8 Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 University,observed that a mould spore from Peni- and Germany.Under investigation is a synthetic hor- cillium notatum inhibited growth in a bacterial culture mone,gestogen,which restricts reproductive processes which it infected accidentally.The therapeutic potential in male gonads. of this discovery was overlooked until re-examined in 1939 by Howard Florey and Ernst Chain at Oxford. Industrial biotechnologies-present value From their results,penicillin was isolated and chemi- The earlier text outlined how food processing and cally characterized.Subsequent research in Britain and pharmaceutical industries progressed over the past 6000 the USA identified other useful species and strains of years.Food processing began with simple artisanal Penicillium,synthesized penicillin derivatives,and technologies,human hands being gradually replaced by developed systems of large scale culture,isolation and machines.Not until the late 19th century did science purification.Penicillin was but the first of an impressive become an influential force in food and drug industries. series of antibiotics extracted from various species of The pharmaceutical industry evolved from medicines Actinomycetes and other microorganisms. compounded by apothecaries,most from local plant Long before Fleming's discovery,primitive Micro- extracts,into chemical isolation,identification and nesian people were known to scrape moulds from trees synthesis of pharmacologically active substances and which they rubbed into wounds to prevent festering. their derivatives. Given their importance to humans,commercial live- Hormones stock and domestic pets,it is not surprizing that food More than 100 years ago,Claude Bernard,a French and drug industries constantly expand and diversify.to physiologist,reported that certain critical bodily func- satisfy demands of expanding,affluent and aging popu- tions are regulated by "centres of internal secretion'. lations.The total world value of industrially processed These were identified as endocrine and ductless glands foods is about S1750 billion USD.Sales value of com- that secrete hormones (Greek hormon'='to urge on'). mercial pharmaceuticals (not including veterinary med- Adrenaline,first extracted from the suprarenal glands of icines)is close to $450 billion USD,49%being sold in animals,was chemically characterized in the 1920s and the USA,24%in the European Union,16%in Japan, later industrially synthesized. with barely 11%for the rest of the world.Food pro- In 1921,in Toronto,insulin was isolated from Lan- cessing industries,with sales over $500B per annum, gerhens Islets extracted from porcine pancreas.During comprise the largest industrial sector in the USA.Food the 1980s,Canadian scientists synthesized an insulin industries in the EU employ more than 2.5 million peo- precursor by a genetically modified bacterium.More ple,they process two-thirds of all farm produce with recently,pancreatic cells that synthesize insulin were sales close to S400 billion.Indian food processors employ cultured,isolated,microencapsulated and transplanted more than 2 million people;at least 200 million Indians into the bodies of diabetic patients to produce insulin in frequently buy processed foods.In 2002 the value of vivo.Thyroxine,generated by the thyroid,was synthe- Indian processed foods was over 1000 times the value in sized in 1926,cortisone was isolated from the cortex of 1962.It is impossible to estimate the total value of foods suprarenal glands in 1935 and commercially synthesized sold direct from farmers to local markets,or the propor- in 1956.In the intervening years,other hormones have tion of food produced that is spoiled or wasted. been synthesized by GM microorganisms including avian and bovine growth hormones which stimulate Pharmaceutical industries-changing patterns body weight gain in farm animals and cultured fish,and Though several similarities between food and drug milk production in bovines. industries have been noted,there are divergent differ- Gonadotropins synthesized by GM bacteria induce ences.Pharmaceuticals are processed by relatively few gravid female fish to deposit their eggs when held cap- large corporations,while food industries include such tive in aquaculture systems.The eggs are later fertilized giants as Nestle and Unilever together with thousands by cryogenically preserved milt(male fish sperm). of medium and small scale companies.Pharmaceutical Synthetic oestrogen and progesteron steroids inhibit companies invest between 9 and 18%of their revenues ovulation and/or fertilization in women.The 50 year in research and development.The average R&D history of oral contraceptives,and the related medical, investment for some 3500 Canadian registered food social and religious issues are reviewed in two recent processors is less than 0.15%of sales revenue.Most books:'Sexual chemistry:a history of the contraceptive pharmaceutical companies began as divisions of,or pill'by Lara Marks (Yale Press),and 'This man's spin-offs from chemical industries and expanded pill:reflections on the 50th birthday of the pill'by through acquisitions and mergers. Carl Djerassi (Oxford University Press).Clinical trials In 1953,Watson and Crick described the helical on chemical contraceptives for males are in progress at structure of DNA.In 1973,the first gene was cloned,in the Human Reproductive Sciences Unit in Edinburgh. 1974 cloned genes were expressed in a foreign bacterial and by pharmaceutical companies in the Netherlands species.In 1976,Genentech became the first company in
University, observed that a mould spore from Penicillium notatum inhibited growth in a bacterial culture which it infected accidentally. The therapeutic potential of this discovery was overlooked until re-examined in 1939 by Howard Florey and Ernst Chain at Oxford. From their results, penicillin was isolated and chemically characterized. Subsequent research in Britain and the USA identified other useful species and strains of Penicillium, synthesized penicillin derivatives, and developed systems of large scale culture, isolation and purification. Penicillin was but the first of an impressive series of antibiotics extracted from various species of Actinomycetes and other microorganisms. Long before Fleming’s discovery, primitive Micronesian people were known to scrape moulds from trees which they rubbed into wounds to prevent festering. Hormones More than 100 years ago, Claude Bernard, a French physiologist, reported that certain critical bodily functions are regulated by ‘‘centres of internal secretion’’. These were identified as endocrine and ductless glands that secrete hormones (Greek ‘hormon’=‘to urge on’). Adrenaline, first extracted from the suprarenal glands of animals, was chemically characterized in the 1920s and later industrially synthesized. In 1921, in Toronto, insulin was isolated from Langerhens Islets extracted from porcine pancreas. During the 1980s, Canadian scientists synthesized an insulin precursor by a genetically modified bacterium. More recently, pancreatic cells that synthesize insulin were cultured, isolated, microencapsulated and transplanted into the bodies of diabetic patients to produce insulin in vivo. Thyroxine, generated by the thyroid, was synthesized in 1926, cortisone was isolated from the cortex of suprarenal glands in 1935 and commercially synthesized in 1956. In the intervening years, other hormones have been synthesized by GM microorganisms including avian and bovine growth hormones which stimulate body weight gain in farm animals and cultured fish, and milk production in bovines. Gonadotropins synthesized by GM bacteria induce gravid female fish to deposit their eggs when held captive in aquaculture systems. The eggs are later fertilized by cryogenically preserved milt (male fish sperm). Synthetic oestrogen and progesteron steroids inhibit ovulation and/or fertilization in women. The 50 year history of oral contraceptives, and the related medical, social and religious issues are reviewed in two recent books: ‘Sexual chemistry: a history of the contraceptive pill’ by Lara Marks (Yale Press), and ‘This man’s pill: reflections on the 50th birthday of the pill’ by Carl Djerassi (Oxford University Press). Clinical trials on chemical contraceptives for males are in progress at the Human Reproductive Sciences Unit in Edinburgh, and by pharmaceutical companies in the Netherlands and Germany. Under investigation is a synthetic hormone, gestogen, which restricts reproductive processes in male gonads. Industrial biotechnologies—present value The earlier text outlined how food processing and pharmaceutical industries progressed over the past 6000 years. Food processing began with simple artisanal technologies, human hands being gradually replaced by machines. Not until the late 19th century did science become an influential force in food and drug industries. The pharmaceutical industry evolved from medicines compounded by apothecaries, most from local plant extracts, into chemical isolation, identification and synthesis of pharmacologically active substances and their derivatives. Given their importance to humans, commercial livestock and domestic pets, it is not surprizing that food and drug industries constantly expand and diversify, to satisfy demands of expanding, affluent and aging populations. The total world value of industrially processed foods is about $1750 billion USD. Sales value of commercial pharmaceuticals (not including veterinary medicines) is close to $450 billion USD, 49% being sold in the USA, 24% in the European Union, 16% in Japan, with barely 11% for the rest of the world. Food processing industries, with sales over $500B per annum, comprise the largest industrial sector in the USA. Food industries in the EU employ more than 2.5 million people, they process two-thirds of all farm produce with sales close to $400 billion. Indian food processors employ more than 2 million people; at least 200 million Indians frequently buy processed foods. In 2002 the value of Indian processed foods was over 1000 times the value in 1962. It is impossible to estimate the total value of foods sold direct from farmers to local markets, or the proportion of food produced that is spoiled or wasted. Pharmaceutical industries—changing patterns Though several similarities between food and drug industries have been noted, there are divergent differences. Pharmaceuticals are processed by relatively few large corporations, while food industries include such giants as Nestle and Unilever together with thousands of medium and small scale companies. Pharmaceutical companies invest between 9 and 18% of their revenues in research and development. The average R&D investment for some 3500 Canadian registered food processors is less than 0.15% of sales revenue. Most pharmaceutical companies began as divisions of, or spin-offs from chemical industries and expanded through acquisitions and mergers. In 1953, Watson and Crick described the helical structure of DNA. In 1973, the first gene was cloned, in 1974 cloned genes were expressed in a foreign bacterial species. In 1976, Genentech became the first company in 8 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18
Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 9 the USA created for research to explore and exploit improved by computer modelling.Diagnostic processes DNA.Between 1981 and 1999,specialist bioscience are enhanced and speeded up by molecular modelling,by companies in the USA grew from 80 to over 1270.Ernst DNA microchips,and by recent advances in genomics,a and Young report 1180 such enterprises among EU name coined in 1980. member countries.Many evolved from university Drugs synthesized by GM organisms include vac- bioscience departments.Some were highly successful. cines,immune regulators,substances to control cardio- others with insufficient venture capital,and inexper- vascular disorders and various hormones.Modern ienced management,did not survive.Academic scientists vaccines include (1)toxoids-inactivated toxins extracted with ambition to own a specialist bioscience company from cultured pathogens (for tetanus and diphtheria); should have access to deep cash pockets.Risks are high (2)attenuated pathogens (for pertussis-whooping and profitable innovations do not come quickly. cough);(3)isolated biochemically modified antigens of The biomedical industry now consists of two inter- various novel applications.Vaccines from GM viruses related entities:(1)large pharmaceutical corporations(2) include whole virions (poliomyelitis);split vaccines specialist bioresearch enterprises,described as 'Second (influenza);isolated antigens (hepatitis B). generation biotechnology companies'.In 2001,total Recent additions to the biosciences lexicon include revenue of the six largest bioscience companies was ca 'Genomics'-study of genomes and DNA nucleotide $8 billion;research and development investment sequences;Proteomics'-related to specific proteins pro- between 20 and 37%of revenue.They devise and duced by genomes;'Metabolomics'-influence of gene develop new processes and products to pilot plant and expression on metabolites:Transcriptomics'-profiling preclinical stages.Pharmaceutical companies expand of gene expressions using DNA/RNA micro assays. the processes and subject the products to in vitro and in vivo clinical trials to determine potency,reliability and Bioengineering processes safety.For a new drug to progress from the laboratory The immense diversity of active products from bio- to final approval may cost between $300 million and technologies includes whole viable or attenuated cells. $800 million and take between 10 and 15 years. metabolites within cells or diffused into the culture medium. Biotechnologies:future prospects Typical industrial processes progress through several Over the past 20 years,biotechnologies have evolved stages: from intellectually intriguing biosciences into diversifying industries that produce useful biologicals from biocata- i.Identification and isolation of cells to be cul- lytic reactions,genetically modified bacteria,funghi, tured. viruses,plant,mammalian and insect cells.Some tech- ii.Determination of optimum culture and harvesting niques modify genetic composition and expression:oth- systems. ers accelerate and adjust metabolic processes.Of mi. Scale-up to large batch or continuous bio- particular interest to bioengineers are reliable means to reactors. expand from laboratory to factory scale,and technolo- iv. Down-stream processes for fractionation, gies for the isolation,purification and sterilization of extraction,purification and sterilization. end products.Equally critical are reliable systems of V. Methods for process control and product quality. product quality and process control. vi.Protocols to ensure safety and containment Earlier processes of extracting,screening and chemi- throughout development and production. cally modifying natural biochemical substances are giv- ing way to identification of how specific diseases are The over-riding objective is to maximise economic caused,how particular drugs act to prevent or cure yield of stable effective products.A bioengineer with them.More effective diagnostics,prophylactics and many years of experience recently said:"Even where therapeutics are being designed and synthesized by genetic modifications,laboratory and pilot plant trials molecular modelling and combinatorial biochemistry. are entirely successful,scale-up to an economically effi- In the past,an organic chemist might synthesize 50 new cient industrial process is inevitably frustrating,more compounds in a year,computer-assisted modern bio- costly and time-consuming than was forecast." chemistry can generate several thousand.Computers In addition to synthesis by microorganisms,develop- devise molecules to be systematically compared with ments are progressing with cells from higher plants, computer-stored molecular structures.One company animals,insects and GM viruses.Bacteria and viruses screens a million compounds against a target protein are cultured for metabolite synthesis,and for use as every 6 months. vectors to transfer genes between organisms.Cells may Rapid biological screening makes use of membranes be cultured in batch bioreactors or in continuous sys- from human or animal organ cells grown in tissue cul- tems where the nutrient medium percolates through or ture.Immunogenicity of specific antibodies can be over and is transformed by the immobilized cells.Simi-
the USA created for research to explore and exploit DNA. Between 1981 and 1999, specialist bioscience companies in the USA grew from 80 to over 1270. Ernst and Young report 1180 such enterprises among EU member countries. Many evolved from university bioscience departments. Some were highly successful, others with insufficient venture capital, and inexperienced management, did not survive. Academic scientists with ambition to own a specialist bioscience company should have access to deep cash pockets. Risks are high and profitable innovations do not come quickly. The biomedical industry now consists of two interrelated entities: (1) large pharmaceutical corporations (2) specialist bioresearch enterprises, described as ‘Second generation biotechnology companies’. In 2001, total revenue of the six largest bioscience companies was ca $8 billion; research and development investment between 20 and 37% of revenue. They devise and develop new processes and products to pilot plant and preclinical stages. Pharmaceutical companies expand the processes and subject the products to in vitro and in vivo clinical trials to determine potency, reliability and safety. For a new drug to progress from the laboratory to final approval may cost between $300 million and $800 million and take between 10 and 15 years. Biotechnologies: future prospects Over the past 20 years, biotechnologies have evolved from intellectually intriguing biosciences into diversifying industries that produce useful biologicals from biocatalytic reactions, genetically modified bacteria, funghi, viruses, plant, mammalian and insect cells. Some techniques modify genetic composition and expression; others accelerate and adjust metabolic processes. Of particular interest to bioengineers are reliable means to expand from laboratory to factory scale, and technologies for the isolation, purification and sterilization of end products. Equally critical are reliable systems of product quality and process control. Earlier processes of extracting, screening and chemically modifying natural biochemical substances are giving way to identification of how specific diseases are caused, how particular drugs act to prevent or cure them. More effective diagnostics, prophylactics and therapeutics are being designed and synthesized by molecular modelling and combinatorial biochemistry. In the past, an organic chemist might synthesize 50 new compounds in a year, computer-assisted modern biochemistry can generate several thousand. Computers devise molecules to be systematically compared with computer-stored molecular structures. One company screens a million compounds against a target protein every 6 months. Rapid biological screening makes use of membranes from human or animal organ cells grown in tissue culture. Immunogenicity of specific antibodies can be improved by computer modelling. Diagnostic processes are enhanced and speeded up by molecular modelling, by DNA microchips, and by recent advances in genomics, a name coined in 1980. Drugs synthesized by GM organisms include vaccines, immune regulators, substances to control cardiovascular disorders and various hormones. Modern vaccines include (1) toxoids-inactivated toxins extracted from cultured pathogens (for tetanus and diphtheria); (2) attenuated pathogens (for pertussis—whooping cough); (3) isolated biochemically modified antigens of various novel applications. Vaccines from GM viruses include whole virions (poliomyelitis); split vaccines (influenza); isolated antigens (hepatitis B). Recent additions to the biosciences lexicon include ‘Genomics’—study of genomes and DNA nucleotide sequences; ‘Proteomics’—related to specific proteins produced by genomes; ‘Metabolomics’—influence of gene expression on metabolites; ‘Transcriptomics’—profiling of gene expressions using DNA/RNA micro assays. Bioengineering processes The immense diversity of active products from biotechnologies includes whole viable or attenuated cells, metabolites within cells or diffused into the culture medium. Typical industrial processes progress through several stages: i. Identification and isolation of cells to be cultured. ii. Determination of optimum culture and harvesting systems. iii. Scale-up to large batch or continuous bioreactors. iv. Down-stream processes for fractionation, extraction, purification and sterilization. v. Methods for process control and product quality. vi. Protocols to ensure safety and containment throughout development and production. The over-riding objective is to maximise economic yield of stable effective products. A bioengineer with many years of experience recently said: ‘‘Even where genetic modifications, laboratory and pilot plant trials are entirely successful, scale-up to an economically effi- cient industrial process is inevitably frustrating, more costly and time-consuming than was forecast.’’ In addition to synthesis by microorganisms, developments are progressing with cells from higher plants, animals, insects and GM viruses. Bacteria and viruses are cultured for metabolite synthesis, and for use as vectors to transfer genes between organisms. Cells may be cultured in batch bioreactors or in continuous systems where the nutrient medium percolates through or over and is transformed by the immobilized cells. SimiJoseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 9