《生物技术与人类》课程教学资源（经典阅读）Biotechnologies past history present state and future prospects

TRENDS IN FOOD SCIENCE ELSEVIER Trends in Food Science Technology 15(2004)3-18 GtECHNOLOGY Biotechnologies: past history, The British physicist Lord Kelvin gave as his opinion that if you can define precisely and measure exactly that of which you speak,your opinions can be counted as present state and credible;if not,they must be deemed doubtful. Let me begin with a definition relevant to this discus- sion:"Biotechnologies are processes that seek to pre- future prospects serve or transform biological materials of animal. vegetable,microbial or viral origin into products of commercial,economic,social and/or hygienic utility and value".Bioengineers are men and women qualified to design,develop,operate,maintain and control bio- Joseph H.Hulse technological processes.One could cite instances in which (i)'Biotechnology'is exclusively equated with Visiting Professor in Industrial Biotechnologies, genetic modifications and transgenesis,(ii)"Bio- UMIST,Manchester,UK and at CFTRI,Mysore,India technology"denotes a bioscientific activity that has not and MS Swaminathon Research Foundation,India progressed beyond the research laboratory.In one American dictionary "biotechnology"is defined as synonymous with 'ergonomics':the study of human The paper presents a chronological review of biotechnologies, work in relation to a prevailing environment. ancient and modern.It outlines the discovery of naturally The name 'Biotechnology'first appeared in Yorkshire occurring drugs by Babylonians,Egyptians,Chinese,Greeks and early in the 20th century.A Bureau of Biotechnology Romans,and the evolution of extraction,preservation and began as a consultant laboratory in Leeds which from transformation technologies.It describes how pharmaceuticals 1899 provided advisory services in chemistry and progressed from empiricism,through chemical identification microbiology to fermentation industries in the north of and synthesis to modern advances in genomics,proteomics England. bio-informatics and syntheses by cultured cells from various The two Manchester universities (soon to be fused genetically modified organisms.While biotechnologies for into one)have long and distinguished records in fer- drugs first progressed through chemistry,until relatively mentation biochemistry.In 1912.Dr Chaim Weizmann recently food technologies evolved by mechanisation,the gra- isolated a strain of Clostridium acetobulylicum which dual replacement of human hands by machines.Present and converted carbohydrate into butanol,acetone and predicted industrial demand for bioengineers exceeds supply. ethanol,a discovery extensively used for industrial The cost and complexity of emerging biotechnologies call for production of acetone and butanol. significant revision of curricula and reorganisation of ace- In 1923,Dr Thomas Kennedy Walker welcomed the demic departments related to life sciences and biotechnol- first students into his Department of Fermentation ogies.Urgently needed is active interdisciplinary cooperation Industries,possibly the first of its kind,in what is now in research and development,both in universities and the University of Manchester Institute of Science and industries,cooperation involving biochemists,bioengineers Technology.Later the departmental name was changed mathematicians,computational scientists,systems analysts to Industrial Biochemistry,semantically similar to and specialists in bioinformatics.Bioscientists and bio- biotechnology'.The undergraduate course was an technologists must acquire more sensitive awareness of civil amalgam of bioscience and bioengineering.From 1923 societies concerns and the ability to communicate with until he retired 35 years later,Professor Walker's students private citizens,politicians and the media.Recognising the advanced to senior positions in food,pharmaceutical and inexorably rising demand for reliable health services,for safe related bio-industries in very many countries. and adequate food supplies,present and future opportu- nities for employment in industries devoted to food and The interrelation of food and drugs drug technologies have never been greater. This presentation assumes that most graduates in C 2003 Elsevier Ltd.All rights reserved. bioengineering will progress to senior positions in food, 0924-2244/$-see front matter C)2003 Elsevier Ltd.All rights reserved. doi10.1016/50924-22440300157-2

Biotechnologies: past history, present state and future prospects Joseph H. Hulse Visiting Professor in Industrial Biotechnologies, UMIST, Manchester, UK and at CFTRI, Mysore, India and MS Swaminathon Research Foundation, India The paper presents a chronological review of biotechnologies, ancient and modern. It outlines the discovery of naturally occurring drugs by Babylonians, Egyptians, Chinese, Greeks and Romans, and the evolution of extraction, preservation and transformation technologies. It describes how pharmaceuticals progressed from empiricism, through chemical identification and synthesis to modern advances in genomics, proteomics, bio-informatics and syntheses by cultured cells from various genetically modified organisms. While biotechnologies for drugs first progressed through chemistry, until relatively recently food technologies evolved by mechanisation, the gra￾dual replacement of human hands by machines. Present and predicted industrial demand for bioengineers exceeds supply. The cost and complexity of emerging biotechnologies call for significant revision of curricula and reorganisation of ace￾demic departments related to life sciences and biotechnol￾ogies. Urgently needed is active interdisciplinary cooperation in research and development, both in universities and industries, cooperation involving biochemists, bioengineers, mathematicians, computational scientists, systems analysts and specialists in bioinformatics. Bioscientists and bio￾technologists must acquire more sensitive awareness of civil societies concerns and the ability to communicate with private citizens, politicians and the media. Recognising the inexorably rising demand for reliable health services, for safe and adequate food supplies, present and future opportu￾nities for employment in industries devoted to food and drug technologies have never been greater. # 2003 Elsevier Ltd. All rights reserved. The British physicist Lord Kelvin gave as his opinion that if you can define precisely and measure exactly that of which you speak, your opinions can be counted as credible; if not, they must be deemed doubtful. Let me begin with a definition relevant to this discus￾sion: ‘‘Biotechnologies are processes that seek to pre￾serve or transform biological materials of animal, vegetable, microbial or viral origin into products of commercial, economic, social and/or hygienic utility and value’’. Bioengineers are men and women qualified to design, develop, operate, maintain and control bio￾technological processes. One could cite instances in which (i) ‘Biotechnology’ is exclusively equated with genetic modifications and transgenesis, (ii) ‘‘Bio￾technology’’ denotes a bioscientific activity that has not progressed beyond the research laboratory. In one American dictionary ‘‘biotechnology’’ is defined as synonymous with ‘ergonomics’: the study of human work in relation to a prevailing environment. The name ‘Biotechnology’ first appeared in Yorkshire early in the 20th century. A Bureau of Biotechnology began as a consultant laboratory in Leeds which from 1899 provided advisory services in chemistry and microbiology to fermentation industries in the north of England. The two Manchester universities (soon to be fused into one) have long and distinguished records in fer￾mentation biochemistry. In 1912, Dr Chaim Weizmann isolated a strain of Clostridium acetobulylicum which converted carbohydrate into butanol, acetone and ethanol, a discovery extensively used for industrial production of acetone and butanol. In 1923, Dr Thomas Kennedy Walker welcomed the first students into his Department of Fermentation Industries, possibly the first of its kind, in what is now the University of Manchester Institute of Science and Technology. Later the departmental name was changed to Industrial Biochemistry, semantically similar to ‘biotechnology’. The undergraduate course was an amalgam of bioscience and bioengineering. From 1923 until he retired 35 years later, Professor Walker’s students advanced to senior positions in food, pharmaceutical and related bio-industries in very many countries. The interrelation of food and drugs This presentation assumes that most graduates in bioengineering will progress to senior positions in food, 0924-2244/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0924-2244(03)00157-2 Trends in Food Science & Technology 15 (2004) 3–18

Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 pharmaceutical and related biotechnological industries. the raw materials and processed products.Foods found Though their historical patterns of growth and devel- to be acceptable and satisfying,and medicinals that opment have differed,food and drugs and the industries cured or alleviated particular maladies were discovered that produce them have long been closely associated. by chance,trial and error,and painful experience. Standards of quality and safety for foods and drugs are The history of food processing,in large part,is a his- customarily administered by the same regulatory tory of bioengineering,the gradual replacement of agency,the US Food and Drug Administration being human hands and energy first by animals,later by typical.As is discussed later,modern food and phar- machines.Industrial processes of fractionation and maceutical processors employ similar technologies and transformation used today were developed hundreds of methods of product and process control. years ago.What began as labour-intensive artisanal Among the earliest historical records(ca 2900 BCE), crafts were progressively mechanized.In addition to the Chinese proclaimed a close association of foods with providing an immense diversity of food products, medicines,both being essential to good health,both food industries have progressively reduced the human derived from plant and animal sources.The Chinese effort and energy needed in factories,restaurants and believe many ailments can be cured by diet.They were homes. the first to add burnt sponge,an aquatic source of iodine,for people suffering from goitre. Food preservation The Emperor Fu-Hsi and his successors advocate that The basic principles of food preservation:control of health depends on two principles:Yin and Yang.Yin (1)active water content,(2)ambient atmosphere.(3) weakness comes from malfunctions among internal temperature,(4)pH;and (5)thermal inactivation of organs and is indicated by a 'hot'condition.red tongue microbial and biochemical sources of spoilage,were and weak pulse.Yang weakness results when internal discovered empirically hundreds of years ago.Medi- organs fail to absorb essential nutrients,indicated by a terranean,Asian and Amerindian people used sun dry- 'cold'condition,Chinese medicinal foods are classified ing to preserve milk,meat,fish,fruits and vegetables, as 'hot'or 'cold','strong'or 'weak'. into their sun-dried pemmican northern Amerindians Among an impressive list of Chinese medicinal foods. added dried berries that provided ascorbic acid.Sliced some are no doubt effective:others of dubious cred- potatoes were freeze-dried by early Amerindians,ice ibility.Horn from deer antlers is claimed to relieve fati- gradually subliming in the dry air and low atmospheric gue,impotence and skeletal deformities.Ginseng root pressure of the high Andes. (Panax schinseng)is claimed,with little reliable phar- Stone age Britons dried grains over open fires to macological evidence,to alleviate diabetes,cardiovas- prevent sprouting.Over 4000 years ago,the Chinese cular,digestive,liver and other diseases.Analyses of preserved fish by osmotic dehydration with salt. different samples from similar ginseng remedies show Republican Romans reduced water activity in meat and significant variance in composition. fruits by adding salt or honey.About 5000 years ago, Oriental beliefs in therapeutic foods is attracting Middle Eastern farmers stored grains in earthenware North Americans,one-third of whom are said to buy amphora each hermetically sealed by an impervious herbal remedies as alternatives to prescription drugs. goat skin.All stages of insect metamorphosis were Americans'search for a nutritional Elixir vitae has been asphyxiated by respired CO2. evident for over half a century.During the 1950s vita- Seneca described how Romans preserved prawns in min supplements were in fashion;during the 1960s pro- snow from the Appenines.The frozen food industry teins and amino acids were in favour:in the 1970s developed after Clarence Birdseye,an American, extensive publicity was given to essential fatty acids and observed how whale,seal and reindeer meat were cholesterol in relation to cardiovascular disfunctions; naturally preserved during the cold Canadian winter. during the 1980s dietary fibre was of paramount inter- Modern canning,bottling and boil-in-the-bag were est.At present the fashion is with 'functional foods' anticipated in Republican Rome where chopped spiced (which beg the question:what are non-functional meats were sealed and boiled inside the cleaned womb foods?)and 'nutraceuticals',foods believed to possess of a sow or the body cavity of a squid. beneficial pharmacological properties.It is not surpriz- Fermentation and pickling of fruits and vegetables is an ing that the Chinese claim to be the originators of ancient practice among Asian and Mediterranean people. nutraceutical concepts. The Babylonians preserved their milk by lactic fermenta- tion.Ethanol was distilled in China over 3000 years ago. Food and drugs:science and technology Homer described wine as“A gift from the gods'”. A characteristic common to food,drugs and most other basic need industries is that technologies dis- Grain milling-the first continuous process covered by perceptive empiricism long preceded any Fractionation of cereal grains by pulverization,siev- scientific understanding of the biochemical properties of ing and winnowing,and extraction of olive oil by

pharmaceutical and related biotechnological industries. Though their historical patterns of growth and devel￾opment have differed, food and drugs and the industries that produce them have long been closely associated. Standards of quality and safety for foods and drugs are customarily administered by the same regulatory agency, the US Food and Drug Administration being typical. As is discussed later, modern food and phar￾maceutical processors employ similar technologies and methods of product and process control. Among the earliest historical records (ca 2900 BCE), the Chinese proclaimed a close association of foods with medicines, both being essential to good health, both derived from plant and animal sources. The Chinese believe many ailments can be cured by diet. They were the first to add burnt sponge, an aquatic source of iodine, for people suffering from goitre. The Emperor Fu-Hsi and his successors advocate that health depends on two principles: Yin and Yang. Yin weakness comes from malfunctions among internal organs and is indicated by a ‘hot’ condition, red tongue and weak pulse. Yang weakness results when internal organs fail to absorb essential nutrients, indicated by a ‘cold’ condition, Chinese medicinal foods are classified as ‘hot’ or ‘cold’, ‘strong’ or ‘weak’. Among an impressive list of Chinese medicinal foods, some are no doubt effective; others of dubious cred￾ibility. Horn from deer antlers is claimed to relieve fati￾gue, impotence and skeletal deformities. Ginseng root (Panax schinseng) is claimed, with little reliable phar￾macological evidence, to alleviate diabetes, cardiovas￾cular, digestive, liver and other diseases. Analyses of different samples from similar ginseng remedies show significant variance in composition. Oriental beliefs in therapeutic foods is attracting North Americans, one-third of whom are said to buy herbal remedies as alternatives to prescription drugs. Americans’ search for a nutritional Elixir vitae has been evident for over half a century. During the 1950s vita￾min supplements were in fashion; during the 1960s pro￾teins and amino acids were in favour; in the 1970s extensive publicity was given to essential fatty acids and cholesterol in relation to cardiovascular disfunctions; during the 1980s dietary fibre was of paramount inter￾est. At present the fashion is with ‘functional foods’ (which beg the question: what are non-functional foods?) and ‘nutraceuticals’, foods believed to possess beneficial pharmacological properties. It is not surpriz￾ing that the Chinese claim to be the originators of nutraceutical concepts. Food and drugs: science and technology A characteristic common to food, drugs and most other basic need industries is that technologies dis￾covered by perceptive empiricism long preceded any scientific understanding of the biochemical properties of the raw materials and processed products. Foods found to be acceptable and satisfying, and medicinals that cured or alleviated particular maladies were discovered by chance, trial and error, and painful experience. The history of food processing, in large part, is a his￾tory of bioengineering, the gradual replacement of human hands and energy first by animals, later by machines. Industrial processes of fractionation and transformation used today were developed hundreds of years ago. What began as labour-intensive artisanal crafts were progressively mechanized. In addition to providing an immense diversity of food products, food industries have progressively reduced the human effort and energy needed in factories, restaurants and homes. Food preservation The basic principles of food preservation: control of (1) active water content, (2) ambient atmosphere, (3) temperature, (4) pH; and (5) thermal inactivation of microbial and biochemical sources of spoilage, were discovered empirically hundreds of years ago. Medi￾terranean, Asian and Amerindian people used sun dry￾ing to preserve milk, meat, fish, fruits and vegetables, into their sun-dried pemmican northern Amerindians added dried berries that provided ascorbic acid. Sliced potatoes were freeze-dried by early Amerindians, ice gradually subliming in the dry air and low atmospheric pressure of the high Andes. Stone age Britons dried grains over open fires to prevent sprouting. Over 4000 years ago, the Chinese preserved fish by osmotic dehydration with salt. Republican Romans reduced water activity in meat and fruits by adding salt or honey. About 5000 years ago, Middle Eastern farmers stored grains in earthenware amphora each hermetically sealed by an impervious goat skin. All stages of insect metamorphosis were asphyxiated by respired CO2. Seneca described how Romans preserved prawns in snow from the Appenines. The frozen food industry developed after Clarence Birdseye, an American, observed how whale, seal and reindeer meat were naturally preserved during the cold Canadian winter. Modern canning, bottling and boil-in-the-bag were anticipated in Republican Rome where chopped spiced meats were sealed and boiled inside the cleaned womb of a sow or the body cavity of a squid. Fermentation and pickling of fruits and vegetables is an ancient practice among Asian and Mediterranean people. The Babylonians preserved their milk by lactic fermenta￾tion. Ethanol was distilled in China over 3000 years ago. Homer described wine as ‘‘A gift from the gods’’. Grain milling—the first continuous process Fractionation of cereal grains by pulverization, siev￾ing and winnowing, and extraction of olive oil by 4 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18

Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 pressing,began in Egypt and nearby Mediterranean the steam engine,was mechanized faster than food countries 7000 years ago.Commercial bakeries and processes. breweries existed in Babylon and Egypt 5000 years In the British baking industry,mechanical dough before Eduard Buchner and Emil Fischer discovered the mixers were not much in evidence until after 1920. enzymic conversion of carbohydrates. Mechanization moved more rapidly after World War II The history of grain milling illustrates how labour- During the 1930s,in a typical Manchester bakery,six intensive artisanal processes were progressively men working an 8 h shift produced about 2400 loaves. mechanized.The primitive pestel and mortar gave way In 1990,three men working an 8 h shift could produce in Egypt to the saddle stone:where grain spread on a over 65,000 loaves:400 versus 22,000 loaves per man. stationary smooth stone slab was pulverized by an The first significant change came in the 1960s when upper stone pushed backwards and forwards by a British scientists replaced traditional long fermentation kneeling slave.Later,the Greeks devised a shearing processes by high energy mixing of bread doughs con- action by incising herring-bone grooves into the inter- taining ascorbic acid. faces of the upper and lower stones. Continuous malting in breweries began with the In the rotary quern,evident in several ancient Medi- Wanderhaufen moving malt couch.Continuous fer- terranean countries,an upper stone was continuously mentations.in which the substrate passes over an rotated over a lower static stone.By cutting an eye-hole immobilized microorganism or biocatalyst,are now in the centre of the upper stone,grain was fed in a common among modern bioindustries. steady stream,the pulverized product being carried to Humphrey Davy's discovery of finely divided plati- the periphery by centrifugal force.Grain milling was the num as a catalyst led to the catalytic hydrogenation of first known continuous industrial process.Rotary vegetable oils to produce hard fats for shortening and querns were at first driven by slaves walking on a margarine.About the same time,solvent extraction of treadmill,later by camels or donkeys. vegetable oils competed with mechanical expression.In After the Romans invented the water wheel,through- contrast to food processing,pharmaceutical industries out the Roman empire grain mills were built close by advanced more from chemistry than engineering,start- rivers or running streams.The Domesday Book.Wil- ing in the 18th century in the German dyestuffs indus- liam I's inventory of the nation's assets published in tries after von Hofmann was appointed Professor of 1085,recorded over 5000 water mills in Britain.The first Chemistry at the University of Berlin. windmills appeared in Persia (now Iran)in the 10th century CE.In 1784,an early version of James Watt's Pharmaceuticals in ancient times steam engine was installed in a London flour mill.Less Survival and health.the fate of the human soul and than 100 years ago,in North America,more grain mills body after death,and the supernatural influence of the were powered by water wheels than by steam engines. sun,moon and stars intrigued many of our early ante- The first mill powered by electric motors came on cedents.Primitive peoples searched for panaceas and stream in 1887 in Wyoming. palliatives to cure their diseases.Early Palestinians and Though more precisely engineered,modern roller Sumerians believed disease was a punishment for sin mills with their incised steel break rolls operate on the and could be mitigated by magical charms and drugs same principles as the early saddle stone and rotary with supernatural powers.Shen-Nung (ca 2700 BCE)is quern.Hand winnowing has its modern equivalent in acclaimed as the Chinese founder of acupuncture and the middlings purifier,an enclosed vibrating gravity drug therapy.He and his contemporaries described table with screens of diverse mesh size.Separated bran diabetes,smallpox,measles.cholera and various dysen- is removed by suction fans. teries.Their 1800 medical prescriptions included ephe- A smart indigenous software programme enables drine,camphor,and cod liver oil.Arsenic and mercury modern wheat flour mills in India to be operated from compounds acted as bactericides.Respiratory diseases a desk top computer.At the same time,poor rural were treated by surrounding the patient in a pile of Indian women grind local grains by pestel and mortar burning herbs. or saddle stone,and extract oil from groundnuts by The Egyptian Ebers papyrus (ca 1550 BCE),dis- rotary querns. covered by 20th century archeologists,describes treat- ments for rheumatism.schistosomiasis,diabetes and Mechanization of traditional biotechnologies intestinal parasites.It lists 875 drugs compounded from The patterns and pace of mechanization have pro- ca 500 substances:metallic salts,such vegetable extracts gressed differently among different industries.Though as gentian,senna,castor oil,vermifiuge and henbane. the transition from rural domestic spinning and weaving Sumerian cuneiform tablets from Hammurabi's reign into large mechanized factories evolved over more describe hepatic diseases,fevers,gonorrhoea,various than two centuries,in Britain the textile industry, strokes and scabies.Drugs included hellebore (believed stimulated by cheap coal carried on canal barges,and to cure madness),mandrake root and opium

pressing, began in Egypt and nearby Mediterranean countries 7000 years ago. Commercial bakeries and breweries existed in Babylon and Egypt 5000 years before Eduard Buchner and Emil Fischer discovered the enzymic conversion of carbohydrates. The history of grain milling illustrates how labour￾intensive artisanal processes were progressively mechanized. The primitive pestel and mortar gave way in Egypt to the saddle stone: where grain spread on a stationary smooth stone slab was pulverized by an upper stone pushed backwards and forwards by a kneeling slave. Later, the Greeks devised a shearing action by incising herring-bone grooves into the inter￾faces of the upper and lower stones. In the rotary quern, evident in several ancient Medi￾terranean countries, an upper stone was continuously rotated over a lower static stone. By cutting an eye-hole in the centre of the upper stone, grain was fed in a steady stream, the pulverized product being carried to the periphery by centrifugal force. Grain milling was the first known continuous industrial process. Rotary querns were at first driven by slaves walking on a treadmill, later by camels or donkeys. After the Romans invented the water wheel, through￾out the Roman empire grain mills were built close by rivers or running streams. The Domesday Book, Wil￾liam I’s inventory of the nation’s assets published in 1085, recorded over 5000 water mills in Britain. The first windmills appeared in Persia (now Iran) in the 10th century CE. In 1784, an early version of James Watt’s steam engine was installed in a London flour mill. Less than 100 years ago, in North America, more grain mills were powered by water wheels than by steam engines. The first mill powered by electric motors came on stream in 1887 in Wyoming. Though more precisely engineered, modern roller mills with their incised steel break rolls operate on the same principles as the early saddle stone and rotary quern. Hand winnowing has its modern equivalent in the middlings purifier, an enclosed vibrating gravity table with screens of diverse mesh size. Separated bran is removed by suction fans. A smart indigenous software programme enables modern wheat flour mills in India to be operated from a desk top computer. At the same time, poor rural Indian women grind local grains by pestel and mortar or saddle stone, and extract oil from groundnuts by rotary querns. Mechanization of traditional biotechnologies The patterns and pace of mechanization have pro￾gressed differently among different industries. Though the transition from rural domestic spinning and weaving into large mechanized factories evolved over more than two centuries, in Britain the textile industry, stimulated by cheap coal carried on canal barges, and the steam engine, was mechanized faster than food processes. In the British baking industry, mechanical dough mixers were not much in evidence until after 1920. Mechanization moved more rapidly after World War II. During the 1930s, in a typical Manchester bakery, six men working an 8 h shift produced about 2400 loaves. In 1990, three men working an 8 h shift could produce over 65,000 loaves: 400 versus 22,000 loaves per man. The first significant change came in the 1960s when British scientists replaced traditional long fermentation processes by high energy mixing of bread doughs con￾taining ascorbic acid. Continuous malting in breweries began with the Wanderhaufen moving malt couch. Continuous fer￾mentations, in which the substrate passes over an immobilized microorganism or biocatalyst, are now common among modern bioindustries. Humphrey Davy’s discovery of finely divided plati￾num as a catalyst led to the catalytic hydrogenation of vegetable oils to produce hard fats for shortening and margarine. About the same time, solvent extraction of vegetable oils competed with mechanical expression. In contrast to food processing, pharmaceutical industries advanced more from chemistry than engineering, start￾ing in the 18th century in the German dyestuffs indus￾tries after von Hofmann was appointed Professor of Chemistry at the University of Berlin. Pharmaceuticals in ancient times Survival and health, the fate of the human soul and body after death, and the supernatural influence of the sun, moon and stars intrigued many of our early ante￾cedents. Primitive peoples searched for panaceas and palliatives to cure their diseases. Early Palestinians and Sumerians believed disease was a punishment for sin and could be mitigated by magical charms and drugs with supernatural powers. Shen-Nung (ca 2700 BCE) is acclaimed as the Chinese founder of acupuncture and drug therapy. He and his contemporaries described diabetes, smallpox, measles, cholera and various dysen￾teries. Their 1800 medical prescriptions included ephe￾drine, camphor, and cod liver oil. Arsenic and mercury compounds acted as bactericides. Respiratory diseases were treated by surrounding the patient in a pile of burning herbs. The Egyptian Ebers papyrus (ca 1550 BCE), dis￾covered by 20th century archeologists, describes treat￾ments for rheumatism, schistosomiasis, diabetes and intestinal parasites. It lists 875 drugs compounded from ca 500 substances: metallic salts, such vegetable extracts as gentian, senna, castor oil, vermifiuge and henbane. Sumerian cuneiform tablets from Hammurabi’s reign describe hepatic diseases, fevers, gonorrhoea, various strokes and scabies. Drugs included hellebore (believed to cure madness), mandrake root and opium. Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 5

6 Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 During the 4th and 5th centuries,BCE,the Greek rational distinction.Though it needed Maxwell's math- school of Hippocrates,published over 70 treatises on ematical genius 40 years later to transform Faraday's medical theories and practices,and prescribed more electromagnetic induction principles into electric motors than 300 remedies,most from plants,to be administered and power generators,the 1850s mark the point from orally or via other orifices.The Greeks were aware of which new technologies based on scientific principles potential dangers in drug therapy;the Greek word appeared alongside empirically discovered technologies oapuokov (Pharmakon)being translated as 'drug', used to process foods,textiles,drugs and ceramics. 'medicine',poison'or 'magic potion'.The Greeks After his mentor Humphrey Davy discovered the believed that health (eucrasia)resulted from a harmonic anaesthetic nitrous oxide,in 1818 Michael Faraday blend,disease (dyscrasia)from imbalance among four demonstrated that ether was a more effective anaes- humours:black bile,yellow bile,phlegm and blood.A thetic.But before von Liebig published his 'Organic tri-humorous concept of air,bile and phlegm existed Chemistry in its Application to Physiology and Pathol- among Ayurvedic Indians. ogy'in the mid-19th century,studies on the effectiveness Some 300 years after Hippocrates,Dioscorides,a of drugs can best be described as blindly empirical. Greek physician,regarded as the father of Materia For many centuries in Europe,pharmacy was the Medica,formulated over 600 remedies from plant and business of apothecaries who extracted and com- animal tissues.Dioscorides'medicines were prescribed pounded medicines from natural vegetable and mineral for more than 1500 years.Galen of Pergamon,a sources.In Ancient Greece,physicians and apothecaries physician of the 2nd century CE,added more veget- were discrete professions (an anoOek was a shop that able remedies,known as Galenicals,to Dioscorides' sold drugs).In 1617,King James I created the collection. Society of Apothecaries,giving them responsibility for Until the middle of the 19th century,medicine and production and sale of drugs and some poisons.Benja- pharmacy were more magical and mystical than scien- min Franklyn defined the respective roles of American tific.Plantagenet physicians treated fevers by burying physicians and apothecaries,with laws that licensed victims up to the neck in a dunghill;gout was treated apothecaries to sell drugs,poisons and narcotics.The with asses'hooves;wealthy patients afflicted with ague, first codified food and drug laws were enacted in 1860 in itch or erysipelas were dosed with finely ground the United Kingdom amethysts,pearls and sapphires. In the 19th century,British apothecaries worked with It is difficult to discover what useful drugs the alche- a Materia Medica cabinet containing 270 samples of mists discovered in their pursuit of the Elixir vitae,the roots,barks,leaves,seeds and chemicals.The British elusive substance that would ensure eternal life.Alche- Pharmaceutical Society received a Royal Charter in mists wrote their reports in cryptic codes and obscure 1843.A consolidated British Pharmacopoeia was pub- symbols to confuse their competitors.What is compre- lished in 1864 and revised in 1898 and 1914.The 1864 hensible is more redolent of the kitchen than the edition described only four synthetic drugs;over 80 laboratory.Alchemical substances included sugar of were listed in the 1914 edition,almost all imported from lead,butter of antimony,oil of vitriol,cream of tartar Germany.Before World War I,Britain had no synthetic and milk of lime. pharmaceutical industry,only a few vaccines being Paracelsus,a Swiss alchemist of the 15th century,is processed. sometimes regarded as the father of chemistry.He dis- puted Galen's theories and developed the notion of From empiricism to science iatrochemistry:examination of substances to detect From the mid-1800s analytical chemistry,microscopy possible medicinal potency.He proposed various medical and cytology made impressive progress.Chemotherapy prescriptions. was stimulated by identification of microbial pathogens The first printed medical book:'Laxierkalender'-a and means by which they could be controlled.Wohler's treatise on laxatives-came from the Gutenberg presses conversion of ammonium isocyanate into urea showed in 1457.In 1564,the world's first Pharmacopoeia that naturally occurring organic substances can be syn- Augustina was published in Augsburg.In 1616,the thesized from non-biological chemicals.Pharmacology Royal College of Physicians published the Pharmaco- progressed through research begun in Strasbourg on poeia Londonensis which listed drugs then permitted in specific actions of drugs on particular body tissues.The Britain. world's first Chair of Pharmacology was in Estonia. Discovery of hormones,extracted from endocrine and Pharmaceutical industries ductless glands and later synthesized,added an important In his book'Brave New World',Aldous Huxley pro- dimension to therapeutic medicine and to development of posed that the history of economic and industrial pharmaceutical industries. development is of two periods:pre-and post-Henry Until the 20th century food processing progressed Ford.I would argue pre-and post-Faraday as a more through engineering, pharmaceutical technologies

During the 4th and 5th centuries, BCE, the Greek school of Hippocrates, published over 70 treatises on medical theories and practices, and prescribed more than 300 remedies, most from plants, to be administered orally or via other orifices. The Greeks were aware of potential dangers in drug therapy; the Greek word farmakon (Pharmakon) being translated as ‘drug’, ‘medicine’, ‘poison’ or ‘magic potion’. The Greeks believed that health (eucrasia) resulted from a harmonic blend, disease (dyscrasia) from imbalance among four humours: black bile, yellow bile, phlegm and blood. A tri-humorous concept of air, bile and phlegm existed among Ayurvedic Indians. Some 300 years after Hippocrates, Dioscorides, a Greek physician, regarded as the father of Materia Medica, formulated over 600 remedies from plant and animal tissues. Dioscorides’ medicines were prescribed for more than 1500 years. Galen of Pergamon, a physician of the 2nd century CE, added more veget￾able remedies, known as Galenicals, to Dioscorides’ collection. Until the middle of the 19th century, medicine and pharmacy were more magical and mystical than scien￾tific. Plantagenet physicians treated fevers by burying victims up to the neck in a dunghill; gout was treated with asses’ hooves; wealthy patients afflicted with ague, itch or erysipelas were dosed with finely ground amethysts, pearls and sapphires. It is difficult to discover what useful drugs the alche￾mists discovered in their pursuit of the Elixir vitae, the elusive substance that would ensure eternal life. Alche￾mists wrote their reports in cryptic codes and obscure symbols to confuse their competitors. What is compre￾hensible is more redolent of the kitchen than the laboratory. Alchemical substances included sugar of lead, butter of antimony, oil of vitriol, cream of tartar and milk of lime. Paracelsus, a Swiss alchemist of the 15th century, is sometimes regarded as the father of chemistry. He dis￾puted Galen’s theories and developed the notion of iatrochemistry: examination of substances to detect possible medicinal potency. He proposed various medical prescriptions. The first printed medical book: ‘Laxierkalender’—a treatise on laxatives—came from the Gutenberg presses in 1457. In 1564, the world’s first Pharmacopoeia Augustina was published in Augsburg. In 1616, the Royal College of Physicians published the Pharmaco￾poeia Londonensis which listed drugs then permitted in Britain. Pharmaceutical industries In his book ‘Brave New World’, Aldous Huxley pro￾posed that the history of economic and industrial development is of two periods: pre-and post-Henry Ford. I would argue pre-and post-Faraday as a more rational distinction. Though it needed Maxwell’s math￾ematical genius 40 years later to transform Faraday’s electromagnetic induction principles into electric motors and power generators, the 1850s mark the point from which new technologies based on scientific principles appeared alongside empirically discovered technologies used to process foods, textiles, drugs and ceramics. After his mentor Humphrey Davy discovered the anaesthetic nitrous oxide, in 1818 Michael Faraday demonstrated that ether was a more effective anaes￾thetic. But before von Liebig published his ‘Organic Chemistry in its Application to Physiology and Pathol￾ogy’ in the mid-19th century, studies on the effectiveness of drugs can best be described as blindly empirical. For many centuries in Europe, pharmacy was the business of apothecaries who extracted and com￾pounded medicines from natural vegetable and mineral sources. In Ancient Greece, physicians and apothecaries were discrete professions (an apoyek was a shop that sold drugs). In 1617, King James I created the Society of Apothecaries, giving them responsibility for production and sale of drugs and some poisons. Benja￾min Franklyn defined the respective roles of American physicians and apothecaries, with laws that licensed apothecaries to sell drugs, poisons and narcotics. The first codified food and drug laws were enacted in 1860 in the United Kingdom. In the 19th century, British apothecaries worked with a Materia Medica cabinet containing 270 samples of roots, barks, leaves, seeds and chemicals. The British Pharmaceutical Society received a Royal Charter in 1843. A consolidated British Pharmacopoeia was pub￾lished in 1864 and revised in 1898 and 1914. The 1864 edition described only four synthetic drugs; over 80 were listed in the 1914 edition, almost all imported from Germany. Before World War I, Britain had no synthetic pharmaceutical industry, only a few vaccines being processed. From empiricism to science From the mid-1800s analytical chemistry, microscopy and cytology made impressive progress. Chemotherapy was stimulated by identification of microbial pathogens and means by which they could be controlled. Wohler’s conversion of ammonium isocyanate into urea showed that naturally occurring organic substances can be syn￾thesized from non-biological chemicals. Pharmacology progressed through research begun in Strasbourg on specific actions of drugs on particular body tissues. The world’s first Chair of Pharmacology was in Estonia. Discovery of hormones, extracted from endocrine and ductless glands and later synthesized, added an important dimension to therapeutic medicine and to development of pharmaceutical industries. Until the 20th century food processing progressed through engineering, pharmaceutical technologies 6 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18

Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 小 through chemistry.Ancient remedies and plant extracts substances found in medicinal plants.The first propri- were the first raw materials of pharmaceutical indus- etary drug Aspirin-acetylsalicylic acid-was synthesized tries.Several drugs in early pharmacopoeias were later by reacting acetic anhydride with salicylic acid from declared ineffective or dangerous. willow bark (Salix spp).Later,codeine was produced by Active substances were dissolved in ethanol and/or methylation of morphine. water;compounded with diluents and pressed into pills In the late 1900s,Paul Ehrlich observed how certain coated with gelatin or sugar;or into tablets with poly- dyes injected into animals,stained specific tissues.Ehr- saccharide gums as binders,and lubricants to permit lich explored whether similar dyes would stain and release from tableting machines.For treatment of skin inactivate microorganisms.He unsuccessfully tested 500 wounds and infections,antiseptic drugs were dispensed dyes on 2000 mice inoculated with pathogenic trypano- as ointments in lanolin or water-in-oil emulsions. somes.He then synthesized more than 600 arsenic compounds with chemical structures similar to diazo Drugs:natural and traditional dyes.His 606th compound inactivated the trypano- Though today roughly 20%of all commercial phar- somes without adverse effect on the mice.The effective maceuticals are derived from natural and genetically compound,named 'salvarsan',contained an -As=As- modified microorganisms,there is lively commercial group analagous to the -N=N-group in diazo dyes and interest in natural and traditional sources.The Pfizer showed affinity with protein in the pathogen compar- drug company was among the first to collect and screen able to the affinity of diazo compounds with protein botanical specimens from tropical forests.Merck in fibres in wool.Salvarsan and its successor neosalvarsan. cooperation with the national Institute of Biodiversity is effective against Spirochaeta pallida the pathogen that screening plants,insects and microorganisms from causes syphilis,laid the basis for chemotherapy. Costa Rica.Ethnobotanical expeditions in the tropical In 1919,Heidelberger and Jakobs in Germany dis- forests of the Amazon have delivered more than 10,000 covered that some azo derivatives of sulphanilamide species for examination.From Colombia over 1500 destroyed bacteria.In 1935,a scientist at the Bayer species,reported by local people to be biologically use- company found the red azo dye prontosil to be effective ful,are being studied. against Streptococci that caused puerperal and scarlet The ethical issue of biopiracy is being raised where fevers.In the 1930s,scientists at May and Baker in foreign companies and their agents,engaged in botani- Britain synthesized over 600 sulphanilamide derivatives. cal collecting,are taking away biological materials and The 693rd.which effectively treated bacterial pneumo- indigenous experience in traditional medicine without nia,was named M&B693.May and Baker synthesized reimbursement to local people.As observed by an Asian over 3000 related compounds,several being effective scientist:"We have the biodiversity,they [the affluent bactericides. nations]steal it to support their biotechnologies".In In 1936,the British Medical Research Council defined response to public interest in ancient and traditional 'Chemotherapy'as medical treatment by synthetic che- medicines,in 1992 the United States National Institutes mical compounds that react specifically with infective of Health established an Office of Alternative Medi- organisms.The process of synthesizing chemother- cines.Data bases on 'natural medicinals'exist at the apeutic substances and determining potency in labora- Royal Danish School of Pharmacy in Copenhagen,and tory animals is expensive and time consuming.Between at the University of Illinois,Chicago School of Medi- 1936 and 1960,one of Britain's largest pharmaceutical cine.The latter,known as NARPALERT,is adminis- companies tested over 45,000 synthetics out of which tered by Professor Norman Farnsworth. only 16 became marketable drugs.During World War Across the planet,there exists a vast unexplored II,Britain lost access to Peruvian bark,the natural source of plants and microorganisms.Of over 100.000 source of the anti-malarial quinine.Antimalarials were identified species,fewer than 200 microorganisms pro- urgently needed to protect armed forces men and duce substances used by food,pharmaceutical or other women posted to humid tropical countries.The only industries.The higher orders of terrestrial plants repre- two synthetics available caused undesirable side effects sent more than 65%of the world's biomass but fewer Between 1942 and 1946.the ICI Pharmaceutical com- than 6%of identified species are commercially culti- pany tested ca 1700 synthetics before discovering pro- vated.Of the 80.000 plants believed to be edible,fewer guanil hydrochloride,given the trade name Paludrine than 20 provide 90%of the world's food calories. 'Malaria'(literally 'bad air'),is also known as palud- ism'or swamp fever (Latin 'palus'='swamp'). Synthetic drugs and chemotherapy During the late 19th century,encouraged by their Antibiotics success with synthetic dyes,the German companies While pursuing his microscopic studies,Pasteur sug- Bayer.Hoechst and Merck began chemical synthesis of gested that microorganisms might be induced to attack drugs,first making analogues and derivatives of active one another.In 1928,Alexander Fleming,at London

through chemistry. Ancient remedies and plant extracts were the first raw materials of pharmaceutical indus￾tries. Several drugs in early pharmacopoeias were later declared ineffective or dangerous. Active substances were dissolved in ethanol and/or water; compounded with diluents and pressed into pills coated with gelatin or sugar; or into tablets with poly￾saccharide gums as binders, and lubricants to permit release from tableting machines. For treatment of skin wounds and infections, antiseptic drugs were dispensed as ointments in lanolin or water-in-oil emulsions. Drugs: natural and traditional Though today roughly 20% of all commercial phar￾maceuticals are derived from natural and genetically modified microorganisms, there is lively commercial interest in natural and traditional sources. The Pfizer drug company was among the first to collect and screen botanical specimens from tropical forests. Merck in cooperation with the national Institute of Biodiversity is screening plants, insects and microorganisms from Costa Rica. Ethnobotanical expeditions in the tropical forests of the Amazon have delivered more than 10,000 species for examination. From Colombia over 1500 species, reported by local people to be biologically use￾ful, are being studied. The ethical issue of biopiracy is being raised where foreign companies and their agents, engaged in botani￾cal collecting, are taking away biological materials and indigenous experience in traditional medicine without reimbursement to local people. As observed by an Asian scientist: ‘‘We have the biodiversity, they [the affluent nations] steal it to support their biotechnologies’’. In response to public interest in ancient and traditional medicines, in 1992 the United States National Institutes of Health established an Office of Alternative Medi￾cines. Data bases on ‘natural medicinals’ exist at the Royal Danish School of Pharmacy in Copenhagen, and at the University of Illinois, Chicago School of Medi￾cine. The latter, known as NARPALERT, is adminis￾tered by Professor Norman Farnsworth. Across the planet, there exists a vast unexplored source of plants and microorganisms. Of over 100,000 identified species, fewer than 200 microorganisms pro￾duce substances used by food, pharmaceutical or other industries. The higher orders of terrestrial plants repre￾sent more than 65% of the world’s biomass but fewer than 6% of identified species are commercially culti￾vated. Of the 80,000 plants believed to be edible, fewer than 20 provide 90% of the world’s food calories. Synthetic drugs and chemotherapy During the late 19th century, encouraged by their success with synthetic dyes, the German companies Bayer, Hoechst and Merck began chemical synthesis of drugs, first making analogues and derivatives of active substances found in medicinal plants. The first propri￾etary drug Aspirin—acetylsalicylic acid—was synthesized by reacting acetic anhydride with salicylic acid from willow bark (Salix spp). Later, codeine was produced by methylation of morphine. In the late 1900s, Paul Ehrlich observed how certain dyes injected into animals, stained specific tissues. Ehr￾lich explored whether similar dyes would stain and inactivate microorganisms. He unsuccessfully tested 500 dyes on 2000 mice inoculated with pathogenic trypano￾somes. He then synthesized more than 600 arsenic compounds with chemical structures similar to diazo dyes. His 606th compound inactivated the trypano￾somes without adverse effect on the mice. The effective compound, named ‘salvarsan’, contained an –As¼As– group analagous to the –N¼N– group in diazo dyes and showed affinity with protein in the pathogen compar￾able to the affinity of diazo compounds with protein fibres in wool. Salvarsan and its successor neosalvarsan, effective against Spirochaeta pallida the pathogen that causes syphilis, laid the basis for chemotherapy. In 1919, Heidelberger and Jakobs in Germany dis￾covered that some azo derivatives of sulphanilamide destroyed bacteria. In 1935, a scientist at the Bayer company found the red azo dye prontosil to be effective against Streptococci that caused puerperal and scarlet fevers. In the 1930s, scientists at May and Baker in Britain synthesized over 600 sulphanilamide derivatives. The 693rd, which effectively treated bacterial pneumo￾nia, was named M&B693. May and Baker synthesized over 3000 related compounds, several being effective bactericides. In 1936, the British Medical Research Council defined ‘Chemotherapy’ as medical treatment by synthetic che￾mical compounds that react specifically with infective organisms. The process of synthesizing chemother￾apeutic substances and determining potency in labora￾tory animals is expensive and time consuming. Between 1936 and 1960, one of Britain’s largest pharmaceutical companies tested over 45,000 synthetics out of which only 16 became marketable drugs. During World War II, Britain lost access to Peruvian bark, the natural source of the anti-malarial quinine. Antimalarials were urgently needed to protect armed forces men and women posted to humid tropical countries. The only two synthetics available caused undesirable side effects. Between 1942 and 1946, the ICI Pharmaceutical com￾pany tested ca 1700 synthetics before discovering pro￾guanil hydrochloride, given the trade name Paludrine. ‘Malaria’ (literally ‘bad air’), is also known as ‘palud￾ism’ or swamp fever (Latin ‘palus’=‘swamp’). Antibiotics While pursuing his microscopic studies, Pasteur sug￾gested that microorganisms might be induced to attack one another. In 1928, Alexander Fleming, at London Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 7

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 Peni￾cillium 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 chemi￾cally 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 Micro￾nesian 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 func￾tions 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 Lan￾gerhens 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 synthe￾sized 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 cap￾tive 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 hor￾mone, 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 live￾stock and domestic pets, it is not surprizing that food and drug industries constantly expand and diversify, to satisfy demands of expanding, affluent and aging popu￾lations. The total world value of industrially processed foods is about $1750 billion USD. Sales value of com￾mercial pharmaceuticals (not including veterinary med￾icines) 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 pro￾cessing 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 peo￾ple, 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 propor￾tion 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 differ￾ences. 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 inexper￾ienced 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 inter￾related 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 biocata￾lytic reactions, genetically modified bacteria, funghi, viruses, plant, mammalian and insect cells. Some tech￾niques modify genetic composition and expression; oth￾ers accelerate and adjust metabolic processes. Of particular interest to bioengineers are reliable means to expand from laboratory to factory scale, and technolo￾gies 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 chemi￾cally modifying natural biochemical substances are giv￾ing 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 bio￾chemistry 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 cul￾ture. 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 vac￾cines, immune regulators, substances to control cardio￾vascular 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 pro￾duced 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 bio￾technologies 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 cul￾tured. ii. Determination of optimum culture and harvesting systems. iii. Scale-up to large batch or continuous bio￾reactors. 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, develop￾ments 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 sys￾tems where the nutrient medium percolates through or over and is transformed by the immobilized cells. Simi￾Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 9

10 Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 larly.metabolites may be synthesized by isolated, fractionation.Supercritical gas/liquid extractions (SGE) immobilized enzymes. are useful for substances sensitive to organic solvents or Plant cell culture begins by propagation of a callus,a susceptible to oxidation.At pressures between 10,000 mass of undifferentiated cells.To derive a new plant and 40,000 kPa,carbon dioxide is a benign solvent for with shoot and root,cells from the callus must be cul- essential oils.oleoresins,natural terpenoids,caffeine. tured in different media.Desirable metabolites can be and other sensitive biochemicals.Unlike many organic extracted from a callus without progression to a shoot solvents.SGE leaves no toxic residues. and root.Plant cell culture seems better suited to Membrane processing,reverse osmosis,ultrafiltra- synthesis of metabolites useful in foods,biopesticides tion,microfiltration,nanofiltration and electrodialysis and cosmetics than for biomedicals. are among other industrial fractionation technologies. Mammalian and insect cell cultures offer more inter- Chromatographic systems include gel filtration,ion- esting opportunities for biomedical applications.Sour- exchange and affinity separations that use binding ces of mammalian cells include kidneys from aborted interactions between proteins and packing materials, embryos and ovarian cells from Chinese hamsters which with various ligands coupled into hydrophilic support replicate relatively rapidly.Insect cell cultures,in com- matrices. bination with GM virus vectors,produce recombinant proteins and viral insecticides.The baculo virus,which Preservation and sterilization infects insect cells,genetically modified yields specific Foods are for healthy nourishment;drugs to diag- proteins in high-density insect cell culture. nose,prevent or cure disease.It is critical that all foods Mammalian cells generate metabolites of greater pur- and drugs be free from organisms that may cause insult ity,potency and complexity than most microbial cul- or injury to those who consume and use them.Gen- tures but,being highly sensitive,require careful culture erally speaking,biological materials such as foods and in relatively small bioreactors.Means to expand mam- pharmaceuticals can be preserved by any process that malian cell culture in batch or continuous systems pre- (1)inhibits,destroys or removes and prevents re-entry sents an interesting challenge to bioengineers. of pathogenic and microorganisms that cause spoilage; Monoclonal antibodies,plasminogen activators,hor- (2)restricts adverse biochemical and biophysical mones to stimulate blood cell growth and Factor VIIl change. to control blood clotting are among products from Degradation of food and other biological materials mammalian cell culture.In association with specific can be restricted by packaging under inert atmosphere, viruses mammalian cells will produce viral vaccines and by reducing water activity and thermal sterilization. recombinant proteins used in gene therapy. Freeze-drying effectively lowers water activity in sensi- In 1997,Human embryonic stem cells (HESC)were tive biologicals.Rapid freezing in liquid nitrogen prior isolated from discarded human embryos.It is postulated to freeze-drying (lyophilisation)restricts cell disruption that pluripotent stem cells may be cultured into different by slow-growing ice crystals. cells with the capacity to replace or repair cellular tis- sues in various human organs.Whether embryo stem Thermal processes and alternatives cells will realise their hypothetical potential seems to Thermal processing in hermetic containers (cans,bot- depend as much on legislation influenced by religious tles,laminated plastics)takes a long time for heat to be belief as on bioscience. conducted throughout the material.Excessive heating of foods and other biologicals can cause adverse change in Downstream processing critical functional properties,nutritional quality,fla- 'Downstream'relates to all that follows bioreactor vour,physical structure and texture.The higher the synthesis:the isolation.purification and sterilization of temperature,the longer the time,the greater the degree end products.Downstream processes are estimated to of biochemical and biophysical change absorb ca 80%of production costs,indicating an urgent Existing processes that reduce heat damage include need for more economical downstream technologies and spray-drying,tubular and scraped surface heat exchan- bioengineers competent to design and operate them. gers,and steam injection followed by aseptic packaging Several alternative means of preservation are in various Isolation stages of investigation and development. Synthesized substances are isolated from various bioreactor fractions:insulin from harvested cells,some Irradiation vaccines from supernatant fluids.intra-cellular metabo- Ionising radiations can inactivate microorganisms lites are released by mechanical,chemical or enzymatic and kill insects.Radiation sources for food and phar- rupture of cell walls;antibiotics by liquid:liquid extrac- maceuticals include gamma rays from radioisotopes tion;tolerant volatile substances by fractional distilla- Co60 or Ces137.X-rays or electrons generated by tion;heat-sensitive enzymes by aqueous phase liquid machines.Absorbed radiation is measured in Grays or

larly, metabolites may be synthesized by isolated, immobilized enzymes. Plant cell culture begins by propagation of a callus, a mass of undifferentiated cells. To derive a new plant with shoot and root, cells from the callus must be cul￾tured in different media. Desirable metabolites can be extracted from a callus without progression to a shoot and root. Plant cell culture seems better suited to synthesis of metabolites useful in foods, biopesticides and cosmetics than for biomedicals. Mammalian and insect cell cultures offer more inter￾esting opportunities for biomedical applications. Sour￾ces of mammalian cells include kidneys from aborted embryos and ovarian cells from Chinese hamsters which replicate relatively rapidly. Insect cell cultures, in com￾bination with GM virus vectors, produce recombinant proteins and viral insecticides. The baculo virus, which infects insect cells, genetically modified yields specific proteins in high-density insect cell culture. Mammalian cells generate metabolites of greater pur￾ity, potency and complexity than most microbial cul￾tures but, being highly sensitive, require careful culture in relatively small bioreactors. Means to expand mam￾malian cell culture in batch or continuous systems pre￾sents an interesting challenge to bioengineers. Monoclonal antibodies, plasminogen activators, hor￾mones to stimulate blood cell growth and Factor VIII to control blood clotting are among products from mammalian cell culture. In association with specific viruses mammalian cells will produce viral vaccines and recombinant proteins used in gene therapy. In 1997, Human embryonic stem cells (HESC) were isolated from discarded human embryos. It is postulated that pluripotent stem cells may be cultured into different cells with the capacity to replace or repair cellular tis￾sues in various human organs. Whether embryo stem cells will realise their hypothetical potential seems to depend as much on legislation influenced by religious belief as on bioscience. Downstream processing ‘Downstream’ relates to all that follows bioreactor synthesis: the isolation, purification and sterilization of end products. Downstream processes are estimated to absorb ca 80% of production costs, indicating an urgent need for more economical downstream technologies and bioengineers competent to design and operate them. Isolation Synthesized substances are isolated from various bioreactor fractions: insulin from harvested cells, some vaccines from supernatant fluids. intra-cellular metabo￾lites are released by mechanical, chemical or enzymatic rupture of cell walls; antibiotics by liquid:liquid extrac￾tion; tolerant volatile substances by fractional distilla￾tion; heat-sensitive enzymes by aqueous phase liquid fractionation. Supercritical gas/liquid extractions (SGE) are useful for substances sensitive to organic solvents or susceptible to oxidation. At pressures between 10,000 and 40,000 kPa, carbon dioxide is a benign solvent for essential oils, oleoresins, natural terpenoids, caffeine, and other sensitive biochemicals. Unlike many organic solvents, SGE leaves no toxic residues. Membrane processing, reverse osmosis, ultrafiltra￾tion, microfiltration, nanofiltration and electrodialysis are among other industrial fractionation technologies. Chromatographic systems include gel filtration, ion￾exchange and affinity separations that use binding interactions between proteins and packing materials, with various ligands coupled into hydrophilic support matrices. Preservation and sterilization Foods are for healthy nourishment; drugs to diag￾nose, prevent or cure disease. It is critical that all foods and drugs be free from organisms that may cause insult or injury to those who consume and use them. Gen￾erally speaking, biological materials such as foods and pharmaceuticals can be preserved by any process that (1) inhibits, destroys or removes and prevents re-entry of pathogenic and microorganisms that cause spoilage; (2) restricts adverse biochemical and biophysical change. Degradation of food and other biological materials can be restricted by packaging under inert atmosphere, by reducing water activity and thermal sterilization. Freeze-drying effectively lowers water activity in sensi￾tive biologicals. Rapid freezing in liquid nitrogen prior to freeze-drying (lyophilisation) restricts cell disruption by slow-growing ice crystals. Thermal processes and alternatives Thermal processing in hermetic containers (cans, bot￾tles, laminated plastics) takes a long time for heat to be conducted throughout the material. Excessive heating of foods and other biologicals can cause adverse change in critical functional properties, nutritional quality, fla￾vour, physical structure and texture. The higher the temperature, the longer the time, the greater the degree of biochemical and biophysical change. Existing processes that reduce heat damage include spray-drying, tubular and scraped surface heat exchan￾gers, and steam injection followed by aseptic packaging Several alternative means of preservation are in various stages of investigation and development. Irradiation Ionising radiations can inactivate microorganisms and kill insects. Radiation sources for food and phar￾maceuticals include gamma rays from radioisotopes Co60 or Ces137, X-rays or electrons generated by machines. Absorbed radiation is measured in Grays or 10 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18

Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 11 kiloGrays (kGy),I Gray being equivalent to 1 Joule tems.Quartz crystals facilitate controlled outputs ran- per kg. ging from 500 W to 50 kW with 80-90%energy In the USA,irradiation is permitted for microbial efficiency.Computer modelling programmes determine control in dehydrated enzymes (10 kGy),spices (30 optimum conditions for different purposes.Main con- kGyJ),poultry (3 kGy),various pharmaceuticals and straints include relatively high capital costs and need for other biological materials.Data in parentheses are highly skilled engineers for operational control. maximum permitted doses.The higher the dose,the greater the inactivation of microorganisms.High doses Ultra-high hydrostatic pressure(UHP) can induce molecular disruption and generate highly Lethal effects on microorganisms of isostatic pres- reactive free radicals which in turn cause unpredictable sures between 500 and 10 k bar(50 kPa-1 MPa)were biochemical modifications.In general,higher doses are discovered over a century ago.UHP food processing permitted in biologicals consumed in small quantities has been applied mainly to fruit juices and jams.Industrial (e.g.spices)or in prescribed pharmaceuticals.A WHO equipment maintains pressures from 400 to 800 MPa. 1997 report states that at legally permitted doses,irra- Biomaterials in flexible or semi-rigid packages,evac- diation of foods will not cause toxicological difficulty or uated before sealing,are immersed in a fluid in a high significant nutrient loss. pressure vessel.The UHP is transmitted through the Apart from consumers'suspicions,still evident,the fluid to the biomaterial.In acidic products vegetative main constraints to food irradiation are economic. cells are inactivated at 400 MPa,bacterial spores after Capital costs are high,emissions from radioactive iso- 30 min at 600 MPa.UHP minimizes loss of nutritional topes cannot be switched off,so to derive maximum and functional properties.Constraints include high benefit there must be a constant supply,24 h every day, capital cost,precise engineering and skilled operational 365 days every year,of high value material to be pro- control cessed.Irradiation processes call for skilled bioengineers and physicists to ensure safety of all workers who must Pulsed energy come close to the equipment.In most cases,irradiation Three forms of pulsed energy for microbial inactiva- is uneconomic for grain disinfestation even at the rela- tion are under study:(1)Pulsed electric fields(PEF):(2) tive low doses required. Pulsed light (PL):(3)Pulsed magnetic fields (PMF) With PEF,induced electric potential causes lethal irre- Ohmic heating versible polarization of cell membranes.Critical poten- When an electric current flows through a substance of tial varies with species,cell morphology and ambient suitable conductivity,heat is uniformly generated.Ohmic conditions.Vegetative cells are inactivated at field heating is effective for fluids and particles suspended in strengths between 15 and 30 kV/cm,alternating polarity fluid media.The fluid is pumped through a column pulses being more effective than constant polarity. between two electrodes between which the current pas- Pulsed energy is not yet effective against spores or ses.The sterilised product is rapidly cooled and passes degradative enzymes. aseptically into sterile containers.Heating is uniform Pulsed light activates an inert gas lamp to generate and of short duration.Commercial models range from a broad band light flashes.20000 times the intensity of 10 kW pilot scale that processes 100 kg/h,to 300 kW sunlight at the earth's surface.PL is effective against machines to process 3 t/h.Capital costs range between surface vegetative organisms. 375,000 and two million pounds sterling.Operating Pulsed energy systems bear high capital costs and costs depend on the power consumed and properties of need precise operational control. the products processed. Ultrasonics (US) Microwave(MW)and radio frequency (RF)heating Ultrasonics use sound waves at frequencies higher MW and RF depend on electromagnetic energy gen- than detected by human ears (20 kHz).Microbes in erated from a magnetron to produce an electric field liquid suspension are inactivated by alternating pres- that alternates at radio or microwave frequencies.Heat sures and cavitation.With mild heat,US inactivates is generated in biological materials by rapid reversal of vegetative cells and can remove dirt inaccessible to con- molecular polarization.MW and RF provide uniform. ventional cleaning.US is used industrially to accelerate short-time heating with high internal temperatures. or control crystallization,filtration,hydrogenation of Most widely known are domestic MW ovens,indust- lipids and aging of alcoholic beverages. rially MW and RF processes are used in dehydration, microbial inactivation and cooking. Process and product quality control (QC) International electromagnetic compatibility regula- Simply defined,QC objectives are to ensure (1)the tions limit industrial processes to specific frequency properties of raw materials and final products comply bands that do not interfere with communication sys- with defined specifications;(2)consistency of essential

kiloGrays (kGy), 1 Gray being equivalent to 1 Joule per kg. In the USA, irradiation is permitted for microbial control in dehydrated enzymes (10 kGy), spices (30 kGyJ), poultry (3 kGy), various pharmaceuticals and other biological materials. Data in parentheses are maximum permitted doses. The higher the dose, the greater the inactivation of microorganisms. High doses can induce molecular disruption and generate highly reactive free radicals which in turn cause unpredictable biochemical modifications. In general, higher doses are permitted in biologicals consumed in small quantities (e.g. spices) or in prescribed pharmaceuticals. A WHO 1997 report states that at legally permitted doses, irra￾diation of foods will not cause toxicological difficulty or significant nutrient loss. Apart from consumers’ suspicions, still evident, the main constraints to food irradiation are economic. Capital costs are high, emissions from radioactive iso￾topes cannot be switched off, so to derive maximum benefit there must be a constant supply, 24 h every day, 365 days every year, of high value material to be pro￾cessed. Irradiation processes call for skilled bioengineers and physicists to ensure safety of all workers who must come close to the equipment. In most cases, irradiation is uneconomic for grain disinfestation even at the rela￾tive low doses required. Ohmic heating When an electric current flows through a substance of suitable conductivity, heat is uniformly generated. Ohmic heating is effective for fluids and particles suspended in fluid media. The fluid is pumped through a column between two electrodes between which the current pas￾ses. The sterilised product is rapidly cooled and passes aseptically into sterile containers. Heating is uniform and of short duration. Commercial models range from a 10 kW pilot scale that processes 100 kg/h, to 300 kW machines to process 3 t/h. Capital costs range between 375,000 and two million pounds sterling. Operating costs depend on the power consumed and properties of the products processed. Microwave (MW) and radio frequency (RF) heating MW and RF depend on electromagnetic energy gen￾erated from a magnetron to produce an electric field that alternates at radio or microwave frequencies. Heat is generated in biological materials by rapid reversal of molecular polarization. MW and RF provide uniform, short-time heating with high internal temperatures. Most widely known are domestic MW ovens, indust￾rially MW and RF processes are used in dehydration, microbial inactivation and cooking. International electromagnetic compatibility regula￾tions limit industrial processes to specific frequency bands that do not interfere with communication sys￾tems. Quartz crystals facilitate controlled outputs ran￾ging from 500 W to 50 kW with 80–90% energy efficiency. Computer modelling programmes determine optimum conditions for different purposes. Main con￾straints include relatively high capital costs and need for highly skilled engineers for operational control. Ultra-high hydrostatic pressure (UHP) Lethal effects on microorganisms of isostatic pres￾sures between 500 and 10 k bar (50 kPa–1 MPa) were discovered over a century ago. UHP food processing has been applied mainly to fruit juices and jams. Industrial equipment maintains pressures from 400 to 800 MPa. Biomaterials in flexible or semi-rigid packages, evac￾uated before sealing, are immersed in a fluid in a high pressure vessel. The UHP is transmitted through the fluid to the biomaterial. In acidic products vegetative cells are inactivated at 400 MPa, bacterial spores after 30 min at 600 MPa. UHP minimizes loss of nutritional and functional properties. Constraints include high capital cost, precise engineering and skilled operational control. Pulsed energy Three forms of pulsed energy for microbial inactiva￾tion are under study: (1) Pulsed electric fields (PEF); (2) Pulsed light (PL); (3) Pulsed magnetic fields (PMF). With PEF, induced electric potential causes lethal irre￾versible polarization of cell membranes. Critical poten￾tial varies with species, cell morphology and ambient conditions. Vegetative cells are inactivated at field strengths between 15 and 30 kV/cm, alternating polarity pulses being more effective than constant polarity. Pulsed energy is not yet effective against spores or degradative enzymes. Pulsed light activates an inert gas lamp to generate broad band light flashes, 20 000 times the intensity of sunlight at the earth’s surface. PL is effective against surface vegetative organisms. Pulsed energy systems bear high capital costs and need precise operational control. Ultrasonics (US) Ultrasonics use sound waves at frequencies higher than detected by human ears (20 kHz). Microbes in liquid suspension are inactivated by alternating pres￾sures and cavitation. With mild heat, US inactivates vegetative cells and can remove dirt inaccessible to con￾ventional cleaning. US is used industrially to accelerate or control crystallization, filtration, hydrogenation of lipids and aging of alcoholic beverages. Process and product quality control (QC) Simply defined, QC objectives are to ensure (1) the properties of raw materials and final products comply with defined specifications; (2) consistency of essential Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 11

12 Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 properties among all production runs.Specifications are name 'Enzyme linked immunosorbent assays'(ELISA). laid down by (1)international protocols,(2)govern- Automated ELISA systems are based on a dipstick ment regulatory agencies,(3)customers,secondary technology originally developed for testing pregnancy in processors and retailers;(4)processing company man- women. agers.Specifications,analyses and assessments of foods An ideal sensor must be accurate,reliably responsive, and drugs are designed to ensure safety to consumers and robust and tolerant to processing conditions,easy to effectiveness within the conditions prescribed for use. install and maintain,inexpensive in relation to product More than 8000 processed foods and 7000 approved market value.Magnetic Resonance Imaging (MRI)and drugs are commercially produced in North America and other expensive systems are economic for pharmaceu- Europe,together with unknown quantities of traditional tical but generally too expensive for most industrial foods and drugs on other continents.A comprehensive food processes. account of all recommended and tentative QC proce- On-line control systems are as much the responsibility dures would fill many CD Roms.This paper offers only of production bioengineers as of quality control bio- an overview of present trends and practices.Bioengi- chemists and microbiologists.Many on-line sensors and neers must ensure that materials of construction are probes determine a reaction or response indirectly rela- compatible with biological materials to be processed. ted to the property critical to product safety and effec- Processing equipment must be easy to clean and,where tiveness.Bioengineers must therefore comprehend the necessary,to sterilize. relation between the response recorded and the critical product property to be determined.Sensors and their On-line systems responses should be systematically checked and correlated Analyses of random samples from finished products with direct methods of determination. in a quality control laboratory is gradually being superseded by control systems that use on-line sensors, Quality control(QC)and genetically modified (GM) probes and monitors that continually assess critical organisms properties.When a defective property is identified,a The use of living organisms to synthesize pharmaceu- feed-back signal corrects the faulty processing para- ticals,the complexity of the process technologies,call meter,all on-line determinations being recorded in a for changing patterns of process and product control.In computer. addition to ensuring product safety and effectiveness, More than 100 devices determine flow rates,apparent control systems must characterize and monitor organisms viscosities and various rheological properties.Others used,cell culture conditions,reaction,recovery and pur- record temperature,pressure and RH gradients.Various ification processes.OC of biologicals produced by viruses critical properties are assessed by change in electrical microbial,plant,insect and mammalian cells is more com- conductivity or dielectric constant.Chemical sensors plicated than of pharmaceutical substances isolated from respond to changes in pH,specific ions,organic radicals medicinal plants or synthesized by chemical reactions. and impurities.Biosensors employ immobilized bac- Accurate analysis of novel proteins synthesized by teria,enzymes,antigen-antibody reactions and DNA rDNA in GM organisms is an important priority.Pro- probes.By multivariant analysis of responses to mixed gress is evident in automation of electrophoresis,amino aromatics,an electronic nose can detect desirable or acid analysis and gene sequencing.HPLC coupled with obnoxious odours mass spectrometry and immunochemistry is extending Spectroscopic on-line methods are too many and the frontiers of protein analysis.Robotics,though rela- diverse to be catalogued.Ultrasonics detect particle size tively slow,are useful for tedious activities such as iso- distribution,emulsion breakdown and various adulter- tope labelling.Of urgent need are reliable methods to ants.Near infra-red can be calibrated to determine determine picogram levels of possible oncogenic DNA moisture,protein,lipid and various other component in mammalian cell cultures. concentrations.Magnetic resonance imaging is an advanced spectroscopic method based on different The future of bioengineering magnetic properties of atomic nuclei when placed in a From the data provided by the Ernst and Young magnetic field.The field induces different energy levels regional biotechnology studies,from other publications between protons aligned with and protons aligned and discussions with biotech industry executives,it is against the field.MRI,most widely used to diagnose clearly evident that the demand for bioengineers and defects in the human body,now is applied to detect biotechnologists exceeds present and predicted supply. infections in aseptically packaged foods and drugs. One study forecasts that over the next decade industrial Being non-destructive,it offers 100%inspection of opportunities for bioengineers will rise by 80%.for critical biological materials. research and development bioscientists by ca 60%. Immunological methods attach enzyme labels to Since the mid-1970s,modern biotechnology industries antibodies to react to specific pathogens,hence the have generated more than 100 new drugs and vaccines

properties among all production runs. Specifications are laid down by (1) international protocols, (2) govern￾ment regulatory agencies, (3) customers, secondary processors and retailers; (4) processing company man￾agers. Specifications, analyses and assessments of foods and drugs are designed to ensure safety to consumers and effectiveness within the conditions prescribed for use. More than 8000 processed foods and 7000 approved drugs are commercially produced in North America and Europe, together with unknown quantities of traditional foods and drugs on other continents. A comprehensive account of all recommended and tentative QC proce￾dures would fill many CD Roms. This paper offers only an overview of present trends and practices. Bioengi￾neers must ensure that materials of construction are compatible with biological materials to be processed. Processing equipment must be easy to clean and, where necessary, to sterilize. On-line systems Analyses of random samples from finished products in a quality control laboratory is gradually being superseded by control systems that use on-line sensors, probes and monitors that continually assess critical properties. When a defective property is identified, a feed-back signal corrects the faulty processing para￾meter, all on-line determinations being recorded in a computer. More than 100 devices determine flow rates, apparent viscosities and various rheological properties. Others record temperature, pressure and RH gradients. Various critical properties are assessed by change in electrical conductivity or dielectric constant. Chemical sensors respond to changes in pH, specific ions, organic radicals and impurities. Biosensors employ immobilized bac￾teria, enzymes, antigen-antibody reactions and DNA probes. By multivariant analysis of responses to mixed aromatics, an electronic nose can detect desirable or obnoxious odours. Spectroscopic on-line methods are too many and diverse to be catalogued. Ultrasonics detect particle size distribution, emulsion breakdown and various adulter￾ants. Near infra-red can be calibrated to determine moisture, protein, lipid and various other component concentrations. Magnetic resonance imaging is an advanced spectroscopic method based on different magnetic properties of atomic nuclei when placed in a magnetic field. The field induces different energy levels between protons aligned with and protons aligned against the field. MRI, most widely used to diagnose defects in the human body, now is applied to detect infections in aseptically packaged foods and drugs. Being non-destructive, it offers 100% inspection of critical biological materials. Immunological methods attach enzyme labels to antibodies to react to specific pathogens, hence the name ‘Enzyme linked immunosorbent assays’ (ELISA). Automated ELISA systems are based on a dipstick technology originally developed for testing pregnancy in women. An ideal sensor must be accurate, reliably responsive, robust and tolerant to processing conditions, easy to install and maintain, inexpensive in relation to product market value. Magnetic Resonance Imaging (MRI) and other expensive systems are economic for pharmaceu￾tical but generally too expensive for most industrial food processes. On-line control systems are as much the responsibility of production bioengineers as of quality control bio￾chemists and microbiologists. Many on-line sensors and probes determine a reaction or response indirectly rela￾ted to the property critical to product safety and effec￾tiveness. Bioengineers must therefore comprehend the relation between the response recorded and the critical product property to be determined. Sensors and their responses should be systematically checked and correlated with direct methods of determination. Quality control (QC) and genetically modified (GM) organisms The use of living organisms to synthesize pharmaceu￾ticals, the complexity of the process technologies, call for changing patterns of process and product control. In addition to ensuring product safety and effectiveness, control systems must characterize and monitor organisms used, cell culture conditions, reaction, recovery and pur￾ification processes. QC of biologicals produced by viruses, microbial, plant, insect and mammalian cells is more com￾plicated than of pharmaceutical substances isolated from medicinal plants or synthesized by chemical reactions. Accurate analysis of novel proteins synthesized by rDNA in GM organisms is an important priority. Pro￾gress is evident in automation of electrophoresis, amino acid analysis and gene sequencing. HPLC coupled with mass spectrometry and immunochemistry is extending the frontiers of protein analysis. Robotics, though rela￾tively slow, are useful for tedious activities such as iso￾tope labelling. Of urgent need are reliable methods to determine picogram levels of possible oncogenic DNA in mammalian cell cultures. The future of bioengineering From the data provided by the Ernst and Young regional biotechnology studies, from other publications and discussions with biotech industry executives, it is clearly evident that the demand for bioengineers and biotechnologists exceeds present and predicted supply. One study forecasts that over the next decade industrial opportunities for bioengineers will rise by 80%, for research and development bioscientists by ca 60%. Since the mid-1970s, modern biotechnology industries have generated more than 100 new drugs and vaccines. 12 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18