Trends in Food Science & Technology 15 (2004) 3–18

Biotechnologies:
The British physicist Lord Kelvin gave as his opinion
past history, 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
# 2003 Elsevier Ltd. All rights reserved. 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
4 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
 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 5

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.
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
farmakon (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 apoyek 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
 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 7

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 –As¼As–
modified microorganisms, there is lively commercial group analagous to the –N¼N– 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
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 $1750 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 $400 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
 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 iii. 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-
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 VIII 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
 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 11

kiloGrays (kGy), 1 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, 20 000 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
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. QC 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.
 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 13

In the year 2000, world-wide investment in biotechnol- present known is almost nothing in comparison with
ogies amounted to $37 billion USD which, according to what remains to be discovered. . . . We could free our-
a recent Canadian study, is expected to increase by selves from an infinity of maladies of body and mind if
30%/year over the foreseeable future. According to a we had knowledge of their causes and the remedies
McKinsey Company report, biotechnology research and provided by nature’’.
industrial development appear attractive to venture
capital of which, in Canada, 90% is invested in the
health care sector. Chronologies of biotechnologies for food and drugs
Whether or not these predictions of future growth will
be precisely accurate, expansion and diversification of BCE (BC)
bioscience and bioindustries seems inevitable given that
most governments among European Union and North 4th/3rd Millennium
American nations declare health care, food safety and Egyptians developed grain milling, baking,
environmental protection related to human and animal brewing.
health as high priorities.
At the time when pharmaceuticals were mainly
derived from medicinal plants and chemical synthetics, 3rd Millennium
factory engineers were mostly chemical engineers. It is Chinese Emperor Fu-Hsi proposed health food
now evident that classical chemical engineering is principles of Yin, Yang.
inadequate for modern and advancing techniques of Chinese Shen-Yung Originator of acupuncture
biosynthesis, extraction, isolation and purification of and natural drug therapy.
biologicals produced by various cell cultures and Prescribed 1800 biological and chemical reme-
genetically modified organisms. dies.
The academic qualifications and experience needed in Egyptians, Sumerians preservation of milk,
industrial bioengineers are rapidly changing. To provide vegetables by acid fermentations.
the knowledge and skills industries need, universities
must evolve from traditional unidisciplinary, narrowly
specialised departments into integrated interdisciplinary 2nd Millennium
units. Egyptians prescribed plant remedies for rheu-
The Manchester Interdisciplinary Biocentre [MIB] matism, diabetes, schistosomiasis.
illustrates how academic bioscientific research and Sumerians treated hepatic diseases, gonorrhoea,
teaching must be organised in the future. In a newly strokes and scabies.
designed facility, the MIB will be staffed by biophysi- Chinese distilled ethanol. Burnt sponge (iodine)
cists, biochemists, mathematicians, computation scien- to alleviate goitre.
tists bioengineers and systems analysts. Bioengineers,
together with all other involved disciplines, must work 1st Millennium
cooperatively from the early synthesis through to fac- Natural, open-air freeze-drying of potatoes by
tory-scale processes, the whole being integrated into an Andean Amerindians.
orderly organisation by mathematically-trained systems
analysts. An academic evolution to active, organized
interdisciplinary teaching, research and development is 5th/4th Century
essential for all biosciences and biotechnologies: phar- Hippocrates School of Medicine Hippocratic
maceuticals, food and all else on which healthy lives Oath; 70 medical treatises; 300 remedies.
depend.
Recognizing the rate at which bioscience is expanding
and diversifying, university departments could profit- 4th Century
ably emulate their schools of management colleagues by Aristotle classified known plants and animals;
offering short, intensive courses to enable industrial Theophrastus wrote ‘History of plants’.
biotechnologists and bloengineers continually to Greek word ‘Pharmacon’ means both medicine
upgrade their knowledge and skills. To satisfy the evol- and poison.
ving needs of modern bioindustries, universities must
critically assess and, in some instances, restructure their
departmental organizations, curricula and research 2nd Century
programmes. Dioscorides: Father of Materia medica; pre-
An obiter dictum from Rene Descartes’ ‘Discourse on scribed > 600 drugs and remedies.
Method’ seems apposite and appropriate. ‘‘All that is at Romans invented the water wheel.
14 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18

CE (AD) Robert Hooke, (cf Hooke’s Law: relation

between stress and strain in elastic materials)
2nd Century described cellular structure of cork and various
Galen of Pergamon: Many drugs known as plant tissues.
Galenicals. Anton von Leeuwenhoek (Netherlands) invented
Alchemy began in Alexandria; continued until a microscope (magnification 30) described
16th Century. blood corpuscles, cells in fish tissues and ‘ani-
Alchemists influenced by chromatic and mor- malcules’ (protozoa) present in organic matter in
phological associations (e.g. red wine and red ponds.
meat generated good blood; white wine and meat 1664 Thomas Willis (Oxford) described human
conducive to anaemia). Yellow saffron prescribed brain and cranial nerves.
for jaundice: lung-shaped leaves of lungwort for 1670 Kaspar Bauhin (Swiss) classified higher
respiratory diseases. plants into genera and species.
1679 Hamm (Netherlands) discovered sperma-
tozoa.
10th/11th Century 1690s First herbarium of North American plants
Persians invented the windmill. by immigrant physician to Canada. First studies
Avicenna translated Aristotle, Dioscorides, of medicinal plants used by native aboriginals.
Galen other early Greeks into Arabic.
Arabians Materia medica: medicinal plants,
extracts from wood and tree bark. 18th Century
Linnaeus (Swede) formulated taxonomic system
of classification for plants and animals later
15th/l6th Century refined by Antoine de Jussieu (for plants) and
First medical text book on Laxatives printed on Georges Cuvier (for animals).
the Gutenberg Press. Edward Jenner observed British milk maids
Paracelsus practised alchemy and medicine, dis- immune to cowpox. Jenner developed refined
covered laudanum and opium. method of vaccination with controlled doses of
Drugs classified by function: hypnotics (opium, cowpox serum. Jenner’s process safer than older
poppy juice, atropine from nightshade); pain Asian processes [‘Vacca’ (Latin)=Cow].
relievers, anti-pyretics (willow bark, laudanum, 1763 Extract of English willow bark relieved
strychnine); laxatives (castor oil, senna); emetics arthritis and rheumatic pain (salicylic acid iso-
(tartar emetic); diuretics (Digitalis later for car- lated a century later).
diovascular disorders). French pharmacien Pelletier isolated an emetic
Derivatives of copper, mercury, antimony and from ipecacuanha, strychnine from an Indian
sulphur—wonder drugs of the Renaissance. tree (genus Strychnos), morphine from opium
Mercury for syphilis later discovered to cause poppy seed, brucine from angostura, quinine
neurological toxicity. from Peruvian bark, caffeine from coffee berries,
World’s first pharmacopoeia printed in Augs- veratrine (jervin) from hellebore.
burg. Spallanzani (Italian) sterilized foods and organic
Antimony (tartar emetic) ‘a panacea’; later materials by heating in hermetic containers.
shown to cause cardiovascular collapse. Spallanzani demonstrated fertilization of eggs by
spermatozoa.
1798 Thomas Malthus ‘Essay on Population’.
17th Century Human population will exceed food supply.
King James I created British Society of Apo- Pharmacy as discrete profession combining apo-
thecaries. thecaries’ arts, botany, chemistry.
Digitalis discovered in UK—foxglove a rural folk First chair of Pharmacology at Dorpat in Estonia
remedy for dropsy. to study effects of therapeutics, toxicology, phy-
Thomas Sydenham, Birmingham physician, dif- siology and botany.
ferentiated between scarlet fever and measles.
William Harvey described heart as stimulus for
blood circulation, measured blood flow. 19th Century
Peruvian bark, brought to Europe by Spanish Humphrey Davy discovered nitrous oxide as
Jesuits, therapeutic for malaria (Lit. ‘bad air’) anaesthetic.
later discovered to contain quinine. Michael Faraday discovered ether as anaesthetic.
 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 15

Rudolph Virchow diagnosed and described 1847 J. Y. Simpson (Edinburgh) nitrous oxide,
leucaemia, thromboses, embolisms. ether and chlorophorm as anaesthetics.
Virchow’s hypothesis: cells ultimate units of all 1855 Nathaniel Pringsheim (German) reported
organic life and pathological disturbance. fusion of male spermatozoa with female ovum
Virchow’s cellular theory of pathology coincident and how resultant cell differentiated into new
with atomic theory of physics. orgnanisms.
Virchow’s studies plus advances in analytical 1870s E. Strasburger and Oskar Herrwig
chemistry formed basis of pharmacology: (Germany) described (1) division of nuclei, (2)
chemical composition related to therapeutic fusion of two nuclei one from each parent.
function. 1858 A. R. Wallace (UK) Theory of evolution—
Alkaloids first therapeutics isolated: morphine transmitted to Charles Darwin.
(1806), strychnine (1818), quinine (1820) 1859 Charles Darwin ‘On the Origin of Species
1816 G. Cuvier (French) categorised animals in by means of Natural Selection’.
four classes: Vertebrata, Mollusca, Articulata, 1850s German chemical and pharmaceutical
Radiata. industries developed.
1832 J. von Liebig (German) demonstrated that Chemical synthesis of drugs. Among first, amyl
chloral hydrate induces sleep. nitrate to treat angina pectoris.
1820 Bracconot (French) hydrolized gelatin to Alkaloids atropine, cocaine and nicotine synthe-
produce glycine, meat and wool—leucine. sized.
1838 Berzelius (Swedish) coined the name ‘‘Pro- 1870 Veronal (phenobarbitol) synthesized by
tein’’ (Greek roteos—Proteos: ‘that which Emil Fischer.
comes first’) for nitrogenous organic compounds. 1835 Agostino Bassi (Italian) reported disease in
1846 von Liebig isolated tyrosine. silk worms caused by microfungus.
1860–1900 Most other essential amino acids 1860s Casimir Davaine (French) identified bac-
isolated. Last was threonine in 1930. teria in blood of animals infected with Anthrax
1840–50s J. von Liebig recognized proteins, bacteria.
lipids, carbohydrates and various minerals as 1860s Louis Pasteur (French) proved micro-
essential to human and animal nutrition. organisms are the cause not the result of fer-
1854 Lawes and Gilbert (UK) demonstrated mentation in decaying matter.
difference in nutritive value among plant proteins 1860s–80s Pasteur revealed the link between
fed to pigs. bacteria and disease by studying infected silk-
1825 F. B. Raspall, using iodine as a dye, worms, other sources of pathogens. He showed
revealed the distribution of starch in plant bacteria as the cause of acidity in beer.
cells. Regarded as the founding father of histo- Whitbreads UK brewery—first to use microscope
chemistry. for quality control.
1828 Friedrich Wohler (German) synthesized 1860s Robert Koch (German) devised selective
urea from inorganic ammonium isocyanate. staining to assist microscopic identification of
1827 K. E. von Baer (Estonian) described the microorganisms.
mammalian egg. 1882 Koch identified Mycobacierium tuberculo-
1830 Robert Brown (Scotland) described nuclei sum as the infective cause of pulmonary tuber-
in plant cells. culosis. Koch’s diagnostic procedure: (1) isolate
1838 M. J. Schleiden and Theodur Schwann and culture the organism; (2) infect laboratory
(Germany) cooperatively recognised the similar- mice with the cultured organism; (3) recover the
ity on nuclei in plant and animal cells. From organism from mouse tissue.
early 1830s active interest in cytology. 1867 Joseph Lister (UK surgeon) used phenol to
1840–80 Progressive discovery of chromosomes— disinfect wounds.
naturally colourless, made visible by selective 1870 C. J. Eberth (German) laid the basis for
affinity with chemical dyes. virology by filtering out Anthrax bacteria from
1840s–60s Several reports that organisms develop blood from which Pasteur diagnosed diseases
by repeated cell division organic cells consist of caused by microscopically invisible organisms
nuclei embedded in protoplasm, (Greek ‘first to that passed through microbial filters. Pasteur
be moulded’). began diagnosis of viral diseases.
1840s William Perkin (UK) trying to synthesise 1866 Gregor Mendel identified inheritable
quinine from analine sulphate accidentally pro- characters in noticeably different pea varieties.
duced first synthetic dye: mauveine, laid basis for Mendel’s results ignored until rediscovered by
the European dyestuffs industries. American scientist in 1900.
16 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18

1880 First pharmaceutical industries in UK. 1914 Thyroxine isolated.

Most R and D in government laboratories cf 1921 In Toronto: Insulin isolated from Lan-
Germany: most by private industry. Burroughs gherens islets in pig pancreas.
Welcome most research active in UK. Pharma- UK Large scale vaccination against diphtheria,
ceutical companies treated with suspicion in tetanus, yellow fever, small pox.
USA, (American Society for Experimental 1900–1930s Adaptation by mutation to ecologi-
Pharmacology excluded industrial pharmacolo- cal conditions by various organisms.
gists until 1941). 1927 H. J. Mueller accelerated mutations by
1883 Johann Kjeldahl (Netherlands) Analytical X-rays; UV, radioctive emanations.
method to determine nitrogen in proteins. Chemical mutations by ethyl methane sulpho-
1890s Isolation of substances active in endo- nate. Plant chromosomes doubled by colchicine,
crines: suprarenin and thyroidin. an alkaloid extracted from seeds and corms of
1890s Paul Ehrlich demonstrated affinity of the Meadow Saffron.
various cells for particular dyes permitting 1929 Alexander Fleming accidentally discovered
microscopic identification by staining of micro- penicillin (anthropologists had much earlier descri-
organisms and cells from various organs. bed how primitive Micronesians rubbed moulds
Ehrlich demonstrated affinities between parti- scraped from trees into wounds to prevent festering).
cular cells and certain drugs. He synthesized 1920s Dyestuffs as antimicrobials.
salvarsan (arsphenamine) and neosalvarsan 1935 Sulphur drugs first developed by Bayer
(neoarsphenamine) effective against Spirochaeta company in Germany. Diversified by May and
pallida the infective pathogen for syphilis. Baker in UK.
Little further advance in chemotherapy until sulphur 1939 Cortisone isolated.
drugs (1930s) antibiotics (1940s) 1939 Florey and Chain cultured P. notatum and
Scientists at Edinburgh University determined isolated penicillin.
composition of various alkaloids, and pharma- Penicillin, subsequent antibiotics effective against
cology of strychnine, codeine, morphine, atro- pathogenic Streptococci, Staphyloccoci, Menin-
pine and derivatives. gococci, Gonococci and Pneumonococci.
Chemotherapy began with discovery and ther- 1930s/40s Chemical pesticides to attack malaria
apeutic control of pathogenic organisms. and typhus vectors.
Vaccines for cowpox, cholera, typhus and 1930s Frederick Hopkins reported first vitamins.
typhoid developed. 1955 Salk Polio vaccine developed.
In vivo synthesis and extraction of hormones 1950–70s Crossing of sexually incompatible spe-
from animal tissues. cies by somatic hybridization (fusion of totipo-
Extracts of thyroid gland relieved myxodemia; tent cells), embryo rescue, cell and tissue culture.
adrenal extracts raised blood pressure. 1953 Watson and Crick discovered double helix
Living tissue used to monitor therapeutic activ- of DNA.
ity, and for quality control. 1973 First gene cloned.
1895 X-rays discovered by Roentgen applied in 1974 Cloned gene first expressed in a foreign
diagnostics. bacterium. First hybridoma created.
1974 US Asilomar Conference proposed safety
guidelines for rDNA research.
20th Century 1976 Genentech—first specialist bioscience com-
Recognition that Mendel’s theory of inheritance pany to exploit rDNA research.
applies to all plants and animals. 1978 Genetic Manipulation Advisory Group
Chromosomes composed of genes that control (GMAG) created by UK government.
sex and biological characters of organisms T. H. 1978 US President’s Commission for Studies of
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