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An introduction to fermentation processes 1
The term “fermentation” is derived from the Latin verb fervere, to boil, thus describing the appearance of the action of yeast on the extracts of fruit or malted grain. The boiling appearance is due to the production of carbon dioxide bubbles caused by the anaerobic catabolism of the sugar present in the extract. However, fermentation has come to have with different meanings to biochemists and to industrial microbiologists. Its biochemical meaning relates to the generation of energy by the catabolism of organic compounds, whereas its meaning in industrial microbiology tends to be much broader.
The catabolism of sugar is an oxidative process, which results in the production of reduced pyridine nucleotides, which must be reoxidized for the process to continue. Under aerobic conditions, reoxidation of reduced pyridine nucleotide occurs by electron transfer, via the cytochrome system, with oxygen acting as the terminal electron acceptor. However, under anaerobic condition, reduced pyridine nucleotide oxidation is coupled with the reduction of an organic compound, which is often a subsequent product of the catabolic pathway. In the case of the action of yeast on fruit or grain extracts, NADH is regenerated by the reduction of pyruvic acid to ethanol. Different microbial taxa are capable of reducing pyruvate to a wide range of end products, as illustrated in Fig. 1.1. Thus, the term fermentation has been used in a strict biochemical sense to mean an energy-generation process in which organic compounds act as both electron donors and terminal electron acceptors.
The production of ethanol by the action of yeast on malt or fruit extracts has been carried out on a large scale for many years and was the first “industrial” process for the production of a microbial metabolite. Thus, industrial microbiologists have extended the term fermentation to describe any process for the production of product by the mass culture of a microorganism. Brewing and the production of organic solvents may be described as fermentation in both senses of the word but the description of an aerobic process as a fermentation is obviously using the term in the broader, microbiological, context and it is in this sense that the term is used in this book.
THE RANGE OF FERMENTATION PROCESSES
There are five major groups of commercially important fermentations:
1. Those that produce microbial cells (or biomass) as the product. 2. Those that produce microbial enzymes.
FIGURE 1.1 Bacterial Fermentation Products of Pyruvate
Pyruvate formed by the catabolism of glucose is further metabolized by pathways which are characteristic of particular organisms and which serve as a biochemical aid to identification. End products of fermentations are italicized (Dawes & Large, 1982).
5. Those that modify a compound that is added to the fermentation—the transformation process.
The historical development of these processes will be considered in a later section of this chapter, but it is first necessary to include a brief description of the five groups.
MICROBIAL BIOMASS
The commercial production of microbial biomass may be divided into two major processes: the production of yeast to be used in the baking industry and the production of microbial cells to be used as human food or animal feed (single-cell protein). Bakers’ yeast has been produced on a large scale since early 1900s and yeast was produced as human food in Germany during the First World War. However, it was not until the 1960s that the production of microbial biomass as a source of food protein was explored to any great depth. As a result of this work, reviewed briefly in Chapter 2, a few large-scale continuous processes for animal feed production were established in the 1970s. These processes were based on hydrocarbon feedstocks, which could not compete against other high protein animal feeds, resulting in their closure in the late 1980s (Sharp, 1989). However, the demise of the animal feed biomass fermentation was balanced by ICI plc and Rank Hovis McDougal establishing a process for the production of fungal biomass for human food. This process was based on a more stable economic platform and has been a significant economic success (Wiebe, 2004).
MICROBIAL ENZYMES
Enzymes have been produced commercially from plant, animal, and microbial sources. However, microbial enzymes have the enormous advantage of being able to be produced in large quantities by established fermentation techniques. Also, it is infinitely easier to improve the productivity of a microbial system compared with a plant or an animal one. Furthermore, the advent of recombinant DNA technology has enabled enzymes of animal origin to be synthesized by microorganisms (see Chapter 12). The uses to which microbial enzymes have been put are summarized in Table 1.1, from which it may be seen that the majority of applications are in the food and related industries. Enzyme production is closely controlled in microorganisms and in order to improve productivity these controls may have to be exploited or modified. Such control systems as induction may be exploited by including inducers in the medium (see Chapter 4), whereas repression control may be removed by mutation and recombination techniques. Also, the number of gene copies coding for the enzyme may be increased by recombinant DNA techniques. Aspects of strain improvement are discussed in Chapter 3.
MICROBIAL METABOLITES
The growth of a microbial culture can be divided into a number of stages, as discussed in Chapter 2. After the inoculation of a culture into a nutrient medium there is a period during which growth does not appear to occur; this period is referred as the lag phase and may be considered as a time of adaptation. Following a period during which the growth rate of the cells gradually increases, the cells grow at a constant maximum rate and this period is known as the log, or exponential, phase. Eventually, growth ceases and the cells enter the so-called stationary phase. After a further
Table 1.1
Commercial Applications of Enzymes
Industry Application
Baking and milling
Reduction of dough viscosity, acceleration of fermentation, increase in loaf volume, improvement of crumb softness, and maintenance of freshness
Improvement of dough texture, reduction of mixing time, increase in loaf volume
Brewing Mashing
Chill proofing
Improvement of fine filtration
Cereals
Chocolate and cocoa
Precooked baby foods, breakfast foods
Manufacture of syrups
Coffee Coffee bean fermentation
Preparation of coffee concentrates
Confectionery
Cotton
Corn syrup
Dairy
Eggs, dried
Fruit juices
Manufacture of soft center candies
Low temperature processing
Manufacture of high-maltose syrups
Production of low D.E. syrups
Production of glucose from corn syrup
Manufacture of fructose syrups
Manufacture of protein hydrolysates
Stabilization of evaporated milk
Production of whole milk concentrates, ice cream, and frozen desserts
Curdling milk
Glucose removal
Clarification
Oxygen removal
Laundry Detergents
Leather Dehairing, baiting
Meat
Paper Tenderization
Removal of wood waxes
Pharmaceutical Digestive aids
Enzyme Source
Amylase Fungal
Protease Fungal/bacterial
Amylase Fungal/bacterial
Protease Fungal/bacterial
β-Glucanase Fungal/bacterial
Amylase Fungal
Amylase Fungal/bacterial
Pectinase Fungal
Pectinase, hemicellulase Fungal
Invertase, pectinase
Pectate lyase Fungal/bacterial Fungal
Amylase Fungal
Amylase Bacterial
Amyloglycosidase Fungal
Glucose isomerase Bacterial
Protease Fungal/bacterial
Protease Fungal
Lactase Yeast
Protease Fungal/bacterial
Glucose oxidase Fungal
Pectinases Fungal
Glucose oxidase Fungal
Protease, lipase Bacterial
Protease Fungal/bacterial
Protease
Lipase Fungal Fungal
Amylase, protease Fungal
Table 1.1 Commercial Applications of Enzymes (cont.)
period of time, the viable cell number declines as the culture enters the death phase. As well as this kinetic description of growth, the behavior of a culture may also be described according to the products that it produces during the various stages of the growth curve. During the log phase of growth, the products produced are either anabolites (products of biosynthesis) essential to the growth of the organism and include amino acids, nucleotides, proteins, nucleic acids, lipids, carbohydrates, etc. or are catabolites (products of catabolism) such as ethanol and lactic acid, as illustrated in Fig. 1.1. These products are referred as the primary products of metabolism and the phase in which they are produced (equivalent to the log, or exponential phase) as the trophophase (Bu’Lock et al., 1965).
Many products of primary metabolism are of considerable economic importance and are being produced by fermentation, as illustrated in Table 1.2. The synthesis of anabolic primary metabolites by wild-type microorganisms is such that their production is sufficient to meet the requirements of the organism. Thus, it is the task of the industrial microbiologist to modify the wild-type organism and to provide cultural conditions to improve the productivity of these compounds. This has been achieved very successfully, over many years, by the selection of induced mutants, the use of recombinant DNA technology, and the control of the process environment of the producing organism. This is exemplified by the production of amino acids where productivity has been increased by several orders of magnitude. However, despite these spectacular achievements, microbial processes have only been able to compete with the chemical industry for the production of relatively complex and high value compounds. In recent years, this situation has begun to change. The advances in metabolic engineering arising from genomics, proteomics, and metabolomics have provided new powerful techniques to further understand the physiology of “over-production” and to reengineer microorganisms to “over-produce” end products and intermediates of primary metabolism. Combined with the rising cost of petroleum and the desirability of environmentally friendly processes these advances are now facilitating the
Table
1.2 Some Primary Products of Microbial Metabolism and Their Commercial Significance
Primary Metabolite
Ethanol
Organic acids
Glutamic acid
Lysine
Nucleotides
Phenylalanine
Polysaccharides
Vitamins
Commercial Significance
“Active ingredient” in alcoholic beverages
Used as a motor-car fuel when blended with petroleum
Various uses in the food industry
Flavor enhancer
Feed supplement
Flavor enhancers
Precursor of aspartame, sweetener
Applications in the food industry
Enhanced oil recovery
Feed supplements
development of economic microbial processes for the production of bulk chemicals and feedstocks for the chemical industry (Otero & Nielsen, 2010; Van Dien, 2013). These aspects are considered later in this chapter and in Chapter 3.
During the deceleration and stationary phases, some microbial cultures synthesize compounds which are not produced during the trophophase and which do not appear to have any obvious function in cell metabolism. These compounds are referred to as the secondary compounds of metabolism and the phase in which they are produced (equivalent to the stationary phase) as the idiophase (Bu’Lock et al., 1965). It is important to realize that secondary metabolism may occur in continuous cultures at low growth rates and is a property of slow-growing, as well as nongrowing cells. When it is appreciated that microorganisms grow at relatively low growth rates in their natural environments, it is tempting to suggest that it is the idiophase state that prevails in nature rather than the trophophase, which may be more of a property of microorganisms in culture. The interrelationships between primary and secondary metabolism are illustrated in Fig. 1.2, from which it may be seen that secondary metabolites tend to be elaborated from the intermediates and products of primary metabolism. Although the primary biosynthetic routes illustrated in Fig. 1.2 are common to the vast majority of microorganisms, each secondary product would be synthesized by only a relatively few different microbial species. Thus, Fig. 1.2 is a representation of the secondary metabolism exhibited by a very wide range of different microorganisms. Also, not all microorganisms undergo secondary metabolism—it is common amongst microorganisms that differentiate such as the filamentous bacteria and fungi and the sporing bacteria but it is not found, for example, in the Enterobacteriaceae. Thus, the taxonomic distribution of secondary metabolism is quite different from that of primary metabolism. It is important to appreciate that the classification of microbial products into primary and secondary metabolites is a convenient, but in some cases, artificial system. To quote Bushell (1988), the classification “should not be allowed to act as a conceptual straitjacket, forcing the reader to consider all products
FIGURE 1.2 The Interrelationships Between Primary and Secondary Metabolism
Primary catabolic routes are shown in heavy lines and secondary products are italicized (Turner, 1971).
as either primary or secondary metabolites.” It is sometimes difficult to categorize a product as primary or secondary and the kinetics of synthesis of certain compounds may change depending on the cultural conditions.
The physiological role of secondary metabolism in the producer organism in its natural environment has been the subject of considerable debate and their functions include effecting differentiation, inhibiting competitors, and modulating host physiology. However, the importance of these metabolites to the fermentation industry is the effects they have on organisms other than those that produce them. Many secondary metabolites have antimicrobial activity, others are specific enzyme inhibitors, some are growth promoters and many have pharmacological properties (Table 1.3). Thus, the products of secondary metabolism have formed the basis of a major section
Table 1.3 Some Secondary Products of Microbial Metabolism and Their Commercial Significance
Secondary Metabolite
Penicillin, cephalosporin, streptomycin
Bleomycin, mitomycin
Lovastatin
Cyclosporine A
Avermectins
Commercial Significance
Antibiotics
Anticancer agents
Cholesterol-lowering agent
Immunosuppressant
Antiparasitic agents
of the fermentation industry. As in the case for primary metabolites, wild-type microorganisms tend to produce only low concentrations of secondary metabolites, their synthesis being controlled by induction, quorum sensing, growth rate, feedback systems, and catabolite repression, modulated by a range of effector molecules (van Wezel & McDowall, 2011). The techniques which have been developed to improve secondary metabolite production are considered in Chapters 3 and 4.
RECOMBINANT PRODUCTS
The advent of recombinant DNA technology has extended the range of potential fermentation products. Genes from higher organisms may be introduced into microbial cells such that the recipients are capable of synthesizing “foreign” proteins. These proteins are described as “heterologous” meaning “derived from a different organism.” A wide range of microbial cells has been used as hosts for such systems including Escherichia coli, Saccharomyces cerevisiae, and filamentous fungi. Animal cells cultured in fermentation systems are also widely used for the production of heterologous proteins. Although the animal cell processes were based on microbial fermentation technology, a number of novel problems had to be solved—animal cells were considered extremely fragile compared with microbial cells, the achievable cell density is very much less than in a microbial process and the media are very complex. These aspects are considered in detail in Chapters 4 and 7. Products produced by such genetically engineered organisms include interferon, insulin, human serum albumin, factors VIII and IX, epidermal growth factor, calf chymosin, and bovine somatostatin. Important factors in the design of these processes include the secretion of the product, minimization of the degradation of the product, and control of the onset of synthesis during the fermentation, as well as maximizing the expression of the foreign gene. These aspects are considered in more detail later in this chapter and in Chapters 4 and 12.
TRANSFORMATION PROCESSES
Microbial cells may be used to convert a compound into a structurally related, financially more valuable, compound. Because microorganisms can behave as chiral catalysts with high positional specificity and stereospecificity, microbial processes are more specific than purely chemical ones and enable the addition, removal, or modification of functional groups at specific sites on a complex molecule without the use of chemical protection. The reactions, which may be catalyzed include dehydrogenation, oxidation, hydroxylation, dehydration and condensation, decarboxylation, animation, deamination, and isomerization. Microbial processes have the additional advantage over chemical reagents of operating at relatively low temperatures and pressures without the requirement for potentially polluting heavy-metal catalysts. Although the production of vinegar is the oldest established microbial transformation process (conversion of ethanol to acetic acid), the majority of these processes involve the production of high-value compounds including steroids, antibiotics, and prostaglandins.
However, the conversion of acetonitrile to acrylamide by Rhodococcus rhodochrous is an example of the technology being used in the manufacturing of a bulk chemical—20,000 metric tons being produced annually (Demain & Adrio, 2008).
A novel application of microbial transformation is the use of microorganisms to mimic mammalian metabolism. Humans and animals will metabolize drugs such that they may be removed from the body. The resulting metabolites may be biologically active themselves—either eliciting a desirable effect or causing damage to the organism. Thus, in the development of a drug it is necessary to determine the activity of not only the administered drug but also its metabolites. These studies may require significant amount of the metabolites and while it may be possible to isolate them from tissues, blood, urine, or faeces of the experimental animal, their concentration is often very low resulting in such approaches being time-consuming, expensive, and far from pleasant. Sime (2006) discussed the exploitation of the metabolic ability of microorganisms to perform these biotransformations. Thus, drug metabolites have been produced in small-scale fermentation, facilitating the investigation of their biological activity and/or toxicity.
The anomaly of the transformation fermentation process is that a large biomass has to be produced to catalyze a single reaction. Thus, many processes have been streamlined by immobilizing either the whole cells, or the isolated enzymes, which catalyze the reactions, on an inert support. The immobilized cells or enzymes may then be considered as catalysts, which may be reused many times.
THE CHRONOLOGICAL DEVELOPMENT OF THE FERMENTATION INDUSTRY
The chronological development of the fermentation industry may be represented as five overlapping stages as illustrated in Table 1.4. The development of the industry prior to 1900 is represented by stage 1, where the products were confined to potable alcohol and vinegar. Although beer was first brewed by the ancient Egyptians, the first true large-scale breweries date from the early 1700s when wooden vats of 1500 barrels capacity were introduced (Corran, 1975). Even some process control was attempted in these early breweries, as indicated by the recorded use of thermometers in 1757 and the development of primitive heat exchangers in 1801. By the mid-1800s, the role of yeasts in alcoholic fermentation had been demonstrated independently by Cagniard-Latour, Schwann, and Kutzing but it was Pasteur who eventually convinced the scientific world of the obligatory role of these microorganisms in the process. During the late 1800s, Hansen started his pioneering work at the Carlsberg brewery and developed methods for isolating and propagating single yeast cells to produce pure cultures and established sophisticated techniques for the production of starter cultures. However, use of pure cultures did not spread to the British ale breweries and it is true to say that many of the small, traditional, ale-producing breweries still use mixed yeast cultures at the present time but, nevertheless, succeed in producing high quality products.
Table 1.4 The Stages in the Chronological Development of the Fermentation Industry
1 Pre-1900
Alcohol
Vinegar
2 1900–1940
Bakers’ yeast glycerol, citric acid, lactic acid and acetone/butanol
Wooden, up to 1500 barrels capacity
Copper used in later breweries Use of thermometer, hydrometer and heat exchangers
Barrels, shallow trays, trickle filters
Steel vessels of up to 200 m3 for acetone/butanol
Air spargers used for bakers’ yeast
Mechanical stirring used in small vessels
3 1940–date
Penicillin, streptomycin, other antibiotics, gibberellin, amino acids, nucleotides, transformations, enzymes
pH electrodes with off-line control Temperature control
Sterilizable pH and oxygen electrodes. Use of control loops which were later computerized
Batch Virtually nil Nil Pure yeast cultures used at the Carlsberg brewery (1886)
Batch Virtually nil Nil Fermentations inoculated with ‘good’ vinegar
Batch and fed-batch systems
Virtually nil Virtually nil Pure cultures used
Batch and fed-batch common Continuous culture introduced for brewing and some primary metabolites
Very important Becomes common Mutation and selection programmes essential
4 1964–date Single-cell protein using hydrocarbon and other feedstocks
5 1982–date Production of heterologous proteins by microbial and animal cells
Monoclonal antibodies produced by animal cells
6 2000–date Use of “synthetic biology” to improve established fermentations and develop new bulk chemical processes
Pressure cycle and pressure jet vessels developed to overcome gas and heat exchange problems Use of computer linked control loops Continuous culture with medium recycle
Fermenters developed in stages 3 and 4. Animal cell reactors developed
Fermenters developed in stages 3 and 4
Control and sensors developed in stages 3 and 4
Control and sensors developed in stages 3 and 4
Batch, fedbatch or continuous Continuous perfusion developed for animal cell processes
Very important Very important Genetic engineering of producer strains attempted
Very important Very important Introduction of foreign genes into microbial and animal cell hosts. In vitro recombinant DNA techniques used in the improvement of stage 3 products
Batch, fedbatch or continuous
Very important Very important Synthetic biology used to develop existing and novel fermentations
Vinegar was originally produced by leaving wine in shallow bowls or partially filled barrels where it was slowly oxidized to vinegar by the development of a natural flora. The appreciation of the importance of air in the process eventually led to the development of the “generator” which consisted of a vessel packed with an inert material (such as coke, charcoal, and various types of wood shavings) over which the wine or beer was allowed to trickle. The vinegar generator may be considered as the first “aerobic” fermenter to be developed. By the late 1800s to early 1900s, the initial medium was being pasteurized and inoculated with 10% good vinegar to make it acidic, and therefore resistant to contamination, as well as providing a good inoculum (Bioletti, 1921). Thus, by the beginning of the twentieth century the concepts of process control were well established in both the brewing and vinegar industries.
Between the years 1900 and 1940, the main new products were yeast biomass, glycerol, citric acid, lactic acid, acetone, and butanol. Probably the most important advances during this period were the developments in the bakers’ yeast and solvent fermentations. The production of bakers’ yeast is an aerobic process and it was soon recognized that the rapid growth of yeast cells in a rich medium (or wort) led to oxygen depletion that in turn, resulted in ethanol production at the expense of biomass formation. The problem was minimized by restricting the initial wort concentration, such that the growth of the cells was limited by the availability of the carbon source rather than oxygen. Subsequent growth of the culture was then controlled by adding further wort in small increments. This technique is now called fed-batch culture and is widely used in the fermentation industry to avoid conditions of oxygen limitation. The aeration of these early yeast cultures was also improved by the introduction of air through sparging tubes, which could be steam cleaned (De Becze & Liebmann, 1944).
The development of the acetone–butanol fermentation during the First World War by the pioneering efforts of Weizmann at Manchester University led to the establishment of the first truly aseptic fermentation. All the processes discussed so far could be conducted with relatively little contamination provided that a good inoculum was used and reasonable standards of hygiene employed. However, the anaerobic butanol process was susceptible to contamination by aerobic bacteria in the early stages of the fermentation, and by acid-producing anaerobic ones, once anaerobic conditions had been established in the later stages of the process. The fermenters employed were vertical cylinders with hemispherical tops and bottoms constructed from mild steel. They could be steam sterilized under pressure and were constructed to minimize the possibility of contamination. Two-thousandhectoliter fermenters were commissioned which presented the problems of inoculum development and the maintenance of aseptic conditions during the inoculation procedure. The techniques developed for the production of these organic solvents were a major advance in fermentation technology and paved the way for the successful introduction of aseptic aerobic processes in the 1940s. In the late 1940s, fermentation still provided 65% of butanol and 10% of acetone produced in the United States of America (Jackson, 1958). However, the solvent fermentations
The chronological development of
became uneconomic with the development of competing processes based on the petrochemical feedstocks and they ceased to exist. It is interesting to note that approximately one hundred years after the development of the solvent fermentations that the competitiveness of fermentation and petrochemical processes for the production of some bulk chemicals may be reversed. As discussed earlier in this chapter, the rising cost of crude oil, the attractiveness of environmentally friendly processes, and the advances in metabolic engineering may lead to the resurrection of modern versions of these old processes.
The third stage of the development of the fermentation industry arose in the 1940s as a result of the wartime need to produce penicillin in submerged culture under aseptic conditions. The production of penicillin is an aerobic process that is very vulnerable to contamination. Thus, although the knowledge gained from the solvent fermentations was exceptionally valuable, the problems of sparging a culture with large volumes of sterile air and mixing a highly viscous broth had to be overcome. Also, unlike the solvent fermentations, penicillin was synthesized in very small quantities by the initial isolates and this resulted in the establishment of strain-improvement programs, which became a dominant feature of the industry in subsequent years. Process development was also aided by the introduction of pilot-plant facilities, which enabled the testing of new techniques on a semi-production scale. The development of a large-scale extraction process for the recovery of penicillin was another major advance at this time. The technology established for the penicillin fermentation provided the basis for the development of a wide range of new processes. This was probably the stage when the most significant changes in fermentation technology (as compared with genetic technology) took place resulting in the establishment of many new processes over the period, including other antibiotics, vitamins, gibberellin, amino acids, enzymes, and steroid transformations. From the 1960s onward, microbial products were screened for activities other than simply antimicrobial properties and screens became more and more sophisticated. These screens have given rise to those operating today utilizing miniaturized culture systems, robotic automation, and elegant assays.
While the products described earlier belonging to stage 3 are all biosynthetic compounds, one catabolic product gained significance in the mid-1970s. Brazil and the United States of America initiated programs for the manufacturing of ethanol as a motor fuel in 1975 and 1978 respectively. This was an attempt by both the countries to lessen their dependency on imported petroleum by using fermentation processes to convert carbohydrates to ethanol (bioethanol); the Brazilian process being based on sugarcane and the American process based on maize starch. Forty years after Brazil’s initiative, energy independence is still the “holy grail” of most governments—the United States of America produced 56 billion liters of bioethanol in 2015 (Renewable Fuels Association, 2016). However, the political and social issues associated with the diversion of land from food production to fuel are obvious and thus the development of processes using cellulose and lignin feedstocks rather than sugar and starch is the next stage in this saga.
In the early 1960s, the decisions of several multinational companies to investigate the production of microbial biomass as a source of feed protein led to a number of developments, which may be regarded as the fourth stage in the progress of the industry. The largest mechanically stirred fermentation vessels developed during stage 3 were in the range 80,000–150,000 dm3. However, the relatively low selling price of microbial biomass necessitated its production in much larger quantities than other fermentation products in order for the process to be profitable. Also, hydrocarbons were considered as the potential carbon sources that would result in increased oxygen demands and high heat outputs by these fermentations (see Chapters 4 and 9). These requirements led to the development of the pressure jet and pressure cycle fermenters that eliminated the need for mechanical stirring (see Chapter 7). Another feature of these potential processes was that they would have to be operated continuously if they were to be economic. At this time batch and fed-batch fermentations were common in the industry but the technique of growing an organism continuously by adding fresh medium to the vessel and removing culture fluid had been applied only to a very limited extent on a large scale. The brewers were also investigating the potential of continuous culture at this time, but its application in that industry was short-lived. Several companies persevered in the biomass field and a few processes came to fruition, of which the most long-lived was the ICI Pruteen animal feed process, which utilized a continuous 3,000,000-dm3 pressure cycle fermenter for the culture of Methylophilus methylotrophus with methanol as carbon source (Smith, 1981; Sharp, 1989). The operation of an extremely large continuous fermenter for time periods in excess of 100 days presented a considerable aseptic operation problem, far greater than that faced by the antibiotic industry in the 1940s and 1950s. The aseptic operation of fermenters of this type was achieved as a result of the high standards of fermenter construction, the continuous sterilization of feed streams, and the utilization of computer systems to control the sterilization and operation cycles, thus minimizing the possibility of human error. However, although the Pruteen process was a technological triumph, it became an economic failure because the product was out-priced by soybean and fishmeal. Eventually, in 1989, the plant was demolished, marking the end of a short, but very exciting, era in the fermentation industry.
While biomass is a very low-value, high-volume product, the fifth stage in the progress of the industry resulted in the establishment of very high-value, low-volume products; a stage often referred as “new biotechnology.” As mentioned earlier in this chapter, in vitro recombinant DNA technology enabled the expression of human and mammalian genes in cultured animal cells and microorganisms, thereby enabling the development of relatively large-scale fermentation processes for the production of human proteins, which could then be used therapeutically. These products have been classified by the regulatory authorities as biologicals, not as drugs, and thus come under the same regulatory controls as do vaccines, and along with vaccines are commonly referred as biopharmaceuticals. The exploitation of genetic engineering coincided approximately with another major development in biotechnology that influenced the progress of the fermentation industry—the production of monoclonal antibodies (mabs). The availability of monoclonals opened the door to sophisticated
The chronological development of
analytical techniques and raised hopes for their use as therapeutic agents. Although the practical use of mabs was initially limited to analytical applications (Webb, 1993), they are now well-established as therapeutic biopharmaceuticals and are produced in fermentation systems employing both mammalian cells and microorganisms as production agents (Walsh, 2012). Table 1.5 lists a selection of the recombinant proteins licensed for therapeutic use and the production systems.
In 1982, recombinant human insulin became the first heterologous protein to be approved for medical use. Eight more products were approved in the 1980s comprising two approvals for human growth hormone, two for interferons, one monoclonal antibody, one recombinant vaccine for hepatitis B, one for tissue plasminogen activator, and one for erythropoietin (Walsh, 2012). During this period, the pharmaceutical industry was also very active in developing “conventional” microbial processes which resulted in a number of new microbial products reaching the marketplace in the late 1980s and early 1990s. Buckland (1992) listed four secondary metabolites which were launched in the 1980s: cyclosporine, an immunoregulant used to control the
Therapeutic Group Recombinant Protein Production System Clinical Use, Treatment of
Blood factors Factor VIII
Thromobolytics, Tissue plasminogen activator
Mammalian cells Anemia
Mammalian cells, E.coli
Clot lysis
Anticoagulants Hirudin S. cerevisiae Anticoagulant
Hormones Insulin
Human growth hormone
Follicle stimulating hormone
Glucagon
Growth factors
E.coli, S. cerevisiae Diabetes
E.coli, S. cerevisiae Hypopituitary dwarfism
Mammalian cells Infertility
E.coli, S. cerevisiae Type 2 diabetes
Erythropoietin Mammalian cells Anemia
Granulocytemacrophage colony, E.coli
stimulating factor
Bone marrow transplantation
Granulocyte colony stimulating E.coli, mammalian cells Cancer
Table 1.5 The Major Groups of Recombinant Proteins Developed as Therapeutic Agents
rejection of transplanted organs; imipenem, a modified carbapenem, which had the widest antimicrobial spectrum of any antibiotic; lovastatin, a drug used for reducing cholesterol levels, and ivermectin, an antiparasitic drug which has been used to prevent “African River Blindness” as well as in veterinary practice. The sale of these four products added together exceeded that of the totality of recombinant proteins at that time. However, the developments over the last twenty years have resulted in biopharmaceuticals reaching annual sales of 100 billion dollars—representing one third of the global pharmaceutical market (Nielsen, 2013). In 2010, thirty biopharmaceuticals recorded sales of more than 1 billion dollars each (Walsh, 2012).
By the end of 2012, approximately 220 biopharmaceuticals had been approved (Berlec & Strukelj, 2013; Reader, 2013) with 31% being produced in E. coli, 15% in yeast, 43% in mammalian cells (mainly Chinese Hamster Ovarian cell lines, CHO), the remaining 11% being produced by hybridoma cells, insect cells, and transgenic animals and plants. One of the 2012 recombinant products, Elelyso, (a human taliglucerase alfa, used for the treatment of the lysosomal storage disorder, Gaucher’s disease) was approved to be produced in plant cell culture. This was the first approval of this production system and may pave the way for future processes. Whereas the approved products in the 1980s were predominantly hormones and cytokines, the approvals over the 2005–12 period were dominated by antibody-based products and engineered proteins, that is, proteins which have been modified postsynthesis. These modifications include:
• Antibody-drug conjugates in which, for example, anticancer drugs are linked to monoclonal antibodies which bind to the tumor, thus directing the drug to its target.
• Modifications which extend the half-life of the therapeutic protein in the body.
• Modifications which alter the pharmacokinetic properties of the therapeutic protein.
The commercial exploitation of recombinant proteins has necessitated the construction of production facilities designed to contain the engineered producing organism or cell culture. Thus, these processes are drawing on the experience of vaccine fermentations where pathogenic organisms have been grown on relatively large scales. Also, as indicated earlier, recombinant proteins are classified as biologicals, not as drugs, and thus come under the same regulatory authorities as do vaccines. The major difference between the approval of drugs and biologicals is that the process for the production of a biological must be precisely specified and carried out in a facility that has been inspected and licensed by the regulatory authority, which is not the case for the production of drugs (antibiotics, for example) (Bader, 1992). Thus, any changes that a manufacturer wishes to incorporate into a licensed process must receive regulatory approval. For drugs, only major changes require approval prior to implementation. The result of these containment and regulatory requirements is that the cost of developing a recombinant protein process is extremely high. Farid (2007) collated industry data which suggests that the investment costs for a 20,000 dm3 plant was $60 M and that for a 200,00 dm3 plant was $600 M, with
validation costs accounting for approximately 10–20% of this expenditure. Earlier in the development of the heterologous protein sector Buckland (1992) claimed that it cost as much to build a 3000 dm3 scale facility for Biologics as for a 200,000 dm3 scale facility for an antibiotic.
While the development of recombinant DNA technology facilitated the production of heterologous proteins, the advances in genomics, proteomics, and metabolic flux analysis are the basis of the sixth stage in the progress of the industry. The sequencing of the complete genomes of a wide range of organisms and the development of computerized systems to store and access the data has enabled the comparison of genomes and the visualization of gene expression in terms of both mRNA and protein profiles, the transcriptome and proteome respectively. Metabolic flux analysis examines the flux (or flow) of intermediates through a pathway (or pathways) and enables the construction of mathematical models mimicking the metabolic networks of the cell. The combination of these approaches has enabled workers to take a more holistic view of the workings of an organism, such that the outlook of the molecular biologist and biochemist have coincided with that of the physiologist in attempting to understand the functioning of the whole organism rather than simply its component parts. The term given to this rediscovery of physiology is “systems biology” and its application to biotechnology, “synthetic biology.” The adoption of a systems biology approach by fermentation scientists has enabled them to build upon established fermentation processes and take them to a further level. For example, Ikeda, Ohnishi, Hayashi, and Mitsuhashi (2006) compared the genome sequence of a lysine-producing industrial strain of Corynebacterium glutamicum with that of the wild type. The industrial strain had been manipulated by many rounds of mutation and directed selection (see Chapter 3) such that it contained not only the lesions giving overproduction but also undesirable mutations which had been inadvertently coselected during strain development. This comparison enabled the construction of a strain containing only the desirable lesions. Becker, Zelder, Hafner, Schroder, and Wittmann (2011) further developed this approach by constructing a lysine-producing strain by modifying the wild-type to optimize precursor supply, feedback control, metabolic flux, and NADPH supply.
Thus the goal of synthetic biology is to maximize the yield of the desired product while minimizing that of unwanted or unnecessary metabolites. Obviously, this has always been the goal of the fermentation scientist but the tools of synthetic biology may make this goal a reality. An exciting application of the approach is in the production of bulk chemicals and feedstocks for the chemical industry, in competition with the petrochemicals. Such products would be low value, high volume (as were the ill-fated biomass processes) necessitating very high yields. The USA company Genomatica has claimed a viable process for the production of 1,4-butanediol, an important chemical intermediate, from a manipulated strain of E. coli, a strain developed using the synthetic biology approach (Yim, Hasselbeck, Niu, & Pujolbaxley, 2011). The success of such processes will depend upon their economic competitiveness and it will be interesting to see whether they thrive or go the way of the biomass processes.
THE COMPONENT PARTS OF A FERMENTATION PROCESS
Regardless of the type of fermentation (with the possible exception of some transformation processes) an established process may be divided into six basic component parts:
1. The formulation of media to be used in culturing the process organism during the development of the inoculum and in the production fermenter.
2. The sterilization of the medium, fermenters, and ancillary equipment.
3. The production of an active, pure culture in sufficient quantity to inoculate the production vessel.
4. The growth of the organism in the production fermenter under optimum conditions for product formation.
5. The extraction of the product and its purification.
6. The disposal of effluents produced by the process.
The interrelationships between the six component parts are illustrated in Fig. 1.3 However, one must also visualize the research and development program which is designed to gradually improve the overall efficiency of the fermentation. Before a fermentation process is established a producer organism has to be isolated, modified such that it produces the desired product in commercial quantities, its cultural requirements determined and the plant designed accordingly. Also, the extraction process has to be established. The development program would involve the continual improvement of the process organism, the culture medium, and the extraction process.
The subsequent chapters in this book consider the basic principles underlying the component parts of a fermentation. Chapter 2 considers growth, comprehension of which is crucial to understanding many aspects of the process, other than simply the
FIGURE 1.3 A Generalized Schematic Representation of a Typical Fermentation Process
growth of the organism in the production fermenter. The isolation and improvement of commercial strains is considered in Chapter 3 and the design of media in Chapter 4. The sterilization of the medium, fermenters, and air is considered in Chapter 5 and the techniques for the development of inocula are discussed in Chapter 6. Chapters 7, 8 and 9 consider the fermenter as an environment for the culture of microorganisms; Chapter 7 considers the design and construction of fermenters including contained systems and animal cell fermenters, Chapter 8 discusses the instrumentation involved in monitoring and maintaining a controlled environment in a fermenter, while the provision of oxygen to a culture is investigated in Chapter 9. The recovery of fermentation products is dealt with in Chapter 10 and the environmental impact of fermentation processes and the regulatory framework in which they must operate is addressed in Chapter 11. Finally, the production of heterologous proteins is discussed in Chapter 12. Throughout the book examples are drawn from a very wide range of fermentations to illustrate the applications of the techniques being discussed but it has not been attempted to give detailed considerations of specific processes as this is well covered elsewhere, for example, in the Comprehensive Biotechnology series edited by Moo-Young (2011). We hope that the approach adopted in this book will give the reader an understanding of the basic principles underlying the commercial techniques used for the large-scale production of microbial products.
REFERENCES
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Becker, J., Zelder, O., Hafner, S., Schroder, H., & Wittmann, C. (2011). From zero to hero –design-based systems metabolic engineering of Corynebacterium glutamicum for L-lysine production. Metabolic Engineering, 13, 159–168
Berlec, A., & Strukelj, B. (2013). Current state and recent advances in biopharmaceutical production in Escherichia coli, yeasts and mammalian cells. Journal of Industrial Microbiology and Biotechnology, 40, 257–274.
Bioletti, F. T. (1921). The manufacture of vinegar. In C. E. Marshall (Ed.), Microbiology (pp. 636–648). London: Churchill.
Boing, J. T. P. (1982). Enzyme production. In G. Reed (Ed.), Prescott and Dunn’s industrial microbiology (4th ed., pp. 634–708). New York: MacMillan.
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Bu’Lock, J. D., Hamilton, D., Hulme, M. A., Powell, A. J., Shepherd, D., Smalley, H. M., & Smith, G. N. (1965). Metabolic development and secondary biosynthesis in Penicillium urticae. Canadian Journal of Microbiology, 11, 765–778.
Bushell, M. E. (1988). Application of the principles of industrial microbiology to biotechnology. In A. Wiseman (Ed.), Principles of biotechnology (pp. 5–43). New York: Chapman and Hall
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Dawes, I., & Large, P. J. (1982). Class 1 reactions: Supply of carbon skeletons. In J. Mandelstam, K. McQuillen, & I. Dawes (Eds.), Biochemistry of bacterial growth (pp. 125–158). Oxford: Blackwell
De Becze, G. I., & Liebmann, A. J. (1944). Aeration in the production of compressed yeast. Industrial Engineering Chemistry, 36, 882–890
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Farid, S. (2007). Process economics of industrial monoclonal antibody manufacture. Journal of Chromatography B, 848(1), 8–18
Ikeda, M., Ohnishi, J., Hayashi, M., & Mitsuhashi, S. (2006). A genome-based approach to create a minimally mutated Corynebacterium glutamcium strain for efficient L-lysine production. Journal of Microbiology and Biotechnology, 33, 610–615.
Jackson, R. W. (1958). Potential utilization of agricultural commodities by fermentation. Economic Botany, 12(1), 42–53.
Nielsen, J. (2013). Production of biopharmaceutical proteins by yeast: advances through metabolic engineering. Bioengineering, 4(4), 207–211.
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Reader, R. A. (2013). FDA biopharmaceutical product approvals and trends in 2012. BioProcess International, 11(3), 18–27.
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Sharp, D. H. (1989). Bioprotein manufacture: A critical assessment. Chichester: Ellis Horwood Sime, J. (2006). Microbial systems to mimic mammalian metabolism. Speciality Chemicals Magazine (pp. 34–35).
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Microbial growth kinetics 2
As outlined in Chapter 1, fermentations may be carried out as batch, continuous, and fed-batch processes. The mode of operation is, to a large extent, dictated by the type of product being produced. This chapter will consider the kinetics and applications of batch, continuous, and fed-batch processes.
BATCH CULTURE
Batch culture is a closed culture system that contains an initial, limited amount of nutrient. The inoculated culture will pass through a number of phases, as illustrated in Fig. 2.1. After inoculation there is a period during which it appears that no growth takes place; this period is referred to as the lag phase and may be considered as a time of adaptation. In a commercial process, the length of the lag phase should be reduced as much as possible and this may be achieved by using a suitable inoculum, and cultural conditions as described in depth in Chapter 6.
EXPONENTIAL PHASE
Following a period during which the growth rate of the cells gradually increases, the cells grow at a constant, maximum rate and this period is known as the log, or exponential, phase and the increase in biomass concentration will be proportional to the initial biomass concentration.
where x is the concentration of microbial biomass (g dm 3), t is time (h), d is a small change.
This proportional relationship can be transformed into an equation by introducing a constant, the specific growth rate (µ), that is, the biomass produced per unit of biomass and takes the unit per hours. Thus:
On integration Eq. (2.1) gives:
where x0 is the original biomass concentration, xt is the biomass concentration after the time interval, t hours, e is the base of the natural logarithm.
On taking natural logarithms, Eq. (2.2) becomes:
Thus, a plot of the natural logarithm of biomass concentration against time should yield a straight line, the slope of which would equal to µ During the exponential phase nutrients are in excess and the organism is growing at its maximum specific growth rate, µmax. It is important to appreciate that the µmax value is the maximum growth rate under the prevailing conditions of the experiment, thus the value of µmax will be affected by, for example, the medium composition, pH, and temperature. Typical values of µmax for a range of microorganisms are given in Table 2.1
It is easy to visualize the exponential growth of single celled organisms that replicate by binary fission. Indeed, animal and plant cells in suspension culture will behave very similarly to unicellular microorganisms (Griffiths, 1986; Petersen & Alfermann, 1993). However, it is more difficult to appreciate that mycelial organisms,
FIGURE 2.1 Growth of a Typical Microbial Culture in Batch Conditions
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raillerie, les montreurs de bêtes savantes habillaient à l’espagnole leurs chiens et leurs singes, avec larges fraises gauderonnées.
Une enseigne qu’on peut regarder comme une satire ad hominem se voyait dernièrement encore, rue de l’École-de-médecine, au coin de la rue de l’Ancienne-Comédie. Il est probable que sa mystérieuse singularité n’a pas nui à sa conservation. «On voit sculpté sur une grande pierre incrustée dans le trumeau qui sépare les deux croisées du premier étage de la maison, dit E.
de la Quérière dans ses Recherches historiques sur les Enseignes (1852), un chapeau rond, à larges bords, dont un côté est retroussé dans la forme usitée parmi la bourgeoisie du temps de Louis XIV. Ce chapeau est comme suspendu au-dessus d’une lunette de fortification, autrement dit ouvrage à cornes. Le sculpteur avait-il voulu faire de cette enseigne une malicieuse épigramme? Nous serions porté à le croire.» C’était sans doute l’enseigne d’un chapelier. La légende portait: Au Chapeau fort, équivoquant sur le mot Château fort; mais bien aussi sur les ouvrages à cornes que ledit couvre-chef était destiné à coiffer. L’enseigne du Chapeau fort est aujourd’hui conservée au musée Carnavalet.
Tallemant des Réaux nous raconte ainsi une vengeance par le moyen de l’enseigne: «Un commis borgne ayant exigé d’un cabaretier des droits qu’il ne lui devoit pas, le cabaretier, pour se venger, fit représenter le portrait du commis, à son enseigne, sous la forme d’un voleur, avec cette inscription: Au Borgne qui prend. Le commis, s’en trouvant offensé, vint trouver le cabaretier et lui rendit l’argent des droits en question, à la charge qu’il feroit réformer son enseigne. Le cabaretier, pour y satisfaire, fit seulement ôter de son enseigne le p, si bien qu’il resta: Au Borgne qui rend, au lieu du Borgne qui prend[183].»
Bonaventure d’Argonne raconte aussi la querelle d’un oiselier avec les Jésuites, à propos d’une enseigne: «Il y avoit autrefois dans la rue SaintAntoine, à Paris, un oiselier qui prenoit la qualité de gouverneur, précepteur et régent des oyseaux, perroquets, singes, guenons et guenuches de Sa Majesté. Ces grands titres paroissoient écrits en lettres d’or, dans un riche cartouche, au-dessus de la boutique de ce personnage. La plupart des passans qui lisoient ce bel écriteau n’en faisoient que rire, mais quelques pédans qui pensèrent y être intéressés, prenant la chose au point d’honneur, en firent du bruit et s’en plaignirent comme d’une profanation des titres les plus glorieux de la république des lettres. La chose vint aux oreilles du digne précepteur, et il disoit: «Je ne sais pas à qui en ont ces Messieurs. Mes écoliers valent bien les leurs, ils sont mieux instruits, et ne sont ni si sots ni si barbouillez.»
L’abbé Boisrobert, à qui j’ai ouï raconter cette histoire, ajoutoit qu’il n’y avoit que du plus ou du moins entre les écoliers de cet homme et ceux de nos collèges, tout n’aboutissant qu’à faire faire aux uns et aux autres de certaines grimaces, ou dire des mots qu’ils n’entendent point[184].»
Le sujet de l’enseigne était quelquefois plus innocent que la légende, et l’on pouvait, par le commentaire, ajouter à cette légende un caractère de
malignité qu’elle n’avait pas originairement. Ainsi, à la fin du premier Empire, quand Béranger eut publié sa fameuse chanson du Roi d’Yvetot, un marchand de vin de la rue Saint-Honoré, près de la rue, aujourd’hui disparue, de la Bibliothèque, tira de la chanson son enseigne. Il commanda et exposa au-dessus de sa boutique un joli tableau qu’il ne supposait pas certainement devoir prendre jamais un caractère séditieux. C’est ce qui arriva cependant; on y vit, comme dans la chanson, une critique des guerres continuelles de Napoléon, et la police ordonna la disparition de l’enseigne. C’est alors que le rusé marchand la plaça dans l’intérieur de sa boutique, où elle est encore, au numéro 182 de la rue Saint-Honoré. La police n’entendait pas raillerie en matière d’enseignes.
La conscription, en s’établissant révolutionnairement avec toutes ses rigueurs, n’avait pas fait disparaître cependant les anciens bureaux de racolage du quai de la Ferraille, où l’enseigne du Racoleur attirait nombreuse clientèle depuis plus d’un siècle. L’arrêt d’expulsion de ces agents d’enrôlement volontaire se trouva formulé gaiement dans ce refrain d’un couplet de M. de Piis, secrétaire général de la préfecture de police:
Enjoignons aux vieux ferrailleurs
De vendre leur vieux fer ailleurs
Il y eut aussi, à cette époque, comme en tout temps, des querelles, des altercations, des procès pour cause de contrefaçon d’enseigne. Le fameux bureau de tabac de la Civette, place du Palais-Royal, fut en guerre ouverte contre toutes sortes de Civettes, qui avaient l’audace de dresser pavillon à peu de distance, sinon en face de l’enseigne primordiale. La contrefaçon usait de ruse pour jouir impunément du bénéfice de la concurrence.
Dans le nouveau passage Delorme, qui avait alors le privilège de centraliser la promenade des flâneurs, un marchand nommé Mercier, ayant
placé sa boutique sous l’invocation du Beau Dunois, que la romance de la reine Hortense venait de mettre à la mode, le locataire de la boutique voisine fit peindre, pour son enseigne, un beau chien blanc moucheté de brun, avec cette inscription: Au Beau Danois. Les rieurs prolongèrent le débat des deux marchands, mais la police refusa d’intervenir en faveur du héros de la romance.
La police de nos jours a été aussi prudente en restant neutre dans l’exhibition d’une enseigne, des plus cocasses, qu’un écrivain public avait apposée sur son échoppe, place de l’Hôtel-de-ville. Nous ne pouvons mieux faire que de transcrire la note publiée, à cet égard, dans le Figaro du 1ᵉʳ décembre 1881: «Cette enseigne est un mascaron ou tête d’homme, à face grimacière, à dents cassées, à chevelure abondante, grosses lunettes, bonne plume d’oie derrière l’oreille, et une paire de cornes magistrales sur lesquelles sont écrits en majuscules ces mots: D , qui réjouiront le cœur de M. Naquet. Mais pourquoi des cornes? C’est l’enseigne d’un écrivain public, qui, pour bien indiquer sa spécialité aux aspirants au divorce, a arboré les redoutables appendices que les épouses folâtres font pousser sur le front des maris que vous savez.»
XVI
ENSEIGNES DE SAINTETÉ ET DE DÉVOTION
NOUS ne reparlerons pas ici des images de saints et de saintes qui ornaient autrefois les enseignes de la plupart des maisons et des boutiques de Paris. Ces images multipliées témoignaient sans doute de la dévotion, qui était alors homogène et générale dans toutes les classes de la population parisienne; mais la plupart de ces bienheureuses images représentaient les corporations, les confréries et les métiers. Quelques-unes, il est vrai, rappelaient les noms de baptême des propriétaires ou des locataires de la maison; d’autres avaient été sans doute inaugurées par le fait d’une vénération spéciale à l’égard de tel ou tel saint, ou par suite d’un vœu particulier en leur honneur. Quant aux images de Notre-Dame, qui étaient si nombreuses dans les enseignes, il faut les attribuer à cette dévotion si sincère, si touchante qu’on avait pour la sainte Vierge Marie, pour la mère de Jésus, le fils de Dieu et le rédempteur des hommes. La piété naïve du moyen âge rendait un culte permanent de respect et d’adoration à ces innombrables Notre-Dame, que les enseignes mettaient sous les yeux du peuple dans toutes les rues de la ville.
Il y eut aussi, depuis le XIIᵉ siècle jusqu’au XVIᵉ, des statues de la Vierge, dans des niches, à l’angle des rues, et quoique ces statues en pierre ou en bois, souvent peintes ou dorées, ne fussent que des enseignes, on leur rendait une espèce de culte public. Non seulement on allumait, la nuit, une lampe devant la niche qui contenait la Notre-Dame, mais encore on y suspendait des ex-voto et des médailles de confréries, on y attachait des bouquets de fleurs, surtout aux grandes fêtes de la sainte Vierge. Les passants saluaient et faisaient le signe de la croix, sans s’arrêter, quand ils avaient à traverser la rue; les femmes et les enfants s’agenouillaient et marmottaient une courte prière, quoique cette Notre-Dame ne fût souvent qu’une simple enseigne d’hôtellerie ou de cabaret. Ce n’étaient pas seulement les Notre-Dame qui avaient droit à ces hommages de la part des bonnes gens du peuple. Beaucoup d’images de saints et de saintes, qui n’étaient que des enseignes
aux portes des maisons et des boutiques, avaient aussi des lampes qui brûlaient devant elles pendant la nuit. Ce pieux usage dura jusqu’au milieu du XVIᵉ siècle. Vers cette époque, plusieurs statues ou images de NotreDame furent l’objet d’outrages et de profanations qui diminuèrent le nombre de ces enseignes vénérées. C’est à partir de ce temps-là que les niches qui contenaient des statues de Notre-Dame furent grillées, pour les préserver du fanatisme iconoclaste des huguenots, qui les brisaient à coups de pierres. On a lieu de s’étonner que quelques-unes de ces madones de la rue soient arrivées jusqu’à nous à peu près intactes. Le protestant Agrippa d’Aubigné remarquait avec quelque dépit qu’à la fin du XVIᵉ siècle il y avait encore dans toutes les rues de Paris un saint ou une Vierge dans sa niche[185] .
Nous pouvons nous faire une idée du nombre d’enseignes de dévotion qu’on voyait dans les rues de Paris, en citant, d’après Berty, celles qui pendaient aux maisons dans les quartiers de la Cité, du Louvre et du bourg Saint-Germain.
CITÉ. RUE DE LA JUIVERIE, maison de l’Annonciation Notre-Dame (1485). RUE DE LA CALANDRE, maison du Paradis (1345). RUE SAINTCHRISTOPHE, maison du Couronnement de la Vierge (1450).
LOUVRE. RUE CHAMPFLEURY, maison du Saint-Esprit (1489). RUE DU CHANTRE, maison ayant un Crucifix sur l’huis (1489), maison du Nom de Jésus (1687). RUE JEAN-SAINT-DENIS, maison du Saint-Esprit (1575), maison du Bon Pasteur (1680). RUE SAINT-HONORÉ, maison de l’Annonciation Notre-Dame (1432), maison de l’Enfant Jésus (1687), maison du Saint-Esprit (1575). RUE DU COQ, maison du Nom de Jésus (1623).
BOURG SAINT-GERMAIN. RUE DES BOUCHERIES, maison de l’Annonciation Notre-Dame (1522), maison de la Trinité (1527), maison du Seygne (cygne) de la croix. RUE DE BUCY, maison de l’Annonciation (1547). RUE DU FOUR, maison de l’Agnus Dei, maison de la Véronique (1595). RUE DU PETIT-LION, maison de l’Image Notre-Dame (1523). RUE DE SEINE, maison de l’Arche de Noé (1654). RUE DES CANETTES, maison du Chef Saint-Jean (1500).
C’étaient là des enseignes de maison, et non des enseignes de boutique, qui furent beaucoup plus nombreuses et qui changèrent souvent, au XVIᵉ siècle, quand la religion réformée fit la guerre aux images de la Vierge et des saints; au XVIIᵉ siècle, quand l’influence des poètes athées de l’école de
Théophile, de Saint-Amant[186] et de Desbarreaux s’exerça jusque sur les enseignes de dévotion, qui poursuivaient leurs regards dans toutes les rues de Paris et qui leur adressaient une sorte de reproche, même à la porte des cabarets; au XVIIIᵉ siècle, enfin, quand l’action sarcastique des philosophes et des encyclopédistes répandit dans les familles bourgeoises l’hérésie d’une nouvelle secte d’iconoclastes irréligieux. Puis, vint la révolution de 93, qui n’eut pas de peine à faire disparaître les dernières enseignes, dans lesquelles s’était perpétuée une pieuse tradition de nos ancêtres. On ne s’expliquerait pas que quelques-unes de ces vieilles enseignes aient pu échapper à la fureur inquisitoriale de la persécution républicaine, si l’on ne savait pas les miracles de courage, d’adresse et de dévouement que la foi chrétienne a pu faire par l’entremise des simples et des faibles. Les enseignes de cette espèce, qui ont traversé impunément une époque terrible où elles étaient proscrites sous peine de mort, avaient été sans doute enlevées de la place qu’elles occupaient et mises en lieu sûr, sinon recouvertes de plâtre ou cachées derrière d’autres enseignes indifférentes. Nous signalerons, parmi ces rares épaves du grand naufrage des enseignes pieuses, deux enseignes sculptées du XVIIᵉ siècle, Au Caveau de la Vierge, rue de Charonne, et A l’Annonciation, rue Saint-Martin; une autre du XVIᵉ siècle, Au Bon Samaritain, nº 15, rue de la Lingerie; une enseigne en fer forgé, A l’Enfant Jésus, rue Saint-Honoré, etc. (voir ci-dessus, à la page 88).
Ces enseignes furent peut-être respectées comme objets d’art, mais nous ne croyons pas qu’on ait sauvé alors une seule des statues de la Vierge, si multipliées dans l’ancien Paris, et qu’on voyait encore avant 1789 en toutes les rues, la plupart dans des niches ou sur des piédestaux extérieurs. Beaucoup de ces statues étaient honorées, depuis des siècles, d’une sorte de culte muet, qui se traduisait par des génuflexions
et des signes de croix; quelques-unes, parmi ces
statues, avaient même été sanctifiées dans la tradition locale, par des récits de guérisons miraculeuses; quelques-unes aussi méritaient d’être conservées, dans les musées, sous le rapport de la beauté ou de la singularité de leur exécution artistique. La charmante statue de la Vierge, en marbre, qui, jusqu’en 1844, servit d’enseigne à la boulangerie Barassé, rue du FaubourgSaint-Antoine, nº 186, provenait de l’abbaye Saint-Antoine-des-Champs, et avait été achetée en 1790 à la liquidation de l’abbaye. Elle appartient aujourd’hui à M. A. Barassé, notaire à Crécy-en-Brie[187] .
L’histoire de l’une de ces saintes images a été racontée par Tallemant des Réaux[188] avec plus de malice que de naïveté: «Il y avoit sur le pont NostreDame une enseigne de Nostre-Dame, comme il y en a en plusieurs lieux. Durant un grand vent, je ne sçay quels sots se mirent dans la teste qu’ils
avoient veu cette image aller d’un bout à l’autre du fer où elle estoit pendue; chose qui ne se pouvoit naturellement, car le vent peut bien faire aller une enseigne d’un costé et d’autre ou l’arracher tout à fait, mais non pas la faire couler le long de ce fer. Après cela ils s’imaginèrent qu’elle avoit pleuré et jetté du sang; enfin, cela alla si loing, que Monsieur de Paris fut contraint de la faire apporter, de peur qu’on n’en fît une Nostre-Dame à miracles. Pour une bonne fois, il devroit défendre de mettre des choses saintes aux enseignes, comme la Trinité et autres semblables.»
L’enseigne du pont Notre-Dame, qui avait paru se mouvoir, qui avait pleuré, qui avait jeté du sang, exaltait au plus haut degré la superstition de la foule; mais il y eut de bons chrétiens qui s’indignèrent de cette comédie pieuse, et les protestants se mirent de la partie pour demander que les images de sainteté ne figurassent plus dans les enseignes. La Notre-Dame qui avait causé tout ce bruit étant remplacée par une nouvelle, qui, au sortir des mains de l’imagier, n’avait fait encore aucun miracle, un quidam, resté inconnu, lui tira, dit-on, un coup de pistolet, qui aurait blessé cette image si réellement, que le sang sortait de la plaie. Tout Paris y courut pour voir l’effet du miracle; par malheur, on ne pouvait reconnaître la blessure faite à l’objet de la vénération publique que par les yeux de la foi. On n’en fit pas moins une gravure qui eut beaucoup de vogue[189] . Ce n’était pas la première fois que ces attentats s’adressaient à des Notre-Dame exposées dans les rues de Paris. Le plus sage eût été de les ôter, mais on n’osa pas chicaner et contrarier les habitudes de la population bourgeoise et marchande. On continua donc de laisser les symboles les plus vénérés de la religion figurer parfois de la manière la plus indécente dans les enseignes.
Ce fut à ce sujet que le poète dramatique Edme Boursault écrivit au commissaire Bizoton cette lettre très sensée, quoique très plaisante: «N’estce pas une allusion grossière, mais criminelle, de faire peindre un cygne à une enseigne, avec une croix, pour faire une équivoque sur le signe de la croix? Ne devroit-on pas condamner à une grosse amende un misérable cabaretier qui met à son enseigne un cerf et un mont, pour faire une ridicule équivoque à sermon? Ce qui autorise des ivrognes à dire qu’ils vont tous les jours au sermon, ou qu’ils en viennent! Ne fait-il pas beau voir un cabaret avoir pour enseigne: Au Saint-Esprit, pour faire une impertinente allusion au nom du Maître, et quoique je le croie assez honnête homme pour n’y penser aucun mal, ne sait-il pas que le cabaret, étant un lieu de débauche, ce n’est pas là que le Saint-Esprit doit être placé? J’en dis autant de la Trinité, de
l’Image Notre-Dame, et de je ne sais combien de saints qui servent d’enseignes de cabaret et qui enseignent peut-être encore pis. J’ai vu, dans une fort petite rue, qui donne d’un bout dans la rue Saint-Honoré et de l’autre dans celle de Richelieu, une de ces petites auberges ou gargotes où l’on prend des repas à juste prix, et voici quelle enseigne il y avoit: c’étoit Jésus-Christ que l’on prenoit au jardin des Oliviers ou jardin des Olives, et pour inscription de l’enseigne: Au juste pris, pour faire voir qu’on mangeoit là dedans à juste prix. Je fus si indigné contre le marchand qui avoit trouvé cette odieuse équivoque, que je ne pus retenir mon zèle, tout indiscret qu’il étoit. Je fis du bruit et menaçai même d’aller chercher un de vos confrères pour la faire abattre, et comme les commissaires sont plus craints de la populace qu’ils n’en sont aimés, la menace que je fis eut son effet, et quand je repassai l’enseigne n’y étoit plus[190].»
Tallemant des Réaux cite un autre trait de l’insolence impie des cabaretiers de Paris: «Un fou de cabaretier de la rue Montmartre avoit pris pour enseigne la Teste-Dieu; le feu curé de Saint-Eustache eut bien de la peine à la luy faire oster; il fallut une condamnation pour cela[191].» La police avait droit sans doute de faire décrocher les enseignes indécentes qui blessaient les yeux ou la conscience du public, mais une enseigne outrageante pour la religion devait certainement amener devant les tribunaux l’auteur de l’impiété ou de l’hérésie qui s’était produite, en pleine rue, de propos délibéré ou avec préméditation. On doit supposer que, dans le cours du XVIᵉ siècle, le Parlement eut à juger plus d’un procès de cette espèce. Il est avéré que les images de saints, et surtout les statues de la sainte Vierge, étaient, à cette époque, exposées à des insultes continuelles de la part des protestants, et qu’il fallut souvent garantir par des grilles ou des barreaux de fer ces statues et ces images contre les attaques nocturnes, qui se renouvelaient fréquemment, malgré la terrible pénalité que pouvaient entraîner de pareils attentats.
Lorsque les premiers imprimeurs furent venus d’Allemagne, de Hollande et de Suisse pour s’établir à Paris, ils annoncèrent, par des enseignes ou des marques mystiques accompagnées de citations de l’Écriture sainte, leur industrie, qu’on regardait comme émanée d’une inspiration divine; puis, quand les idées de réformation religieuse qui étaient entrées dans les esprits depuis Wiclef ou Jean Huss prirent une forme et un corps de doctrine sous l’influence de Luther, de Zwingle et de Mélanchthon, les imprimeurs se trouvaient tout préparés à recevoir ces idées et à les répandre; il en résulta
que la Réforme se propagea rapidement dans l’imprimerie et la librairie de Paris. On peut dire avec certitude que libraires et imprimeurs devinrent la plupart sympathiques à ce mouvement général du protestantisme, que les savants et les lettrés avaient si puissamment encouragé à la cour de François Iᵉʳ. Voici quelques marques ou enseignes typographiques dont les devises sont tirées de la Bible et des Évangiles. Jean André, libraire: un cœur au milieu des flammes, avec ce mot, Christus, et au-dessous, cette inscription: Horum major charitas (c’est-à-dire: le plus grand amour des vrais chrétiens); Conrad Badius, libraire et imprimeur: un atelier d’imprimerie, avec ces mots traduits de l’Écriture: A la sueur de ton visage, tu mangeras ton pain; mais quand cet imprimeur se fut retiré à Genève pour se consacrer à l’impression des ouvrages de Calvin, il adopta une autre marque, représentant le Temps, qui fait sortir du fond d’une caverne la Vérité nue, avec ce distique pour devise:
Des creux manoirs et pleins d’obscurité, Dieu, par le Temps, retire Vérité.
Gilles Corrozet, libraire, avait pris pour marque et pour enseigne: un cœur, chargé d’une rose (rébus sur Cor rozet), avec ces paroles du livre des Proverbes: In corde prudentis requiescit patientia; Nicole de la Barre, imprimeur: un cœur, contenant son monogramme, surmonté de signes
hiéroglyphiques, avec cette sentence biblique: Benedicite et nolite maledicere, hæc dicit Dominus (Bénissez, et gardez-vous de maudire, dit le Seigneur); Michel Fezandat, le libraire éditeur de Rabelais: un serpent, au milieu d’un bûcher, s’élance sur une main qui sort d’un nuage, et cherche à la mordre, avec ces mots: Ne la mort, ne le venin; Alain Lotrian, libraire: un écusson, à son monogramme, entre un évêque et un docteur, avec cette devise: Nulluy ne peut Jésus-Christ décevoir, etc. Les libraires et les imprimeurs attachés sincèrement à la religion catholique n’hésitaient pas à faire figurer le Christ dans leurs marques et leurs enseignes: par exemple, le libraire Jean de Brie avait dans sa marque saint Jean-Baptiste soutenant un écusson qui porte l’Agnus Dei; Guillaume Du Puy faisait représenter dans son enseigne Jésus et la Samaritaine s’entretenant auprès d’un puits.
Ce n’étaient pas là les derniers beaux jours de l’enseigne sacrée, qui se maintint en honneur jusqu’en 1789, malgré l’opposition d’un grand nombre de propriétaires, qui se refusaient à donner à leurs maisons le caractère d’un établissement catholique ou protestant. Cependant on conservait les anciennes enseignes de dévotion, et on en créait de nouvelles dans les nouveaux quartiers de Paris. Ainsi, en 1628, un propriétaire, qui fit bâtir dans la rue Mazarine quatre maisons, à la place d’une seule, que le siège de Paris avait ruinée pendant la Ligue, leur donna pour enseignes: le Port de salut, l’Image Sainte Geneviève, l’Image Sainte Catherine et la Trinité[192] . En cette même rue, la même année 1628, le nommé Salomon Champin, qui avait fait élever une maison neuve, au coin de la rue de Seine, lui donnait pour enseigne le Jugement de Salomon, pour faire allusion à son propre nom de baptême, car nous n’osons pas supposer que ce Salomon Champin était juif. Ce n’est que de notre temps qu’une enseigne juive a pu, sans aucune difficulté, être inaugurée au-dessus de la boutique d’un cordonnier israélite de la rue Croix-des-Petits-Champs, enseigne peinte, qui représentait Moïse, avec ses cornes de feu, descendant du mont Sinaï et présentant les tables de la loi au peuple d’Israël[193] .
XVII
ANECDOTES SUR QUELQUES ENSEIGNES
NOUS n’avons jamais eu l’intention de rassembler ici toutes les anecdotes relatives aux enseignes de Paris; ce serait un livre à faire, plutôt qu’un chapitre de cet ouvrage. Une pareille entreprise exigerait trop de temps et trop de recherches, car il faudrait feuilleter tous les volumes d’histoire qui ont été écrits depuis qu’il y a des enseignes de maison et de boutique, c’est-à-dire depuis le XIIᵉ ou le XIIIᵉ siècle. Nous devons donc nous borner à réunir un petit nombre d’anecdotes anciennes et modernes que nous n’avons pas eu l’occasion de citer dans le cours de notre travail.
Nous ne sommes pas parvenu à découvrir quelle était l’enseigne de la maison de Nicolas Flamel, dans la rue des Écrivains, au coin de la rue Marivault, près de l’église Saint-Jacques de la Boucherie. Nous supposons que cette enseigne était l’écritoire que Flamel avait adoptée comme armes parlantes et qu’il avait fait sculpter au-dessous de son monogramme N F, sur la petite porte de son église paroissiale Saint-Jacques de la Boucherie. On voyait à la façade de sa maison de la rue des Écrivains son image et celle de sa femme Perennelle, entaillées dans la pierre; ces deux sculptures naïves, mais assez grossières, subsistaient encore vers le milieu du dernier siècle[194] . L’emplacement de cette maison du célèbre écrivain hermétique n’est plus reconnaissable, depuis les démolitions qui ont permis d’ouvrir le square de la Tour Saint-Jacques, mais on le trouve bien indiqué dans les Comptes et ordinaires de la Prévôté de Paris en 1450: «Rue de la Pierre au lait (nouvelle dénomination de la rue des Écrivains). Maison en ladite rue, près de l’église Saint-Jacques de la Boucherie, à l’opposite de la ruelle du porche Saint-Jacques, à l’enseigne du Barillet, tenant d’une part à un hôtel de l’Image Saint Nicolas, qui fut à feu Nicolas Flamel, et de présent à Ancel Chardon, et d’autre part à un hôtel où pendoit l’enseigne du Gril[195].» Ces trois maisons nous paraissent avoir appartenu à Nicolas Flamel; l’enseigne du Barillet n’était autre que celle de l’Écritoire; l’enseigne de Saint Nicolas représentait le patron de l’écrivain, et l’enseigne du Gril faisait allusion au
gril ou à la grille que les secrétaires du roi et des grands seigneurs mettaient au-devant de leur signature particulière. Toutes les enseignes et tous les emblèmes que Nicolas Flamel avait fait sculpter ou peindre sur les maisons qu’il possédait à Paris, en les accompagnant d’inscriptions religieuses ou mystiques en vers, furent enlevées, à prix d’argent, par les souffleurs ou les alchimistes, qui croyaient y voir le secret de la Pierre philosophale.
L’enseigne du Cheval d’airain, qui désignait en 1581 une maison de la rue de Tournon, rappelait que cette maison, occupant l’emplacement du nº 27 actuel, avait été acquise, en 1531, pour le roi François Iᵉʳ, sous le nom d’un certain Pierre Spine, qui y fit construire des bâtiments et des hangars destinés à la fonte d’une statue équestre confiée au fondeur florentin Jean Francisque. Pierre Spine était sans doute l’entrepreneur de l’œuvre, puisqu’il dut fournir 10,000 livres de cuivre, dont six milliers environ entrèrent dans la fonte du cheval, qu’on appela le Cheval de bronze; mais il paraîtrait que la statue qui devait être sur ce cheval ne fut pas exécutée. Quant au statuaire, auteur du modèle en terre, nous croyons que c’était un artiste français, nommé François Roustien, qui touchait 1200 livres tournois de pension annuelle. On ne sait quel était ce cheval de bronze, fondu par ordre de François Iᵉʳ, ni quelle fut sa destinée. On avait cessé d’y travailler, au mois de juillet 1539, lorsque, par lettres patentes délivrées sous cette date, le roi fit don de la maison du Cheval d’airain à l’illustre poète Clément Marot, «pour ses bons, continuels et agréables services»[196] . Quelques historiens ont pensé que le Cheval de bronze qui fut placé sur le terre-plein du Pont-Neuf, avec la figure de Henri IV, fondue par Jean de Bologne et son élève Tacca, n’était autre que le cheval d’airain coulé en 1531 dans l’atelier de Pierre Spine, et resté jusque-là sans destination dans les magasins de l’État. Le procès-verbal retrouvé dans l’un des pieds du cheval[197] , quand le monument fut démoli le 12 août 1792, est venu détruire cette opinion. Nous avons raconté ailleurs l’histoire de cette statue, cheval et cavalier[198] .
La maison des Carneaux, dans la rue des Bourdonnais, ne devait pas avoir d’autre enseigne que les armes de la Trémoille, car c’était un véritable châtel à carneaux ou créneaux que cette maison seigneuriale, «fief de la Trémoille, dit Sauval, dont relèvent quantité de maisons tant de la rue des Bourdonnois que de celle de Béthisy[199]». De là le nom de Carneaux, donné à tout le quartier qui entourait cet ancien hôtel, dont il n’existait plus d’apparent qu’un beau donjon renfermant un escalier à vis, quand les architectes de la ville le firent démolir, en 1841, sous prétexte d’alignement.
Cet hôtel, qu’il était facile de restaurer de fond en comble et qui eût offert un admirable spécimen de l’architecture du XIVᵉ siècle, avait été depuis bien des années envahi par le commerce, qui y arbora l’enseigne de la Couronne d’or, en sorte que l’hôtel de la Trémoille ne s’appelait plus que l’hôtel de la Couronne d’or. Un marchand enrichi avait alors pris la place de l’illustre Guy de la Trémoille, favori du duc de Bourgogne, ce vaillant seigneur «entre les mains de qui Charles VI mit l’oriflamme en 1393» et dont les actions éclatantes firent sortir sa famille de «l’obscurité du Poitou».
Si une enseigne de marchand parvint à éclipser le nom d’une des plus glorieuses familles de France, nous voyons d’un autre côté un grand artiste, dont l’origine était certainement très vulgaire, se faire un grand honneur de cette origine et ajouter à son nom de famille le nom de l’enseigne qu’il ne rougissait pas d’avoir vu pendre à sa maison natale. Le plus fameux architecte français du XVIᵉ siècle, «Jacques Androuet, Parisien, comme l’a dit expressément La Croix du Maine dans sa Bibliothèque françoise, fut surnommé du Cerceau, qui est à dire Cercle, lequel nom il a retenu pour avoir un cerceau ou cercle pendu à sa maison, pour la remarquer et y servir d’enseigne; ce que je dis, en passant, pour ceux qui ignoreroient la cause de ce surnom.» Jacques Androuet du Cerceau était né vers 1540, dans une maison du faubourg Saint-Germain, où son père vendait du vin aromatisé et se trouvait ainsi obligé de se conformer aux ordonnances qui prescrivaient aux marchands de vin de sauge et de romarin, ou mélangés de substances aromatiques et liquoreuses, de pendre un cerceau à la porte de leur boutique. Jacques Androuet, dit du Cerceau, signa de son surnom les premières études d’architecture qu’il grava et publia d’abord à Orléans, où il paraît avoir passé sa jeunesse, sans doute parce que son père avait des vignobles et des caves dans l’Orléanais. Quand il revint à Paris et qu’il y recueillit les Dessins et Portraits de la plupart des anciens et modernes bâtimens et édifices de la capitale, il se préparait à mettre au jour, sous les auspices de la reine mère Catherine de Médicis, les deux grands volumes Des plus excellents bâtimens de France, «dressés par Jacques Androuet, dit du Cerceau.» On rapporte même que cet habile architecte, devenu l’architecte de la reine mère et du roi, acheta une maison à l’entrée du petit Pré aux Clercs, à la porte de Nesle, et qu’il donna pour enseigne à cette maison le Cerceau, qui rappelait son origine et son surnom, «comme une espèce de titre seigneurial[200]».
Pierre Costar, écrivain prétentieux de l’école de Balzac, n’avait ni l’esprit ni le talent de Jacques Androuet du Cerceau; il fut poursuivi toute sa vie par
