
573 Industry representatives agreed to make research teams avail- produced, and by February 1943 there was sufficient mate- 600
574 able to work on the problem of supplying adequate quantities rial to treat approximately 100 patients. Production was by 601
575 of penicillin. By 1943, the amazing curative properties of surface culture flasks, the most reliable method at the time. 602
576 penicillin were becoming pretty well-known, and there was In 1942, 2-years intensive development had resulted in 603
577 a huge demand for the drug. The prime goal established by the increasing the level of output of penicillin by some 604
578 government representatives was to have ample stocks on hand 140,000-fold. The most efficient approach was submerged 605
579 for the US army’s invasion of Europe in the spring of 1944. or deep-tank fermentation, but there were a number of 606
580 That goal finally was met—by a huge effort, and a hitherto severe practical problems, the solutions of which were not 607
608 obvious, but which were finally achieved (Fig. 2) (Greene resistant. Factors that exacerbate this phenomenon are misuse 642
609 and Schmitz Jr. 1970; Silcox 1970). Downstream opera- and overuse, and the widespread use of antibiotics in 643
610 tions, the isolation of penicillin, also represented a huge aquariums, in agriculture and animal husbandry (Bud 2007, 644
611 challenge. They included new methods for biological pro- pp.116-139; Hubschwerlen 2007). 645
612 cesses, such as liquid–liquid extraction, centrifugation, By the 1950s, large-scale production not only of tradi- 646
613 freeze drying, crystallization and others (Silcox 1970; tional goods, for example, beer, alcohol, cheese, but also 647
614 Perlman 1970). new products, including citric acid and pharmaceuticals and 648
615 ‘Thus began a wartime collaboration which was to in- other products of particularly high social and economic 649
616 volve the efforts of literally hundreds of biochemists, chem- relevance, had become well established. Growing economic 650
617 ists, bacteriologists, biologists, chemical engineers, relevance followed notably the success of penicillin manu- 651
618 physicians, toxicologists, pharmacologists, and pathologists facture, and further antibiotics, like streptomycin, became 652
619 on both sides of the Atlantic, managed and coordinated by available, followed by a new class of high value-added 653
620 industrial executives, academic administrators, and govern- products, mainly secondary metabolites, e.g. steroids 654
621 ment leaders’. (Greene and Schmitz Jr. 1970). At the polit- obtained by biotransformation. Other major products of 655
ical level, ‘the injection of funds, people, companies, and
F
622 growing market relevance included amino acids, organic 656
623 government interest meant a transformation in the ways of acids, carbohydrates, and derivatives (hydrolysates, iso- 657
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624 doing science’. A range of smaller projects on penicillin mers), vitamins, solvents, and enzymes for new applications 658
O
625 production were undertaken in several other countries, includ- (Demain 1981; Demain 2001). 659
626 ing Germany, the Netherlands, France and by Czech scientist A new generation of biocatalysts, based on immobiliza- 660
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627 (Bud 2007, pp. 75–96). Penicillin became a public property tion techniques developed in the academic field, led to a 661
628 and big business (Bud 2007, pp. 23–53, 54–74). The pros- breakthrough in processing of food and pharmaceutical 662
629 pects, and later the success of penicillin, prompted further compounds. Large-scale processes were established using
D 663
630 research on antibiotics. Waksman isolated actinomycyin in biocatalysts for penicillin hydrolysis (for the synthesis of 664
631 semisynthetic β-lactam antibiotics) and glucose isomeriza- 665
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1940, streptotricin in 1942, and streptomycin in 1944 from
632 cultures of actinomycetes (Ohno et al. 2000). (The patent on tion (Poulson and Buchholz 2003; Buchholz et al. 2012, 666
633 Streptomycin and for starter cultures for yoghurt largely fi- chapters 7 and 8). Waste water treatment became more 667
EC
634 nanced the establishment of the Life Sciences Faculty at the wide-spread, due to legislation, and gained great attention. 668
635 University of Wisconsin in Madison for the next 50 years and This resulted in new developments, and capital investment, 669
636 provided many stipends for students.) However, the therapeu- both in the public and industrial sectors (Jördening and 670
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637 tic potential has been threatened by the emergence of increas- Winter 2005). 671
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638 ingly resistant bacterial strains as a natural consequence of Significant events are summarized in Table 4 672
639 their use, first observed by Abraham and Chain (1940). In Starting in the 1970s and 1980s, BT gained the attention 673
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640 clinical settings, more than 50 % of Escherichia coli isolates of governmental agencies in Germany, the UK, Japan, the 674
C
641 and more than 90 % of S. aureus isolates are ampicillin USA and others as a field of innovative potential and eco- 675
nomic growth. This was also in response to the first oil price 676
N
crisis in the beginning 1970s, and the realization that renew- 677
U
able material resources would become more important in the 678

future. These approaches led to expansion of the field. The 679
first enthusiastic report by the German chemical technology 680
organization Dechema was issued in 1974 for the German 681
Ministry for Education and Science (Bundesministerium für 682
Bildung und Wissenschaft, BMBW). It was the first system- 683
atic approach for BT research funding, emphasizing classi- 684
cal BT, and developing a research and development strategy, 685
which finally aimed at encouraging innovations in industry 686
(Dechema 1974; Buchholz 1997; Bud 1994, pp. 192–198). 687 Q7
This study has been an intriguing example of interaction 688
between policy makers, industry and science, and was 689
termed a corporatist approach by Jasanoff (1985). Further 690
studies on BT were issued in the UK, Japan and France (Bud 691
1993, pp. 189–210). Essential topics and aims of the 692
Fig. 2 Penicillin fermenters in operation at E.R. Squibb & Sons, 1946 Dechema study reflected the main established scientific 693
(Langlykke 1970) and applied fields of BT at that time. The basic disciplines 694
AUTHOR'S PROOF!
t4:1 Table 4 The period from 1940 to 1975 (Buchholz and Poulson 2000; Bud 2007; Buchholz and Collins 2010, chapters 4 and 5)
t4:2 Time scientists Scientific findings, events Technical progress, industrial innovation
t4:3 End of 1930s Florey and Chain Resume research on penicillin

t4:4 1940 Protein structure solved
t4:5 1940s Waksman Extended research on antibiotics: actinomycin,
streptomycin
t4:6 1941 USA: penicillin project, due to war requirements
t4:7 1944 Large-scale industrial penicillin production; Pfizer:
deep tank penicillin fermentation
t4:8 1948 Brotzu and Oxford team Cephalosporin, broad spectrum antibiotic
t4:9 1949 First biochemical engineering symposium
t4:10 1952/1953 Production of further antibiotics: Pfizer, Lederle:
tetracycline; Eli Lilly: erythromycin
t4:11 1953 Watson, Crick, Franklin Structure of DNA
F
t4:12 1950s Development of immobilized enzymes Industrial steroid biotransformation (prednisolone)
O
t4:13 1958 Gaden (Ed.) First biotech journal a Expanding waste water treatment due to government
requirements
O
t4:14 1959 Chain et al. with Beecham Begin of research on 6-APA
t4:15 End of 1960s Large-scale enzyme processes: detergents, starch processing;
PR
t4:16 1971
t4:17 1972 Industrial production of 6-APA (Bayer, Germany; Beecham GB))
t4:18 1973 Cohen and Boyer Gene cloning D Large-scale enzymatic glucose isomerisation
t4:19 1974 Political level: Germany: DECHEMA-report, Expanding production of amino and organic acids, vitamins,
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followed by other studies on biotechnology enzymes in food manufacture
t4:20 in UK, Japan, France Failures: SCP production; cellulosics utilization; biosensorsb,c
EC
This and the following table overlap in time scale due to events that are part of the two different periods
6-APA 6-aminopenicillanic acid, intermediate for the production of ampicillin and other semisynthetic penicillin derivatives
a
Journal of Microbiological and Biochemical Engineering; it later became Biotechnology and Bioengineering
R
b
There were of course other failures which would be worth investigation
c
R
An exception are glucose sensors

O
695 involved in BT research and development work were mi- discipline and there were no books, rather no journals, cur- 716
C
696 crobiology, cell biology, biochemistry, and—to a limited ricula or scientific conferences devoted to the subject. A few 717
697 extent—molecular biology and genetics in addition to UK and American universities offered special courses; 718
N
698 chemical engineering. Recombinant DNA methods were University College London established a curriculum granting 719
U
699 not mentioned since they were not available at the time of a Master of Science in Biochemical Engineering in the 1960s, 720
700 writing the study (1972–74) (Buchholz 1979; Buchholz and and another BT curriculum was established in the 1970s at 721
701 Collins 2010, chapter 5). the Technical University of Berlin (Buchholz 1979, pp. 69, 722
702 Research work in the field of BT proceeded as subtopic 71). The first BT journal of high reputation was established in 723
703 within a motley collection of scientific and engineering dis- 1958 by Elmer Gaden as the Journal of Microbiological and 724
704 ciplines with a low level of coherence and little integration up Biochemical Engineering. It later became Biotechnology and 725
705 till the 1960s and 1970s. During the 1940s, Stephenson’s Bioengineering and is still a leading journal in the field. A 726
706 Bacterial Metabolism and of Kluyver’s Chemical Activities few other journals appeared in the 1950s and 1960s, for 727
707 of Micro-Organisms appeared, the Gärungschemische example Applied Microbiology, renamed Environmental and 728
708 Praktikum, by Bernhauer was published in 1936 (Bud Applied Microbiology and Applied Microbiology and 729
709 1993). Later, textbooks dealt with specific topics (not on Biotechnology. 730
710 BT as an integrated field), signifying increased attention to
711 the field: on applied microbiology (Rehm 1967, Pirt 1975), as
712 well as on biochemical engineering (Aiba et al. 1965; Bailey The period from 1975 on—the new biotechnology 731
713 and Ollis 1977). The first encyclopedias and series on BT
714 were issued by Rehm and Reed (1981) and Flickinger and The turning point in genetics ensued from the establishment 732
715 Drew (1999). Thus, biotechnology did not exist as a scientific of a model for the molecular structure of DNA by Jim 733
734 Watson and Francis Crick, based on the crystallography data merging of molecular biology and biochemical engineering. 787
735 of Rosalind Franklin, who was working in Morris Wilkins Industrial interest and the range of products expanded sig- 788
736 lab in 1953 (Watson and Crick 1953). This was the culmi- nificantly, and many new companies, mainly in the USA, 789
737 nation of work initiated by Sir William Henry Bragg and his were founded. New methods and tools played a key role in 790
738 son William Lawrence on X-ray diffraction by crystals, to the rapid expansion of recombinant technologies. These 791
739 study molecular structure, initially of minerals but later of include: gel electrophoresis, centrifugation, restriction endo- 792
740 more complex organic structures, including the first 3-D nucleases, plasmid cloning, a range of further cloning 793
741 structure of a protein, myoglobin (Max Perutz and John methods extending to most known species of microorgan- 794
742 Kendrew, see Kendrew et al. 1958), further of penicillin, isms and eukaryotes, in particular in plants, cloning of larger 795
743 vitamin B 12, and insulin (Hodgkin 1979). The significance (gene-sized) DNA fragments via virus cosmid, fosmid, 796
744 of DNA structure, as the material of which genes are made, BAC and YAC (this latter in yeast) cloning, oligonucleotide 797
745 was immediately recognized due to the ground-breaking synthesis, DNA sequencing, gene mining, metagenomics, 798
746 work, during the preceding 50 years, of a great number of and recently synthetic biology; protein design has become a 799
747 scientists in chemistry and biology, mostly microbiology rational tool for biopharmaceuticals and enzyme develop- 800
F
748 including Gregor Mendel, Friedrich Miescher, Phoebus ment (Winnacker 1987; Demain 2001; Bornscheuer and 801
749 Levene, William Astbury, Erwin Chargaff, Oswald Avery, Buchholz 2005; Buchholz and Collins 2010, chapters 7, 9). 802
O
750 Francois Jacob, Jacques Monod, Ole Maaloe, Max Once the tools for gene cloning in the Gram-negative E. coli 803
O
751 Delbrück, Sydney Brenner and others (Judson 1979; had been established it became easy to develop gene cloning 804
752 Winnacker 1987; Buchholz and Collins 2010, Chapter 7). vectors which could be transferred to other species. This 805
PR
753 But the ‘DNA Revolution’ as Hotchkiss termed it, involved the identification of plasmids that replicated in 806
754 progressed or penetrated slowly into technology, initially other hosts and genes (promoters) that could be expressed 807
755 having little effect on traditional processes and products and used for selection in the new host, including bacteria,
D 808
756 (Hotchkiss 1979). The Asilomar conference 1975 initiated yeast, insect cell lines and plant cells (Collins 1977). Thus 809
757 810
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a public discussion on the possible hazards of recombinant all the elements for the new recombinant DNA technology,
758 DNA research (for details, see Buchholz and Collins 2010, at least for bacterial and animal cells are available: Methods 811
759 section 8.1.2). The following two decades saw many years to prepare DNA, which, following restriction cleavage 812
EC
760 of discussion of possible risks and containment require- (i.e. treatment with restriction endonucleases) could be co- 813
761 ments associated with recombinant technologies which valently joined to a ‘vector’ with a DNA ligase; a ‘vector’ 814
762 eventually formed the basis of the guidelines for recombi- (plasmid or virus) to ensure maintenance in the cell; a 815
R
763 nant DNA work and finally culminated in international method to prepare ‘clean’ vector DNA; an efficient method 816
R
764 legislation (see for example Cartagena Protocol on Biosafety, to incorporate DNA into the cell; culture techniques to 817
765 http://bch.cbd.int/protocol/text/. ) isolate single clones carrying a single recombinant hybrid 818
O
766 Subsequent to Watson and Crick’s publication in 1953 of molecule, including selective techniques to enrich for the 819
C
767 the DNA structure, a large number of significant scientific cells ‘transformed’ with the vectors, for example selection 820
768 breakthrough events as well as technological progress pro- for antibiotic-resistance genes (Buchholz and Collins 2010, 821
N
769 vided a new basis for BT. Selected events are summarized in chapter 7). More recently, since the 1990s, the so called 822
U
770 Table 5. Berg, Cohen, and Boyer in 1972 introduced recom- ‘omics’ approaches: genomics, proteomics, metabolomics, 823
771 binant DNA (rDNA) technology when they constructed the bioinformatics, and their integration into systems biology 824
772 first recombinant plasmids and viruses, which were intro- and biotechnology aimed at understanding, quantitative de- 825
773 duced into bacteria, or animal cells respectively, where they scription and rational modification of whole organisms. 826
774 were autonomously propagated. A patent granted to Cohen Biosystems engineering or systems biotechnology aims at 827
775 and Boyer, and the University of California was critically the integration of biology, mathematics, bioinformatics, and 828
776 commented by Berg (Cohen et al. 1972; Cohen and Boyer systems engineering to gain a holistic view of complex 829
777 1979/1980; Berg and Mertz 2010). ‘Entrepreneur’ was still biological and biotechnological systems, including quanti- 830
778 a dirty word in molecular biology, leading one to reflect on tative description and improvement of whole organisms and 831
779 the situation in engineering a century earlier with the slan- the rational development of novel production processes 832
780 dering of George Stephenson (later inventor of the steam (Deckwer et al. 2007; Klein-Marcuschamer et al. 2010; 833 Q8
781 engine) by Sir Humphrey Davy at the time of his ‘invention’ Papini et al. 2010; Buchholz and Collins 2010, sections 834
782 of the miner’s lamp (not patented), already produced as 13.6 and 15.6). 835
783 Stephenson’s prototype (patented). As a consequence of this development, in the USA, also 836
784 Based on the new genetic techniques, a significant on the political level, the perception of BT diverged greatly 837
785 change occurred during the 1980s and 1990s with common by the 1980s as compared to that in Europe particularly in 838
786 approaches in different disciplines underlying BT, and the Germany in the 1970s. This is perceived from a report of the 839
AUTHOR'S PROOF!
t5:1 Table 5 The new biotechnology
t5:2 Scientific events Technical application
t5:3 1944 Avery et al.: chemical nature of chromosomes: DNA

t5:4 1950 Chargaff: rule of nucleotide ratios
t5:5 1953 Sanger: sequence of insulin
t5:6 1953 Watson and Crick: structure of DNA
t5:7 (For technical application up to the 1960s, see Table 4)
t5:8 1955f Kornberg et al.: enzymatic DNA replication
t5:9 1957f Zamecnik and Hoagland: amino acid activation, translation in
protein synthesis
t5:10 1959 Kendrew: first X-ray enzyme structure
t5:11 1960–1961 Jacob and Monod: operon model of gene regulation;
concept of mRNA
t5:12 1961–1966 Nirenberg, Khorana et al.: genetic code
F
t5:13 1963 Merrifield: solid-phase protein synthesis
O
t5:14 1968 Arber and Linn: restriction endonucleases
t5:15 1971f Nathans: southern: DNA separation 1971 Farley, Cape, Glaser: establishment of Cetus, the first Biotech
O
Company
PR
t5:16 1972 Mertz, Davies: recombinant 1972 Industrial production of 6-amino-penicillanic acid
t5:17 Berg: first recombinant virus
t5:18 Khorana et al.: first chemically synthesized gene
t5:19 1973 Cohen, Boyer: recombinant plasmid/microorganism D
t5:20 1974 Large-scale production of glucose/fructose syrup
TE
t5:21 1975f Maxam and Gilbert; Sanger: methods for DNA sequencing
t5:22 1975 Köhler and Millstein: monoclonal antibodies 1976 Swanson, Boyer: foundation of second biotech company: Genentec
t5:23 1975 Asilomar conference (moratorium on recombinant DNA research) 1977f Further New Biotech companies founded
EC
t5:24 1978 Heffron et al.: directed mutagenesis 1978 Recombinant human insulin (Genentec)
t5:25 1979 Mayer, Collins and Wagner: recombinant penicillin acylase
t5:26 1980f Work on recombinant α-amylase (Novo)
R
1980 Chakrabarty: first patent for recombinant bacterium

t5:27 1982 FDA approval of human insulin (Eli Lilly)
R
t5:28 1983f Frank and Blöcker; Carruthers: mechanized DNA synthesis 1982 Large-scale production of recom-binant α-galactosidase
O
(Boehringer Mannheim, D)
t5:29 1983 Schell and Montagu: first transgenic plant (tobacco)
C
t5:30 1984 Political level: OTA study; mechanized DNA sequencing

t5:31
N
1988 Mullis: polymerase chain reaction (PCR) 1988 Leder, Stewart: patent for transgenic mouse
t5:32 1990 Start of human genome project a
U
t5:33 1994 Stemmer: DNA shuffling

t5:34 1995 First complete bacterial genome sequence
t5:35 1995f Metabolic engineering b 1996 Mass cultivation of recombinant seeds (commercial corn seeds)
t5:36 1997 First cloned animal: Dolly
t5:37 1998 Argonne Structural Genomics Meeting human chromosome 22 1999 Start of CELERA—industrial genome sequencing
t5:38 2000 First approximate version of the human Genome a 1999 Vitamin C via microbial pathway
a
These topics are difficult to assign, a range of arguments being raised in terms of their classification as technical application, not fundamental
research
b
Bailey (1991, 1996)
840 OTA of 1984 (OTA 1984). It refers to methods that arose of scientific results, closely associated with the business 846
841 with knowledge on DNA and that revolutionized what world. 847
842 was ‘thinkable’. In contrast to the reports mentioned The industrial breakthrough came with recombinant 848
843 before, emphasis in the OTA study was on genetic engi- human insulin, developed by Genentech in cooperation with 849
844 neering and rDNA technology, resulting in commercial Ely Lilly in 1978, and approved by the US Food and Drug 850
845 opportunity and support of fast commercial exploitation Administration in 1982 (Bud 1993/1995, pp. 232, 237; 851
852 Walsh 2007, pp. 297, 298); this was at a time when some both aerobic and anaerobic, being applied in numerous 905
853 heads of European pharmaceutical companies did not be- small up to very large-scale installations, as well as a great 906
854 lieve that a recombinant DNA product would ever be ap- number of exhaust air treatment units (Jördening and Winter 907
855 proved for clinical use. This precedent , notably the 2005). Ethanol, traditionally based on starch and sugar to 908
856 approval human insulin as the first recombinant DNA produce it as gasoline additive on a very large scale, pro- 909
857 product on the market, was followed by a series of further voked heavy criticism, with respect to using traditional 910
858 recombinant products, mostly drugs, which in general could agriculture crops for biofuels rather than food. A major 911
859 not be produced by other technical means, and which are of crisis occurred in 2007 and most notably in mid-2008, 912
860 great medical interest. Some of these products previously causing a dramatic increase in food prices. The growing 913
861 isolated in small amounts from human blood or tissue were use of cereals for ethanol was thought to be in part respon- 914
862 in danger of being contaminated with human pathogenic sible for this price increase. Recently a trend emerged for 915
863 viruses (not all known at that time, e.g. AIDS virus, HCV). using cellulosic biomass as a source of biofuels (Buchholz 916
864 In this respect, this alternative production route provided prod- et al. 2012, section 12.2). Production of biogas and electric- 917
865 ucts not only in sufficient quantity for general use but also with ity generated by microbial fuel cells gained much attention 918
F
866 an improved and reproducible quality. The products included and impetus (Buchholz and Collins 2010, chapter 16). 919
867 human growth hormone in 1983, β-interferon, and a hepatitis Recombinant DNA methods also greatly affected enzyme 920
O
868 B vaccine in 1986, tissue plasminogen activator (tPA) in 1987, technology since the late 1970s. Over expression in fast- 921
O
869 and erythropoietin in 1989 (product approval). Actually, re- growing host organisms with high protein productivity 922
870 combinant proteins, including hormones and growth factors, allowed many enzymes, which were not readily accessible, 923
PR
871 blood clotting factors, cytokines, monoclonal antibodies and to be produced cheaply on an industrial scale. This technol- 924
872 vaccines are most important biopharmaceuticals, with a mar- ogy allowed design of enzymes with modified specificity 925
873 ket size estimated of some $50 billion per year around 2010 through iterative rapid cycles of gene mutation, screening or
D 926
Q9 874 (Walsh 2007, Aggarwal 2007). Antibiotics remained an im- selection and testing in addition to crystallography and 927
875 928
TE
portant sector of biopharmaceuticals, with many different molecular modelling. Such products are used on a large
876 specialties and sales estimated at more than $50 billion per scale for starch products (used in food preparations with a 929
877 year (Hubschwerlen 2007). production volume of >10 million t/a, and ethanol with >37 930
EC
878 Large investment by multinational companies, the foun- million t/a), enzymes in detergents, for pharmaceuticals 931
879 dation of many small new companies, a few of which have manufacture, and many other fields (Buchholz et al. 2012, 932
880 grown remarkably, and state funded big research merged in chapters 7, 8, sections 12.1, 12.2). Plant biotechnology has 933
R
881 a ‘gold rush’ into the ‘New Biotechnology,’ as recombinant successfully been established, aiming at improved yields, 934
R
882 technology was termed in the USA. Key steps toward the disease and herbicide resistance, etc. of crops. However, 935
883 transfer of science into the economic sphere resulted in the controversies are ongoing with respect to political, ethical 936
O
884 foundation of new BT companies, the first being Cetus, and biosafety aspects. Transgenic crops are cultivated on a 937
C
885 started in 1971, later the originator of the ‘polymerase chain very large scale notably in the USA, Argentina, Brazil, 938
886 reaction’ (PCR; Kary Mullis) which gave birth to the era of Canada, and other countries (Slater et al. 2008; Buchholz 939
N
887 gene diagnostics and personalized medicine. Herbert Boyer and Collins 2010, Chapter 18). 940
U
888 and Robert Swanson founded Genentech in 1976; amongst Two achievements since 2000 gained major public reso- 941
889 the most important companies founded were Biogen (1978), nance: First, the major goal of the Human Genome Project 942
890 Amgen (1980) and Chiron (1981), later bought by Cetus was achieved in 2000 with international cooperation and a 943
891 (Demain 2001, 2003, personal communication; Buchholz total expenditure of some $ 3 billion. The task which was 944
892 and Collins 2010, chapters 5, 6, 17; for a recent survey, carried out by a major international consortium and largely 945
893 see Table 17.5). independently by Craig Venters group was recognized as 946
894 Industrial products, other than pharmaceuticals, expanded essentially complete in 2000 and commemorated by a com- 947
895 as well, based both on traditional and recombinant methods, munication in the presence of Francis Collins, Craig Venter 948
896 with sales worldwide estimated over 50 billion €. The most and the President of the USA. The result of the Human 949
897 important bulk products are ethanol, amino and organic Genome Project may possibly allow the discovery and pro- 950
898 acids, produced in large amounts, vitamins, and biopoly- duction of hundreds of novel pharmaceuticals, many of 951
899 mers. Metabolic engineering has been used successfully for which are natural human gene products previously not 952
900 the optimization of yields, e.g. for the production of amino available in significant amounts or as virus-free prepara- 953
901 acids (for a survey, see Buchholz and Collins 2010, chapter tions, significantly improving diagnosis and eventually rev- 954
902 16). A very large sector for application of biotechnology is olutionizing medicine. However, a number of arguments 955
903 in fact environmental technology which has become an have been raised in terms of their classification as technical 956
904 important industry. This includes waste water treatment, application, not fundamental research. After 10 years of 957
AUTHOR'S PROOF!
958 expectation, e.g. with respect to drug targeting, the follow- interpreted the development from early fermentation re- 1008
959 ing comment was put forward ‘… a transformational tech- search to Pasteurs concept of microbiology and technical 1009
960 nology will always have its immediate consequences innovations, from Buchner and Fernbach towards Perkin’s 1010
961 overestimated and its long-term consequences underestimated, and Weizmann’s processes, from Fleming towards Florey’s 1011
962 and ....you may just start to imagine all the projects that will and Chain’s work, and the penicillin project, and Watson’s 1012
963 spin-off…’ (C&EN 2010). Much progress took place and Crick’s solution of the DNA structure towards the 1013
964 largely through the involvement of flexible biotech compa- cloning concept by Berg, Cohen, Boyer, and towards the 1014
965 nies such as Genentech, Cetus, Amgen and Biogen which establishment of new companies and New Biotechnology. 1015
966 concentrated on innovative development in parallel with a Recently, applied microbiology, biochemical engineering 1016
967 lethargy and bad management in large (particularly and molecular biology have merged to form biotechnology 1017
968 European) pharmaceutical companies which lost their as a new scientific discipline in its own right, sharing a 1018
969 dominance in this new field. common paradigm at the molecular level with all the other 1019
970 The second major event may be considered the under- life sciences (Buchholz 2007). Biotechnology continues, as 1020
971 standing of the factors which control pluripotent and toti- well, as a field of technology, to develop new technical 1021
F
972 potent stem-cells and the controlled reprogramming of many processes and products based on a rational scientific basis. 1022
973 differentiated cells to such stem cells. This opens a new area A diversification arose through the formation of subdisci- 1023
O
974 of medical research, production of models for genetic plines, such as genomics, transcriptomics, proteomics, met- 1024
O
975 diseases (for personalized medicine), and a radical new abolic flux analysis with quantitative analysis of complex 1025
976 approach to understanding cancer, developments which will metabolites, and finally biochemical engineering, which 1026
PR
977 give potential to a new area of biotechnological develop- merged into biosystems engineering. 1027
978 ment. This found its origin in the work of those studying the Finally, we note that critical events during the historic 1028
979 molecular biology of cell differentiation and embryogenesis, development of Biotechnology are associated with excep-
D 1029
980 originally in insect, worm or animal models, as did for tional personalities who often had the vision and insight of 1030
981 1031
TE
example the Nobel laureate Christiane Nusslein-Volhardt how their findings could be developed for the benefit of
982 and as those most recently recognized with a Nobel Prize science and humanity, translating them into practical inven- 1032
983 (2012 Physiology or Medicine) for Sir John B. Gurdon and tion finally leading to innovation. Public and private invest- 1033
EC
984 Shinya Yamanaka. ment programs often came slowly on advice or practical 1034
985 A further event that received inordinate publicity was the validation of radical advances by a few pioneers (This latter 1035
986 chemical synthesis of the entire genome of Mycoplasma aspect is treated in more detail throughout Buchholz and 1036
R
987 genitalium by the group of Craig Venter; transferring this Collins 2010). 1037
R
988 DNA into a foreign Mycoplasma caused replacement of the 1038

989 resident genome by the completely synthetic genome, Acknowledgment The authors gratefully acknowledge valuable 1039
O
information by Arnold Demain. 1040

990 forming a novel strain capable of continuous self-replication
1041
C
991 (Gibson et al. 2010). The scientific relevance of this experi-

992 ment, however, has been extensively debated, but subsequent
N
993 steps in synthetic biology may become a key technology 1042

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U
994 (Bornscheuer 2010). Although it is definitely not ‘creation

995 of life’, as many journalists sensationalized this milestone, it
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996 may still be considered as a further step in the tradition of penicillin. Nature 146:837 1045
997 Pasteur making use of living organisms, e.g. creating novel Aiba S, Humphrey AE, Millis NF (1965) Biochemical engineering. 1046
998 cells with new synthetic potential. Academic Press, New York 1047
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999 Conclusions Bailey JE, Ollis DF (1977/1986) Biochemical engineering fundamentals, 1051
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1000 The history of biotechnology comprises exciting develop- Béchamp MA (1864) Sur la fermentation alcoolique. Bulletin de la 1053
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1001 ments over more than 200 years, from mysterious concepts Béchamp MA (1865) Matière albuminoide, ferment de l’urine. Bulletin 1055 Q12
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The roots - A short history of industrial microbiology and biotechnology

Article in Applied Microbiology and Biotechnology · March 2013

Klaus Buchholz John - Collins

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1 Article Title The roots—a short history of industrial microbiology and

Appl Microbiol Biotechnol

4 The roots—a short history of industrial microbiology

8 Received: 20 December 2012 / Revised: 8 February 2013 / Accepted: 9 February 2013

Appl Microbiol Biotechnol

Appl Microbiol Biotechnol

Q5 t1:1 Table 1 Dates and events in early biotechnology

t1:2 Ancient handicraft

t1:3 6000 BC Beer fermentation

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microorganisms in diseases sake. Industrial-scale beer fermentation in GB

Investigations on alcohol fermentation (1858)

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Fig. 1 Pasteur’s technical

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483 the manufacture of L-ephedrine as a pharmaceutical using

486 tinued to represent a major product of outstanding economic

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t3:3 1894 E. Fischer Specificity of enzymes Enzyme technology expanding (Takadiastase)

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able material resources would become more important in the 678

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t4:3 End of 1930s Florey and Chain Resume research on penicillin

An exception are glucose sensors

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Appl Microbiol Biotechnol

t5:1 Table 5 The new biotechnology

t5:2 Scientific events Technical application

t5:3 1944 Avery et al.: chemical nature of chromosomes: DNA

1980 Chakrabarty: first patent for recombinant bacterium

t5:30 1984 Political level: OTA study; mechanized DNA sequencing

t5:33 1994 Stemmer: DNA shuffling

Appl Microbiol Biotechnol

Appl Microbiol Biotechnol

988 DNA into a foreign Mycoplasma caused replacement of the 1038

information by Arnold Demain. 1040

991 (Gibson et al. 2010). The scientific relevance of this experi-

993 steps in synthetic biology may become a key technology 1042

994 (Bornscheuer 2010). Although it is definitely not ‘creation

Appl Microbiol Biotechnol

Appl Microbiol Biotechnol

Pasteur L (1857b) Mémoire sur la fermentation alcoolique. Compt pp 3–29

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