Advanced Fermentation and Cell Technology E-Book

Byong H. Lee

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 2149

Veröffentlichungsjahr: 2021

Beschreibung

ADVANCED FERMENTATION AND CELL TECHNOLOGY

A comprehensive and up-to-date reference covering both conventional and novel industrial fermentation technologies and their applications

Fermentation and cell culture technologies encompass more than the conventional microbial and enzyme systems used in the agri-food, biochemical, bioenergy and pharmaceutical industries. New technologies such as genetic engineering, systems biology, protein engineering, and mammalian cell and plant cell systems are expanding rapidly, as is the demand for sustainable production of bioingredients, drugs, bioenergy and biomaterials. As the growing biobased economy drives innovation, industrial practitioners, instructors, researchers, and students must keep pace with the development and application of novel fermentation processes and a variety of cell technologies.

Advanced Fermentation and Cell Technology provides a balanced and comprehensive overview of the microbial, mammalian, and plant cell technologies used by the modern biochemical process industry to develop new and improved processes and products. This authoritative volume covers the essential features of advanced fermentation and cell technology, and highlights the interaction of food fermentation and cell culture biopharmaceutical actives. Detailed chapters, organized into five sections, cover microbial cell technology, animal and plant cell technology, safety issues of new biotechnologies, and applications of microbial fermentation to food products, chemicals, and pharmaceuticals. Written by an internationally-recognized expert in food biotechnology, this comprehensive volume:

• Covers both conventional and novel industrial fermentation technologies and their applications in a range of industries
• Discusses current progress in novel fermentation, cell culture, commercial recombinant bioproducts technologies
• Includes overviews of the global market size of bioproducts and the fundamentals of cell technology
• Highlights the importance of sustainability, Good Manufacturing Practices (GMP), quality assurance, and regulatory practices
• Explores microbial cell technology and culture tools and techniques such as genome shuffling and recombinant DNA technology, RNA interference and CRISPR technology, molecular thermodynamics, protein engineering, proteomics and bioinformatics, and synthetic biology

Advanced Fermentation and Cell Technology is an ideal resource for students of food science, biotechnology, microbiology, agricultural sciences, biochemical engineering, and biochemistry, and is a valuable reference for food scientists, researchers, and technologists throughout the food industry, particularly the dairy, bakery, and fermented beverage sectors.

Leseprobe

Table of Contents

Cover

Title Page

Title Page

Copyright

Volume I

Preface

Overview on Market Size of Bioproducts and Fundamentals of Cell Technology

Biotechnology and global market size of bioproducts

Cellular organization and membrane structure of three domains

Part I: Microbial Cell Technology

1.1 Basic bacterial growth and mode of fermentation

1.2 Basic fungal growth

1.3 Classical strain improvements and tools

1.4 Modern strain improvement and tools

1.5 Bioengineering and scale‐up process

1.6 New bioprocesses of fermentation

Part II: Applications of Microbial Fermentation to Food Products, Chemicals and Pharmaceuticals

2.1 Fermented dairy products

2.2 Fermented meat and fish products

2.3 Fermented vegetable and cereal products

2.4 Organic acids

2.5 Fermentation‐derived food and feed ingredients

2.6 Bacteriocins and bacteriophages

2.7 Enzymes

2.8 Biomass (SCP) and mushrooms

2.9 Functional foods and nutraceuticals

2.10 Alcoholic beverages

2.11 Other fermentation chemicals

2.12 Pharmaceuticals, growth promoters, and biopesticides

Volume II

Part III: Animal Cell Technology

3.1 Animal cell culture

3.2 Transgenic animal bioreactors

Part IV: Plant Cell Technology

4.1 Introduction

4.2 Plant tissue culture

4.3 Applications of plant tissue culture

Part V: Safety Issues of New Biotechnologies on Microbial, Animal, and Plant Cells

5.1 Introduction

5.2 Safety evaluation of novel foods and cell culture products

Index

End User License Agreement

List of Tables

Intro

Table 1 Fermentation biotechnology milestones and some recombinant proteins

Table 2 Some of recombinant biopharma products

Table 3 Different features in cells of bacteria, animal, and plant cells

Chapter 1

Table 1.1 The important bacterial family in biotechnological processes

Table 1.2 Some bacteria of biotechnological importance among 19 bacterial g...

Table 1.3 μ‐dependent product formation kinetics in continuous cultures

Table 1.4 Different strategies used to control the growth in a fed‐batch pr...

Table 1.5 Different parts of fermenter and its function

Table 1.6 Historically developed types and applications of bioreactors

Table 1.7 Advantages of immobilized enzymes and cells

Table 1.8 Some adsorbents for the immobilization of enzymes

Table 1.9 Applications of developed immobilized enzyme reactors

Table 1.10 Half‐lives of some immobilized enzymes

Table 1.11 Application and stability of various immobilized cells

Table 1.12 Examples of enzyme electrodes

Table 1.13 Comparison of Km and activation energy (kcal/g.mol) values of so...

Table 1.14 Temperature ranges of bacterial growth

Table 1.15 Some of recognized biotechnologically important fungi and molds

Table 1.16 Examples of analog resistant deregulated mutants which overprodu...

Table 1.17 Examples of auxotrophic mutants that overproduce primary metabol...

Table 1.18 Examples of chemical mutagens and their mode of action

Table 1.19 Some examples of restriction endonucleases, their origins, and s...

Table 1.20 Some examples of different vectors

Table 1.21 Advantages and disadvantages of the three cloning techniques

Table 1.22 Advantages and disadvantages of different expression hosts

Table 1.23 Comparison of next‐generation sequencing methods

Table 1.24 Milestones of CRISP‐Cas technology

Table 1.25 Major components and functions of CRISPR/Cas9.

Table 1.26 Applications of molecular thermodynamics in various fields of bi...

Table 1.27 The heat shock protein family of molecular chaperones

Table 1.28 Examples of bacterial quorum sensing controlled processes and tr...

Table 1.29 Models for studying QS in cooperative and competitive microbial ...

Table 1.30 Solubilities of substrates and metabolites in water at 25 °C

Table 1.31 Effect of substrate and cell yield on oxygen requirement and hea...

Table 1.32 Heat production during the continuous culture of microorganisms ...

Table 1.33 Estimated operating costs for biomass production from different ...

Table 1.34 Flow characteristics of three types of pressure‐driven membrane ...

Table 1.35 Two‐phase aqueous extractions of enzymes from microbial cells*

Table 1.36 Different methods and characteristics of chromatographic process...

Table 1.37 Type of data required from laboratory and pilot experiments for ...

Table 1.38 Scale factors in translation of pilot plant data into production

Table 1.39 Basic process control parameters that can be measured in ferment...

Table 1.40 Some affinity tags of proteins and peptides used for purificatio...

Chapter 2

Table 2.1 Lactic acid bacteria and predominant species

Table 2.2 Contributions of lactic acid bacteria as natural ingredients, hea...

Table 2.3 Plasmid encoded functions of lactic acid bacteria

Table 2.4 Genetic transfer systems in lactic acid bacteria

Table 2.5 Cloning and expression of heterologous genes in lactic acid bacte...

Table 2.6 Possible targets of genetic engineering in modifying starter cult...

Table 2.7 Classification of various fermented sausages

Table 2.8 Classification of fermented sausages in Europe (non–heat treated)

Table 2.9 Bacteria used as starter cultures in meat, poultry, and fish prod...

Table 2.10 Some bacteria investigated for their potential use as starter cu...

Table 2.11 Fish sauces

Table 2.12 Fish pastes and their ingredients

Table 2.13 Key characteristics of the four genera of acetic acid bacteria c...

Table 2.14 Comparison of acetic acid productivity between two transformants...

Table 2.15 Raw materials used in lactic acid production by fermentation and...

Table 2.16 Bacteria capable of producing vanillin from ferulic acid.

Table 2.17 World production and applications of amino acids for the food an...

Table 2.18 Overview of yield obtained with different amino acids production...

Table 2.19 Overview of metabolic engineering strategies to improve amino ac...

Table 2.20 Some consumer and industrial applications of gums

Table 2.21 Sales of major food‐approved polysaccharides

Table 2.22 Microbial polysaccharides related to the food industry

Table 2.23 Global PHA producers and their substrates.

Table 2.24 Bacteriocins of bacteria and archea

Table 2.25 Pros and cons of the use of bacteriophages and phage lytic prote...

Table 2.26 Applications of important commercial food enzymes

Table 2.27 Some properties and applications of commercial lactases

Table 2.28 Some properties and applications of commercial lipases

Table 2.29 Few important therapeutic enzymes in medicine

Table 2.30 Source organisms and substrate used for the production of bacter...

Table 2.31 Substrates for microbial protein production

Table 2.32 Comparative analysis of various biomass products

Table 2.33 Industrial establishments involved in SCP production

Table 2.34 Economics of the five SCP processes versus soymeal and fish meal

Table 2.35 Examples of functional food components

Table 2.36 Properties and benefits of good probiotic strains

Table 2.37 Other potential applications of probiotics

Table 2.38 Non‐digestible oligosaccharides with bifidogenic functions comme...

Table 2.41 World production of wine and annual per capita consumption in 20...

Table 2.39 World beer production (2011) in different countries

Table 2.40 Per capita consumption of beer in different countries (2015–2016...

Table 2.42 Some targeted desirable characteristics of a wine yeast that may...

Table 2.43 Annual fuel ethanol production (millions of US. liquid gallons p...

Table 2.44 Theoretical ethanol yield from different biomass feedstocks

Table 2.45 Fermentation ethanol from feedstocks

Table 2.46 Chemical and physical properties of gasoline, diesel, butanol an...

Table 2.47 Butanol fermentation from starch‐based substrates

Table 2.48 Comparisons of ABE fermentation from lignocellulosic materials

Table 2.49 Improvement strategies for biobutanol production

Table 2.50 Typical results of microbial production of diols in different pr...

Table 2.51 Some typical yields of biodiesel from different crops

Table 2.52 Biogas composition (%) from different substrates by anaerobic di...

Table 2.53 Biomethane production of selected lignocellulosic biomass.

Table 2.54a Comparison of production rate of biological H

2

in different pro...

Table 2.54b

Advantages and disadvantages of biohydrogen production processes.

Table 2.55 Fermentative hydrogen production from various biomass

Table 2.56a Classification of antibiotics based on chemical structure and me...

Table 2.56b Some of common commercial antibiotics

Table 2.57 Overview of various discovery platforms for antibacterial drugs

Table 2.58 Some examples of natural products (NP), semisynthetic natural pr...

Table 2.59 Production of other antibiotics and productivity using fermentat...

Table 2.60 Penicillin production and strain development by mutagenesis and ...

Table 2.61 Types and effectiveness of penicillin (PEN) including natural an...

Table 2.62 Antibiotic use for growth promotion in livestock production

Table 2.63 Antimicrobial classes and products on the basis of importance of...

Table 2.64 The estimated numbers of new cases and deaths for each common ca...

Table 2.65 The top ten best‐selling cancer drugs of 2018 (in terms of reven...

Table 2.66 Lists of FDA‐approved anticancer drugs from 1949 to 2014

Table 2.67 Some known microbial anti‐tumour compounds

Table 2.68 Examples of biopharmaceutical compounds produced by applying yea...

Table 2.69 Major steroids and their physiological functions

Table 2.70 Some enzymes used for steroid biotransformation and their functi...

Table 2.71 Microbial production of steroidal intermediates from natural ste...

Table 2.72 Improved statin production through chemical and physical mutagen...

Table 2.73 Milestone of commercial development and discovery on biopesticid...

Chapter 3

Table 3.1 Large‐scale manufacturing facilities for the production of viral ...

Table 3.2 Different types of microcarriers commercially available

Table 3.3 Comparisons of batch, fed‐batch and continuous (perfusion) of cel...

Table 3.4 Some examples of industrial‐scale animal cell suspension culture

Table 3.5 Therapeutic monoclonal antibodies approved or under review in the...

Table 3.6 Milestones of vaccine development

Table 3.7 Composition of the pertussis component of selected vaccines

Table 3.8 Some licensed polysaccharide and conjugate vaccines by 2016*

Table 3.9 Advantages and disadvantages of next generation vaccines platform...

Table 3.10 Licensed and promising vaccine adjuvants

Table 3.11 Few types of micro‐and nanoparticles studied for antigen deliver...

Table 3.12 Comparison between traditional and reverse vaccinology

Table 3.13 Some of commercial hepatitis vaccines produced by different comp...

Table 3.14 Completed phase II and III human HIV‐1 vaccine trials*

Table 3.15 Package inserts and manufacturers for some US‐licensed vaccines ...

Table 3.16 COVID‐19 candidate vaccines undergoing clinical trials by 2020

Table 3.17 Milestones of some successful transgenic animals and fishes

Chapter 4

Table 4.1 Milestone of plant tissue culture

Table 4.2 Advantages and disadvantages of plant tissue culture

Table 4.3 Applications of embryo plant tissue culture

Table 4.4 Factors affecting viability of plant cells frozen for cryopreserv...

Table 4.5 Some useful plant variants generated through somaclonal variation...

Table 4.6 Some successful asymmetric protoplast fusion in different plant f...

Table 4.7 Summary of the applications, advantages and disadvantages of soma...

Table 4.8 Substances reported from plant cell cultures

Table 4.9 Some known commercial natural products and heterologous proteins ...

Table 4.10 Some selected secondary metabolites produced by wild‐type HR cul...

Table 4.11 Some selected secondary metabolites and recombinant proteins pro...

Table 4.12 Some selected phytoremediation of various pollutants by wild or ...

Table 4.13 Other biotransformation for secondary plant metabolites with pot...

Table 4.14 Composition of media most frequently used*

Table 4.15 Classification of plant cell bioreactors for production of prote...

Table 4.16 Transformation advantages of chloroplast genome over nuclear gen...

Table 4.17 Many vaccine antigens and biopharmaceuticals produced by enginee...

Table 4.18 Commercially grown genetically modified crops and food species

Table 4.19 Global area of GM crops in 2017 by country (million hectares)**

Table 4.20 Top ten and rest countries which granted food, feed and cultivat...

Table 4.21 Application of CRISPR based genome editing approach in plants fo...

Chapter 5

Table 5.1 Summary of criteria used in the safety evaluation of novel foods ...

Table 5.2 Some areas of safety consideration in the regulation of foods, fo...

Table 5.3 Regulatory framework for food, food products, feed products deriv...

Table 5.4a Some of the transgenic animals with potential commercial applica...

Table 5.4b The sequence availability of the GM animals listed in Table 5.4a.

Table 5.5 Some of pros and cons for genetically modified animals and crops

Table 5.6 Safety consideration and regulation of genetically modified foods...

Table 5.7 Summary of several detection methods for GMO* products

List of Illustrations

Intro

Figure 1 Concept of cell culture technology derived from microbes, animals, ...

Figure 2 (a) Scheme of microbial bioproducts except for fermented foods and ...

Figure 3 A phylogenetic tree based on rRNA data, showing the separation of b...

Figure 4 Fluid mosaic model for cell membrane (

Source

: http://www.biology.ar...

Figure 5 Concept of three life domains based on rRNA data, showing the separ...

Chapter 1

Figure 1.1 The graph showing the principle of a substrate limited fed‐batch ...

Figure 1.2 Simplified schematic illustration of different culture methods. (...

Figure 1.3 Types of submerged‐culture fermenter. (a) Stirred‐tank fermenter,...

Figure 1.4 Basic immobilized enzyme or cell reactor types.

Figure 1.5 Representation of wave bioreactor (

Source

: OpenWAVE25). (

See inse

...

Figure 1.6 Sexual reproduction cycle in yeast

Figure 1.7 Pathway and control of lysine production in auxotrophic mutant of...

Figure 1.8 Outline of the three general strategies of gene cloning.

Figure 1.9 Scheme of cloning a foreign chromosomal DNA fragment using a vect...

Figure 1.10 Outline structure of the cloning vector pUC18 with some of the r...

Figure 1.11 Simplified scheme of using reverse transcriptase to convert mRNA...

Figure 1.12 Principles of the polymerase chain reaction (PCR).

Figure 1.13 A brief history of RNAi evolution (www.thermofisher.com/kr/ko/ho...

Figure 1.14 RNAi mechanism. (i) The entry of long double‐stranded RNA such a...

Figure 1.15a Mechanism of CRISPR/Cas immunity divided into three stages. Sta...

Figure 1.15b Mechanism of CRISPR immunity in all three types of CRISPR/Cas s...

Figure 1.15c The structural features of CRISPR. The repeat sequences with co...

Figure 1.16 Biological and crystal structure of Cas‐9. The Cas9 protein is r...

Figure 1.17 Different steps involved in synthesis of stable protein (adapted...

Figure 1.18 Protein folding inside the cell. A new protein is synthetized at...

Figure 1.19 The rational/semi‐rational design (site‐directed mutagenesis) an...

Figure 1.20 Reaction scheme for the Kemp elimination of 5‐nitrobenzisoxazole...

Figure 1.21 (a) A microarray may contain thousands of “spots”. Each spot con...

Figure 1.22 (a‐c) Illustration of the overlap between metabolic engineering ...

Figure 1.23 Contribution and overlap of systems/synthetic biology to metabol...

Figure 1.24 Model of quorum sensing in

Vibrio fischeri

. Permission from Poph...

Figure 1.25 General process scheme for upstream and downstream fermentation....

Figure 1.26 Resistance to oxygen transfer from the air bubble to a microbial...

Figure 1.27 Factors contributing to and phenomena affected by heat effects i...

Figure 1.28 Correlation of heat production Y

Δ

and biomass yield Y

s

on d...

Figure 1.29 General schemes of protein recovery operation through sequences ...

Figure 1.30 A process flow sheet for product recovery.

Figure 1.31 Separation methods based on physico‐chemical properties of parti...

Figure 1.32 Flow processes in the production of recombinant chymosin.

Figure 1.33 Scale‐up requiring a highly interdisciplinary task, concepts and...

Figure 1.34 Scaling fermentation vessels by the 1:10 ratio method.

Figure 1.35 RITE Bioprocess®, an innovative growth‐arrested bioprocess devel...

Figure 1.36 RITE bioprocess for producing biofuels and other green chemicals...

Figure 1.37 Overall process set‐up of fully integrated reactive extraction i...

Figure 1.38 Bioprocessing approaches for the conversion of lignocellulosic b...

Chapter 2

Figure 2.1 Basic steps of most cheese varieties (e.g. Cheddar).

Figure 2.2 Dynamic nature of cheese flavor development.

Source

: Steele et al...

Figure 2.3 Secondary biochemical changes during cheese ripening.

Figure 2.4 Transformation of fatty acids.

Figure 2.5 Catabolic pathways of lactose and galactose by lactococci: 1, the...

Figure 2.6 Citrate metabolism in lactic acid bacteria.

Figure 2.7 General proteolytic system of lactic acid bacteria in cheese.

Figure 2.8 Overview of the putative functions of plasmid‐encoded genes in

L.

...

Figure 2.9 The overall process of chymosin production using recombinant

K. l

...

Figure 2.10 Flowchart for soy sauce manufacture.

Figure 2.11 Flowchart for rice–miso manufacture.

Figure 2.12 Pathways from glucose to fumaric acid.

Source

: Xu et al., 2012....

Figure 2.13 Oxidative formation of methyl ketones by

Penicillium roqueforti

....

Figure 2.14 Production of diacetyl from citrate.

Figure 2.15 Oxidative conversion of ricinoleic acid into γ‐decalactone by

Ca

...

Figure 2.16 Highest reported value for each terpenoid class produced by diff...

Figure 2.17 Vanillin production by eugenol degradation by

Corynebacteirum

sp...

Figure 2.18 Schematic representation of the non‐β‐oxidative pathway for conv...

Figure 2.19 Construction of plasmids pBB1 containing genes from

Pseudomonas

...

Figure 2.20 Production of 10–15 DE syrup by thermostable α‐amylase.

Figure 2.21 Process flowchart for dextrose production.

Figure 2.22 Schematic diagram of the production of HFCS 55 and HFCS 90 from ...

Figure 2.23 Conversion of D‐glucose to 2‐KGA by way of (1) two‐stage ferment...

Figure 2.24 Summary of major natural pigment classes in the market and their...

Figure 2.25 Fermentation process for the production of microbial xanthan.

Figure 2.26 Schematic representation of the alginate biosynthetic steps in

A

...

Figure 2.27 Structure of nisin.

Figure 2.28 Structure of pediocin PA‐1.

Figure 2.29 Schematic overview of the suggested machinery for production of ...

Figure 2.30 Global versus Chinese enzyme market in 2010.

Figure 2.31 General scheme for enzyme production and downstream processing....

Figure 2.32 Flow diagram of stages in the production of

Agaricus bisporus

.

Figure 2.33 Mechanisms of immunomodulation by beneficial microbes. Probiotic...

Figure 2.34 Restorative strategies for dysbiosis. Probiotics may be administ...

Figure 2.35 Schematic outline of the brewing process.

Figure 2.36 Structure of humulone and isomerization.

Figure 2.37 Schematic outline of wine making.

Figure 2.38 Formation of ethyl carbamate.

Figure 2.39 Schematic operation of sake production.

Figure 2.40 Classification of biofuels.

Source

: Nigam and Singh, 2011.

Figure 2.41 Scheme for a continuous flow fermentation process of bioethanol....

Figure 2.42 Timeline of notable events and advances in butanol fermentation ...

Figure 2.43 Pathway of acetone–butanol–ethanol (ABE) fermentation by clostri...

Figure 2.44a A representative schematic diagram of fermentative butanol prod...

Figure 2.44b Common (i) pretreatment methods, (ii) detoxification methods, (...

Figure 2.45 Condensation of dehydrated bioethanol (100% anhydrous state) to ...

Figure 2.46 Major routes for bioproduction of diols from different feedstock...

Figure 2.47 Natural (a) and engineered metabolic pathways (b–d) enabling bio...

Figure 2.48 Some important derivatives of 2,3‐butanediol and their potential...

Figure 2.49 The metabolic pathways for 2,3‐butanediol synthesis in bacteria....

Figure 2.50 World biodiesel production and capacity.

Source

: Biodiesel 2020:...

Figure 2.51 Cultivation of microalgae species in waste‐water and photo‐biore...

Figure 2.52a The scheme of the anaerobic digestion plant (www.globalmethane....

Figure 2.52b Schematic representation of the sustainable cycle of anaerobic ...

Figure 2.53 Process stages of the conversion of lignocellulosic biomass to b...

Figure 2.55 Biohydrogen gas production through

in vitro

artificial enzymatic...

Figure 2.55 Schematic of (a) a single and (b) dual‐chambered microbial elect...

Figure 2.56a Roadmap from microalgae to hydrogen.

Source

: Wang and Yin, 2018...

Figure 2.56b The production of biohydrogen in microalgae. In the alga

Chlamy

...

Figure 2.57 Antibiotic targets and mechanisms of resistance.

Source

: Wright,...

Figure 2.58 Early stages of antibiotic discovery from microbial product libr...

Figure 2.59 Outline diagram of current penicillin production by fed‐batch su...

Figure 2.60 Chemical structures of different classes of penicillins. Example...

Figure 2.61 Schematic overview of the penicillin biosynthetic pathway. ACVS,...

Figure 2.63 Global antimicrobial use in food animals. (a) Major users of ant...

Figure 2.63 Structures of some microbial anticancer compounds such as mithra...

Figure 2.64 Structures of different type II polyketides synthases (PKSs) pro...

Figure 2.65 Mode of action of doxorubicin (DXR) inside the cancer cell. Doxo...

Figure 2.66 Physical and functional map of the daunorubicin and doxorubicin ...

Figure 2.67 Overall scheme used for enhanced production of daunorubicin and ...

Figure 2.68 Schematic representation of genes involved in regulation of daun...

Figure 2.69 Four axes of yeast's contribution to cancer research. (a) Elucid...

Figure 2.70 Yeast‐based cancer studies. Top: Synthetic lethality interaction...

Figure 2.71 Editing of BGCs based on CRISPR/Cas9 strategies. (a) HDR‐mediate...

Figure 2.72 Classification of the microbial bioprocesses for steroid synthes...

Figure 2.73 Chemical structures of relevant steroidal compounds containing t...

Figure 2.74 Scheme of the rational construction of mycobacterial strains pro...

Figure 2.75 Chemical structure of statins and the enzyme substrate HMG‐CoA. ...

Figure 2.76 The HMG‐CoA reductase pathway, which is blocked by statins via i...

Figure 2.77 Biosynthesis pathway of lovastatin.

Source

: Subhan et al., 2016....

Figure 2.78 Chemical structures of lovastatin acid, monacolin J acid, and si...

Chapter 3

Figure 3.1 (a) Roller bottles

Source

: Amy T. Lang/Corning, Inc. and (b) mult...

Figure 3.2 MDCK cells grown in serum‐free medium (MDSS2N with 0.45% plant ex...

Figure 3.3 Schematic representation of the hybridoma technology for producin...

Figure 3.4 Scheme of downstream process for manufacturing recombinant protei...

Figure 3.5a Strains development of animal cell cultures by several methods i...

Figure 3.5b Genetic engineering scheme of animal cell culture for recombinan...

Figure 3.6a Steps in the production and selection of monoclonal antibody/sec...

Figure 3.6b Overview of mABs production.

Source

: European‐Molecular‐Biology ...

Figure 3.7 Typical downstream process for monoclonal antibody production....

Figure 3.8 Schematic overview of the different strategies used to generate b...

Figure 3.9 The convention vaccine development using two methods in general....

Figure 3.10 Comparison between production of glycoconjugates through (a) che...

Figure 3.11 Schematic illustration in the making of a DNA vaccine against We...

Figure 3.12 GenePro® strategic vaccine approach for the induction of therape...

Figure 3.13 Induction scheme of cellular and humoral immunity by DNA vaccine...

Figure 3.14 Representative structures of various nanoparticles for drug deli...

Figure 3.15 Schematic diagram summarizing the pathway of vaccine development...

Figure 3.16 Summary of the reverse vaccinology protocol applied to

Campyloba

...

Figure 3.17 The mRNA‐based strategy for Zika vaccine by cloning of genes for...

Figure 3.18 The production scheme of recombinant hepatitis B vaccine.

Figure 3.19a HIV retrovirus schematic of (a) cell infection, virus productio...

Figure 3.19c Steps of retrovirus replication cycle (With permission of wikip...

Figure 3.20 Somatic‐cell nuclear transfer.

Chapter 4

Figure 4.1 Basic procedure for obtaining a culture of plant tissue.

Figure 4.2The protocol and procedure for plant micropropagation of seed.

Figure 4.3 General steps involved in callus culture.

Figure 4.4 The common protocol for plant protoplast isolation.

Figure 4.5 General cryopreservation method of plant cell cultures.

Figure 4.6a Basic procedure for obtaining somatic hybrids from normal cell p...

Figure 4.6b Basic procedure for obtaining somatic hybrids by either symmetri...

Figure 4.7 Production of novel interspecific and intergenic hybrid pomato be...

Figure 4.8 Large‐scale production scheme of shikonin by

L. erythrorhizon

cel...

Figure 4.9 Pathway for

in vivo

production of taxadiene and 5‐α‐hydroxytaxadi...

Figure 4.10a,b (a) Representative multistep semisynthesis of paclitaxel (R =...

Figure 4.10 (

Continued

)

Figure 4.11 Artemisinin biosynthesis pathway occurs in the glandular trichom...

Figure 4.12 Engineering of

E. coli

for the biosynthesis of artemisinic acid ...

Figure 4.13a Production of artemisinic acid or β‐farnesene by engineered yea...

Figure 4.13b Sanofi industrial semi‐synthesis of artemisinin by large‐scale ...

Figure 4.14 Scheme on de novo production of resveratrol from glucose or etha...

Figure 4.15 The ecy of algal biodiesel production.

Figure 4.16 Plant bioreactor system via protein compartmentation within a pl...

Figure 4.17 Research network in elemental and functional research areas of H...

Figure 4.18 Global area of GM crops from 1996 to 2017 (million hectares)....

Figure 4.19 Global map of GM crop countries and mega‐countries in 2017 (*18 ...

Figure 4.20 Adoption status of GM crops in the US during 1996–2017. Data for...

Figure 4.21 Status of approved GM crops used in food, feed, processing, and ...

Figure 4.22 Contribution of GM crops to food security, sustainability and cl...

Guide

Cover Page

Table of Contents

Title Page

Title Page

Copyright

Begin Reading

Index

WILEY END USER LICENSE AGREEMENT

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Advanced Fermentation and Cell Technology

Volume 1

Byong H. Lee

SportBiomics, CA, USA and Heilenex Pharma Inc., Toronto, CanadaKangwon National University, Chuncheon, South KoreaJiangnan University, Wuxi, ChinaMcGill University and AAFC, Quebec, Canada

Advanced Fermentation and Cell Technology

Volume 2

Byong H. Lee

SportBiomics, CA, USA and Heilenex Pharma Inc., Toronto, CanadaKangwon National University, Chuncheon, South KoreaJiangnan University, Wuxi, ChinaMcGill University and AAFC, Quebec, Canada

This edition first published 2022

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Names: Lee, Byong H., author.

Title: Advanced fermentation and cell technology / Byong H. Lee,

SportBiomics, CA, USA and Heilenex Pharma Inc., Toronto, Canada, Kangwon National

University, Chuncheon, South Korea, Jiangnan University, Wuxi, China, McGill University and

AAFC, Quebec, Canada.

Description: Hoboken, NJ, USA : Wiley‐Blackwell, 2022. | Includes

bibliographical references and index.

Identifiers: LCCN 2020026477 (print) | LCCN 2020026478 (ebook) | ISBN

9781119042761 (cloth) | ISBN 9781119042785 (adobe pdf) | ISBN

9781119042778 (epub)

Subjects: LCSH: Fermentation. | Industrial microbiology.

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LC record available at https://lccn.loc.gov/2020026477

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Cover Design: Wiley

Cover Images: Tubular bioreactors filled green algae fixing CO2 © Santiago Urquijo / Getty Images, Cultures growing on Petri dishes © WLADIMIR BULGAR/SCIENCE PHOTO LIBRARY / Getty Images, CAR T cell immunotherapy, illustration © KEITH CHAMBERS/SCIENCE PHOTO LIBRARY / Getty Images, Bison or Aurochs in winter season in their habitat © danm / Getty Images, CoronaVirus CopySpace © BlackJack3D / Getty Images, illustration 3d DNA Spin Futuristic digital background, Abstract background for Science and technology © Jackyenjoyphotography / Getty Images

Preface

The term fermentation derived from the Latin verb fevere (boil) used by humans for the production of food and beverages since the Neolithic age is the oldest of all biotechnological processes. The fermentation process used in the production of antibiotics, alcohol, bread, vinegar and other food or industrial products differs from respiration in that organic substances rather than molecular oxygen are used as electron acceptors. After successful microbial fermentation processes on microbial cells (biomass), microbial enzymes, microbial metabolites including antibiotics, and other fermented foods, currently more than 3500 different fermented foods are consumed by humans worldwide. The potential of fermentation techniques was dramatically increased in the late 1960s and 1970s through achievements in molecular genetics, cell fusion, and enzyme technology. However, additional completely novel, powerful techniques such as genetic engineering via recombinant DNA technology in 1973 and hybridoma technology (monoclonal antibody) in 1975 were responsible for the current biotechnology boom.

In genetic engineering, a known gene is inserted into a microbial, animal, or plant cell in order to achieve a desired trait for the overproduction of target compounds, but microorganisms have played a major role in the development of biotechnology. This is due to the rapid growth of microbes, cheap growth media, massive diversity in the metabolite types and easy of genetic manipulation. However, mass culture of animal cell lines is also important to manufacture viral vaccines and other therapeutic recombinant products such as enzymes, hormones, immunologicals (monoclonal antibodies, interleukins, lymphokines, etc), and anticancer agents. Mammalian cells cultivated in bioreactors have surpassed microbial systems for producing therapeutic recombinant proteins because of their capacity for proper protein folding, assembly and post‐translational modification. Major therapeutic recombinant proteins are successfully commercialized, but expensive animal free media, cost of production in large scale with low yield (the tens‐of‐milligrams/liter), microbial contamination, and gene regulation are the important issues to be resolved. Other cell culture research is also underway to produce such complex therapeutic proteins in insect cell (baculovirus) or in higher plants. Molecular biopharming using transgenic animals such as goat and pig for rDNA proteins have also successfully commercialized.

Fermentation technology for the production of compounds that find application in food, biochemical, biomaterial, bioenergy, pharmaceutical sectors encompasses a broad field, not only including (1) conventional microbial and enzyme systems, (2) genetic and metabolic engineering, along with systems biology/synthetic biology, and genome editing, but also including (3) mammalian cell and plant cell systems. Despite a long history of fermentation processes for generations, the requirement for sustainable production of bioenergy and biomaterials is also demanding innovation and development of novel fermentation concepts. Continued introduction of new technology in cell culture systems demands innovation in new bioreactor process development and scale up processes for cell factory potential.

This book reflects this transition from traditional fermentation technology to new cell fermentation technology, that provides equal emphasis on microbial, mammalian as well as plant cell technologies for new and improved processes and products in today's biochemical process industry.

Currently two fermentation textbooks available on the market (1999) are outdated and do not deal with current progress in fermentation and cell culture technologies and commercial recombinant bioproducts. Most other edited volumes are the work of multiple contributors and normal didactic criteria for explanation of evolving new techniques and applications are lacking. Experience in teaching this subject has made clear that the basic concepts and essential features have not been covered in a typical science curriculum. The primary objective of writing this book is to relate the food fermentation and cell culture biopharmaceutical actives using different expression hosts. Product diversity makes fermentation technology a multi ‐disciplinary expertise associated with microbiology, organic chemistry, biochemistry, and molecular biology. Remarkable advances in these areas will help to lift people out of wretched and empower them with new knowledge. The subject matter is divided into Part V, including microbiology, biotechnology, molecular biology, biochemical engineering, and global market size of bioproducts, and their applications.

Part I covers microbial cell technology and culture tools (including classical strain improvements and tools) and modern strain improvement and tools (genome shuffling, recombinant DNA technology, RNA interference (RNAi) and CRISPR)/Cas technology for genome editing; also includes molecular thermodynamics for biotechnology, protein engineering, genomics, proteomics and bioinformatics, systems/synthetic biology and metabolic engineering, quorum sensing and quenching. Other bioengineering and scale‐up processes and new bioprocesses of fermentation such as growth‐arrested bioprocess, integrated bioprocess, and consolidated bioprocessing (CBP) are included.

Part II deals applications of microbial fermentation to food products (dairy, meat/fishes, vegetable/cereals), organic acids, food ingredients, chemicals, and pharmaceuticals. Food products/ingredients included flavors and amino acids, sweeteners, vitamins and pigments, microbial polysaccharides/biopolymers, bacteriocins and bacteriophages, enzymes, biomass (SCP)/mushrooms, functional foods and nutraceuticals such as probiotics and prebiotics, and microbiome. Others included alcoholic beverages and other fermentation chemicals (bioethanol, biobutanol/biobutandiol, biodiesel, biomethane, biohydrogen). In final section, pharmaceuticals such as antibiotics, antibiotic growth promoters, antitumor drugs, steroids/statins, and biopesticides included.

Part III covers (i) animal cell technology including animal cell culture, bioprocessing, strain development, applications (monoclonal antibodies, different vaccines (DNA vaccines, edible vaccines, zika vaccines, hepatitis vaccines, HIV vaccines, COVID 19 vaccines), and (ii) transgenic animal bioreactors, and applications in animals and fishes, etc. Part IV on plant cell technology covered plant tissue and cell culture and applications, bioreactor types (seed‐based bioreactor, plant cell suspension bioreactor, hairy root bioreactor, chloroplast bioreactors) and modern plant breeding or biotech/GM crops and their applications.

Finally, Part V deals with safety issues of new biotechnologies on microbial, animal, and plant cells.

This book aims to give readers, general science students, researchers, and industrial practitioners as well as instructors, an overview of the essential features of advanced fermentation and cell culture technology. I would like to thank my students, post‐docs, and former colleagues at McGill University (Canada), Jiangnan University (China) and Kangwon National University (Korea), who, for the past 37 years, have helped and suggested me in teaching this subject course.

Among the over hundres of my former graduate students and post‐docs, I would like to dedicate this book specifically to my beloved former students, Dr. Young J. Choi and Dr. Marcio Belem in Montreal, whom both passed away suddenly.

Last but not least, I must thank my wife Young for her love and encouragement, together with the patience of my sons, Edward and his family (wife Maria, son Maxim) in Toronto and David and his family (wife Ronit, daughter Romy) in Santa Monica, California during the preparation of this volume.

September, 2021

Byong H. Lee

Toronto, Canada

Overview on Market Size of Bioproducts and Fundamentals of Cell Technology

Biotechnology and global market size of bioproducts

The term “biotechnology” was first used by Karl Ereky in 1919, meaning the production of products from raw materials with the aid of living cells such as microbe, animal, and plant in fermenters or bioreactors through process optimization.

Biotechnology is a broad discipline using all living cells, or parts of this to develop products, and services to meet the needs of humans. New tools and products developed by biotechnology have been useful in research, agriculture, industry, and the clinic. Industrial biotechnology experience in fermentation technology started in the field of single‐cell protein production and then moved on to the developments of fermentation technologies producing antibiotics, amino acids, antitumor agents, statins, vitamins, steroids, and majority of fermented foods. As a result of this process development activity, microbial cell culture technology has become one of the leading suppliers of top‐quality fermentation technologies. This domain market is continuously expanding in all continents, with confidential cooperation involving small and multinational companies. Microbial cell fermentation technology has been a long‐favored organic process because of its simplicity of reaction, high specificity, low costs, and flexibility of application. Majority industries have complemented the essential principle of fermentation with advances in techniques and biotechnology to increase its application to the assembly of a spread of biochemicals, biomolecules, and biofuels.

Table 1 shows the fermentation biotechnology milestones and some recombinant proteins.

Table 1 Fermentation biotechnology milestones and some recombinant proteins

Source: Lee, 2015.

Date

Milestone

Old biotechnology

Before 6000 B.C.

Bread leavening, alcoholic drinks, and fruit vinegars

Before 14th century

Beer and wine, vinegar by the Orleans process

1650

Cultivation of French mushrooms

1680

Anton van Leeuwenhoek first observation of yeast cells

1857–1876

Louis Pasteur first discovery of microorganisms causing fermentation

1881

Lactic acid production by microbe

1885

Artificial growing of mushrooms in the USA)

19th century

Production of ethanol, acetate, butanol, acetone, and citrate, glycerol, baker's yeast, and sewage treatment

1940s

Mass cultivation of microbes for antibiotics (penicillin, streptomycin, chlorotetracycline), bioingredients (amino acids, enzymes, vitamins, polysaccharides), steroids, and vaccines

1953

Discovery of DNA by Watson and Crick

1957

L ‐Glutamate production by Kinoshita et al.

1955–60

Citric acid production by submerged fermentation

New Biotechnology

1970–1972

Transformation of

E

.

coli

by plasmid DNA

1973

First discovery of restriction enzymes and DNA ligases by Cohen and Chang

1974

First expression of heterologous gene in

E. coli

1975

Invention of hybridoma technique for monoclonal antibodies by César Milstein and Georges J. F. Köhler

1978

First discovery of recombinant protein, somatostatin

1980

Cohen/Boyer patent on recombinant DNA technology; Genentech established

1982

Recombinant human insulin (Humulin®) by

E. coli

1983

Heterologous plant gene expression; Polymerase Chain Reaction (PCR) by Kary Mullis/Cetus (Nobel prize)

1985

Recombinant human growth hormone (Protropin®) by

E. coli

1986

Recombinant vaccine, Recombivax HB (hepatitis B vaccine by

S. cerevisiae

Recombinant gamma−interferon, Roferon A® by

E. coli

1987

Recombinant tryptophan, recombinant tissue plasminogen activator, Activase®) by CHO

*

1989

Recombinant interleukin‐2, Proleukin® by

E. coli

, Recombinant γ‐interferon, Immuneron® by

E. coli

1989–1991

Recombinant chymosin (Gist‐Brocades, Genencor, and Pfizer) by

E. coli

and

Aspergillus oryzae

Recombinant production of vitamin C (ascorbic acid) by Genencor International, lactic acid bacteria resistant to bacteriophage

1990

Maltase‐enhanced baker's yeast (Gist‐Brocades)

1992

Recombinant blood clotting factor VIII (Recombinate® by Genetic Institute/Baxter; Kogenate® by Bayer, Defacto® (Wyeth) using animal cell lines; Lipase (Unilever), Amylase (Novomil®)

1993

Site‐directed mutagenesis by Michael Smith at UBC (Nobel prize)

1994

Genetically modified Flavr Savr tomato (Calgene, discontinued in 1997), recombinant bovine somatotropin, BST (Eli Lilly; Monsanto), engineered brewing yeast (Carlsberg Research Centre), and acetolactate decarboxylase (Maturex)

2003–2013

Epogen (erythropoietin, EPO) by mammalian cells (Amgen), Neupogen (granulocyte colony‐stimulating factor, G‐CSF) by

E. coli

(Amgen), Fabrazyme (human alpha‐galactosidase, Genzyme) by CHO 1996–2015

Over 47 herbicide‐resistant (HT) and insect‐resistant (BT) crops on market 2018

Golden Rice (a provitamin) approved by US FDA; GM Atlantic salmon developed by AquaBounty Technologies on market in Canada and USA (FDA approved)

* CHO: Chinese Hamster ovaries.

The fermentation's application areas are broad from food stuffs like wine, cheese, bread, and beer, into high‐value chemicals, pharmaceutical products, and food‐related chemicals. Among many more than 100 recombinant proteins known (Sandez‐Garcia et al., 2016), only few are listed in this table. Further, rising hydrocarbon costs and depleting fuel reserves have also created a strong case for affordable and easy fermentation processes for manufacturing biofuel chemicals. Microbial cell factories for the production of bio‐based chemicals have been useful for diverse industrial applications and for achieving a sustainable future, but the overexpression of heterologous enzymes in recombinant strains often leads to metabolic imbalance, resulting in growth retardation and suboptimal production of the target compounds (Lu et al., 2018). Thus, it is essential to address metabolic imbalances caused by engineered pathways in microbial hosts. For establishing a vibrant bio‐based economy, multivariate modular metabolic engineering, modular co‐culture engineering, systems biology, and integrative genome‐scale metabolic modeling can be exploited to expedite strain optimization and improve the production yield of many high‐value bio‐based chemicals.

Figure 1 shows concept of cell culture technology derived from microbes, animals, and plants. In transgenic (genetic engineering) technology either in cells of microbes, animals, or plants, a known gene for a desired trait is inserted into them by recombinant DNA techniques or genome editing by CRISPER/Cas9 techniques. Despite of the potential use of all living forms, a major player in the development of fermentation biotechnology is microorganisms, because of the ease of mass growth, the rapid growth in cheap waste materials as media, and the massive diversity of metabolic types, which in turn gives diverse potential products and the ease of genetic manipulation to improve strains for new products.

Figure 1 Concept of cell culture technology derived from microbes, animals, and plants.

Source: Nader Khouri/Getty Images; Toni Barros / https://en.wikipedia.org/wiki/Dolly_(sheep)#/media/File:Dolly_face:closeup.jpg / CC BY-SA 2.0; Dreamstime; Shutterstock.com; Flickr, Inc.; Thomas Northcut/Getty Images; maksym yemelyanov/123RF. (See insert for color representation of this figure.)

It is estimated that the global economic value of industrial biotechnology, renewable chemicals and polymers, biofuels, enzymes, and bio‐based materials is about US$355.28 billion, among which US generates 58% of the value, or more than US$205 billion (www.bio.org/worldcongres). The production of bio‐based chemicals alone can yield an annual revenue of US$10–15 billion in the global chemical industry by 2020 (www.iwbio.de/fileadmin/Publikationen/IWBio‐Publikationen/WEF_Biorefineries_Report_2010.pdf).

Fermentation's application areas are broad from food stuffs like wine, cheese, bread, and beer, into high‐value chemicals, pharmaceutical products, and food‐related chemicals. Among many more than 100 recombinant proteins (Sandez‐Garcia et al., 2016), only few are listed in this table. Further, rising hydrocarbon costs and depleting fuel reserves have also created a strong case for affordable and easy fermentation processes for manufacturing biofuel chemicals. Microbial cell factories for the production of bio‐based chemicals have been useful for diverse industrial applications and for achieving a sustainable future, but the overexpression of heterologous enzymes in recombinant strains often leads to metabolic imbalance, resulting in growth retardation and suboptimal production of the target compounds (Lu et al., 2018). Thus, it is essential to address metabolic imbalances caused by engineered pathways in microbial hosts. For establishing a vibrant bio‐based economy, multivariate modular metabolic engineering, modular co‐culture engineering, systems biology, and integrative genome‐scale metabolic modeling can be exploited to expedite strain optimization and improve the production yield of many high‐value bio‐based chemicals. Genetically modified bacteria such as the Gram‐negative Escherichia coli (E. coli) are used to produce large amounts of proteins for industrial use, but because of the high cost of extraction and purification, only high value products have been produced at an industrial scale. Although the recently developed secretary expression system of E. coli using signal peptide optimization, periplasmic leakage, and chaperones co‐expression are reported (Zhou et al., 2017), the E. coli species exhibits some limitations as the heterologous proteins are typically expressed intracellularly, which results in problems with formation of inclusion bodies and incorrect protein folding. Thus, Bacillus subtilis has become an industrial workhorse for recombinant protein production due to an easy cultivation, the products of generally recognized as safe (GRAS), ease of genetic manipulation, well‐characterized expression systems, absence of significant codon bias, and exceptional ability to secrete heterologous proteins allowing cost‐effective downstream processing (Eivind et al., 2018). However, many recombinant proteins require protein modifications, such as glycosylation that are available only in eukaryotic cells in that this sometimes leads to the use of yeast, insect cells, and mammalian cell culture systems. Some medicinal use of recombinant bacteria (E. coli) or yeasts (Saccharomyces cerevisae, Pichia pastoris) was to produce the protein insulin to treat diabetes, clotting factors to treat hemophilia, human growth hormone to treat various forms of dwarfism, interferon to treat some cancers, erythropoietin for anemic patients, and tissue plasminogen activator which dissolves blood clots.

Outside of medicine they have been used to produce recombinant chymosin (cheese coagulating enzyme), lipase, biofuels, and bioremediation, etc. Besides, with greater understanding of the role that the microbiome plays in human health, there is the potential to treat diseases by genetically altering the bacteria to themselves be therapeutic agents in our review (Daliri et al., 2018). The main ideas include altering gut bacteria to destroy harmful bacteria or using bacteria to replace or increase deficient enzymes or proteins. One research focus is to modify Lactobacillus bacteria that naturally provide some protection against HIV, with genes that will further enhance this protection. However, the microbiome could also raise safety concerns as interactions between bacteria and the human body are less well understood than with traditional drugs. There are concerns that horizontal gene transfer to other bacteria could have unknown effects. As of 2018 there are many clinical trials underway testing the efficacy and safety of these treatments (Reardon, 2018).

Besides microbial fermented foods, for over a century, bacteria have also been used in agricultural crops in which Rhizobia (and more recently Azospirillum) have been inoculated to increase their production or to allow them to be grown outside their original habitat. It is well known that application of Bacillus thuringiensis (Bt) and other bacteria can help protect crops from insect infestation and plant diseases. With advances in genetic engineering, these bacteria have been manipulated for increased efficiency and expanded host range as well as tracing the spread of the bacteria by markers. Pseudomonas strains of bacteria causing frost damage by nucleating water into ice crystals around themselves led to the development of ice‐minus bacteria, that have the ice‐forming genes removed. When applied to crops they can compete with the ice‐plus bacteria and confer some frost resistance (Yetisen et al., 2015). Other applications of genetically modified bacteria include bioremediation, where the bacteria are used to convert pollutants into a less toxic form such as removal of petroleum hydrocarbon pollutants by increasing the levels of the enzymes used to degrade a toxin or to make the bacteria more stable under environmental conditions (Fuentes et al., 2014; Yuniati, 2018).

However, mass culture of animal cell lines is fundamental to the manufacture of viral vaccines and many biological products produced by recombinant DNA technology in animal cell cultures include enzymes, synthetic hormones, immunobiologicals such as monoclonal antibodies, interleukins, lymphokines, and anticancer agents.

Many simpler proteins can be produced by engineered bacterial cell cultures, but protein glycosylation (post‐translational modification, PTM) is only made in animal cells. As the production cost of mammalian cell cultures is high, however, other insect cells or higher plants using single embryonic cell and somatic embryos are using as a source for direct gene transfer through particle bombardment, and transit gene expression. Mammalian cell‐line products produced from CHO, BHK, NSO, meyloma cells, C127, HEK293) account for over 70% of currently approved biotherapeutic products including monoclonal antibodies.

Biopharmaceuticals may thus be produced from engineered microbial cells such E. coli or yeast, mammalian cell culture, plant cell/tissue culture, and moss plants in various bioreactors or photo‐bioreactors. The main issues of mammalian cell culture are cost of production and microbial contamination by bacteria, viruses, mycoplasma, or viruses. Potential safety and ethical issues include in engineered whole plants and animals, which represent a significant investor risk and risks over consumer acceptance.

Major kinds of recombinant therapeutic proteins (biopharmaceuticals) include: blood factors (Factor VIII and Factor IX), thrombolytic agents (tissue plasminogen activator), hormones (insulin, glucagon, growth hormone, gonadotrophins, hematopoietic growth factors (erythropoietin, colony stimulating factors), interferons (interferons‐α, ‐β, ‐γ), interleukin‐based products (interleukin‐2), vaccines (hepatitis B surface antigen), monoclonal antibodies (various), and additional products (tumor necrosis factor, therapeutic enzymes).

The important animal cell culture products as monoclonal antibodies are produced by fusing normal cells with an immortalized tumor cell line. Recent advances in therapeutic protein drug development are available from: www.researchgate.net/publication/313463806_Recent_advances_in_therapeutic_protein_drug_development.

Many other transgenic animals have also been used to secrete human proteins secreted in the milk of transgenic livestock. Since 1985, several animals, including cow, goat, pig, horse, cat, rabbits, chickens, and most recently dog as well as fishes, have been cloned, but the most research has been on cattle. Many applications of animal biotechnologies are controversial for environmental, health, animal welfare, and social reasons. For example, only a small percentage of cloning attempts produce live off‐spring and many animal clones are unhealthy. Human‐animal chimeras raise safety concerns about whether new diseases could be transmitted to humans, legal issues about whether such creatures can be patented and owned, and the troubling possibility that they could display human‐like behavioral characteristics (www.geneticsandsociety.org/topics/animal‐biotechnologies).

Molecular pharming is based