1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. In the year 2000, world-wide investment in biotechnol-
ogies amounted to $37 billion USD which, according to
a recent Canadian study, is expected to increase by
30%/year over the foreseeable future. According to a
McKinsey Company report, biotechnology research and
industrial development appear attractive to venture
capital of which, in Canada, 90% is invested in the
health care sector.
Whether or not these predictions of future growth will
be precisely accurate, expansion and diversification of
bioscience and bioindustries seems inevitable given that
most governments among European Union and North
American nations declare health care, food safety and
environmental protection related to human and animal
health as high priorities.
At the time when pharmaceuticals were mainly
derived from medicinal plants and chemical synthetics,
factory engineers were mostly chemical engineers. It is
now evident that classical chemical engineering is
inadequate for modern and advancing techniques of
biosynthesis, extraction, isolation and purification of
biologicals produced by various cell cultures and
genetically modified organisms.
The academic qualifications and experience needed in
industrial bioengineers are rapidly changing. To provide
the knowledge and skills industries need, universities
must evolve from traditional unidisciplinary, narrowly
specialised departments into integrated interdisciplinary
units.
The Manchester Interdisciplinary Biocentre [MIB]
illustrates how academic bioscientific research and
teaching must be organised in the future. In a newly
designed facility, the MIB will be staffed by biophysi-
cists, biochemists, mathematicians, computation scien-
tists bioengineers and systems analysts. Bioengineers,
together with all other involved disciplines, must work
cooperatively from the early synthesis through to fac-
tory-scale processes, the whole being integrated into an
orderly organisation by mathematically-trained systems
analysts. An academic evolution to active, organized
interdisciplinary teaching, research and development is
essential for all biosciences and biotechnologies: phar-
maceuticals, food and all else on which healthy lives
depend.
Recognizing the rate at which bioscience is expanding
and diversifying, university departments could profit-
ably emulate their schools of management colleagues by
offering short, intensive courses to enable industrial
biotechnologists and bloengineers continually to
upgrade their knowledge and skills. To satisfy the evol-
ving needs of modern bioindustries, universities must
critically assess and, in some instances, restructure their
departmental organizations, curricula and research
programmes.
An obiter dictum from Rene Descartes’ ‘Discourse on
Method’ seems apposite and appropriate. ‘‘All that is at
present known is almost nothing in comparison with
what remains to be discovered. . . . We could free our-
selves from an infinity of maladies of body and mind if
we had knowledge of their causes and the remedies
provided by nature’’.
Chronologies of biotechnologies for food and drugs
BCE (BC)
4th/3rd Millennium
Egyptians developed grain milling, baking,
brewing.
3rd Millennium
Chinese Emperor Fu-Hsi proposed health food
principles of Yin, Yang.
Chinese Shen-Yung Originator of acupuncture
and natural drug therapy.
Prescribed 1800 biological and chemical reme-
dies.
Egyptians, Sumerians preservation of milk,
vegetables by acid fermentations.
2nd Millennium
Egyptians prescribed plant remedies for rheu-
matism, diabetes, schistosomiasis.
Sumerians treated hepatic diseases, gonorrhoea,
strokes and scabies.
Chinese distilled ethanol. Burnt sponge (iodine)
to alleviate goitre.
1st Millennium
Natural, open-air freeze-drying of potatoes by
Andean Amerindians.
5th/4th Century
Hippocrates School of Medicine Hippocratic
Oath; 70 medical treatises; 300 remedies.
4th Century
Aristotle classified known plants and animals;
Theophrastus wrote ‘History of plants’.
Greek word ‘Pharmacon’ means both medicine
and poison.
2nd Century
Dioscorides: Father of Materia medica; pre-
scribed >600 drugs and remedies.
Romans invented the water wheel.
Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 13

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

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

14. 1880 First pharmaceutical industries in UK.
Most R and D in government laboratories cf
Germany: most by private industry. Burroughs
Welcome most research active in UK. Pharma-
ceutical companies treated with suspicion in
USA, (American Society for Experimental
Pharmacology excluded industrial pharmacolo-
gists until 1941).
1883 Johann Kjeldahl (Netherlands) Analytical
method to determine nitrogen in proteins.
1890s Isolation of substances active in endo-
crines: suprarenin and thyroidin.
1890s Paul Ehrlich demonstrated affinity of
various cells for particular dyes permitting
microscopic identification by staining of micro-
organisms and cells from various organs.
Ehrlich demonstrated affinities between parti-
cular cells and certain drugs. He synthesized
salvarsan (arsphenamine) and neosalvarsan
(neoarsphenamine) effective against Spirochaeta
pallida the infective pathogen for syphilis.
Littlefurtheradvanceinchemotherapyuntilsulphur
drugs (1930s) antibiotics (1940s)
Scientists at Edinburgh University determined
composition of various alkaloids, and pharma-
cology of strychnine, codeine, morphine, atro-
pine and derivatives.
Chemotherapy began with discovery and ther-
apeutic control of pathogenic organisms.
Vaccines for cowpox, cholera, typhus and
typhoid developed.
In vivo synthesis and extraction of hormones
from animal tissues.
Extracts of thyroid gland relieved myxodemia;
adrenal extracts raised blood pressure.
Living tissue used to monitor therapeutic activ-
ity, and for quality control.
1895 X-rays discovered by Roentgen applied in
diagnostics.
20th Century
Recognition that Mendel’s theory of inheritance
applies to all plants and animals.
Chromosomes composed of genes that control
sex and biological characters of organisms T. H.
Morgan (USA) elucidated nature and function of
genes by work on Drosophila spp.
From 1900 More scientific progress in pharma-
cology, biosciences than in past 5000 years.
Purified isolates, derivatives and synthetics
replaced simple remedies.
Animal experiments complemented in vitro and
empirical studies from human patients.
Early 1900s Emil Fischer (German) synthesised
long-chain peptides form 18 amino acids.
1914 Thyroxine isolated.
1921 In Toronto: Insulin isolated from Lan-
gherens islets in pig pancreas.
UK Large scale vaccination against diphtheria,
tetanus, yellow fever, small pox.
1900–1930s Adaptation by mutation to ecologi-
cal conditions by various organisms.
1927 H. J. Mueller accelerated mutations by
X-rays; UV, radioctive emanations.
Chemical mutations by ethyl methane sulpho-
nate. Plant chromosomes doubled by colchicine,
an alkaloid extracted from seeds and corms of
the Meadow Saffron.
1929 Alexander Fleming accidentally discovered
penicillin (anthropologists had much earlier descri-
bed how primitive Micronesians rubbed moulds
scrapedfromtreesintowoundstopreventfestering).
1920s Dyestuffs as antimicrobials.
1935 Sulphur drugs first developed by Bayer
company in Germany. Diversified by May and
Baker in UK.
1939 Cortisone isolated.
1939 Florey and Chain cultured P. notatum and
isolated penicillin.
Penicillin, subsequent antibiotics effective against
pathogenic Streptococci, Staphyloccoci, Menin-
gococci, Gonococci and Pneumonococci.
1930s/40s Chemical pesticides to attack malaria
and typhus vectors.
1930s Frederick Hopkins reported first vitamins.
1955 Salk Polio vaccine developed.
1950–70s Crossing of sexually incompatible spe-
cies by somatic hybridization (fusion of totipo-
tent cells), embryo rescue, cell and tissue culture.
1953 Watson and Crick discovered double helix
of DNA.
1973 First gene cloned.
1974 Cloned gene first expressed in a foreign
bacterium. First hybridoma created.
1974 US Asilomar Conference proposed safety
guidelines for rDNA research.
1976 Genentech—first specialist bioscience com-
pany to exploit rDNA research.
1978 Genetic Manipulation Advisory Group
(GMAG) created by UK government.
1978 US President’s Commission for Studies of
Ethics in Medicine & Biomedical Research.
1980 US Supreme Court ruled microorganisms
may be patented under US law
1980 Genentech’s public stock offering recorded
highest ever price per share increase on New
York stock exchange. Price/share rose from $35
to $89 in 20 min.
1980 Name ‘Genomics’ first used.
1981 Eighty new specialist bioscilbiotech com-
panies formed in USA.
16 Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18

15. 1980s/90s Rockafella Foundation and Interna-
tional Rice Research Institute devised transgenic
means to transfer pest resistances between wild
and cultivated Oryza spp. Other transgenic food
crops created.
1982 First rDNA vaccine for colibacillosis
approved in Europe.
1982 Human insulin by rDNA approved in US
and UK.
1992 US NIH Office of Alternative Medicine.
1994 US Dietary Supplement Education Act
legally defined food/drug supplements: vitamins,
minerals, herbs, amino acids, other plant meta-
bolites and extracts.
Late 1900s Increased understanding of (i) geno-
mics—molecular characterization of species, (ii)
bioinformatics—data banks and data processing
for genomic analysis, (iii) genetic transforma-
tions—various transgenic techniques to transfer
genes between unrelated species, (4) molecular
breeding—identification and translocation of
useful biological properties by marker assisted
selection, (5) diagnostics—identification of
pathogens by molecular characterization, (6)
improved immunology in humans, animals,
plants and fish by recombinant DNA vaccines.
1998 Human embryonic stem cells first isolate
from aborted fetus.
21st Century
2000 Human genome sequenced.
2001 US President’s Stem Cell Research Council.
Estimated 1/3 of all Americans buy herbal
remedies in place of prescription drugs.
Herbal remedies offered for colds, influenza,
gastrointestinal disturbances, rheumatoid and
osteoarthritis, diabetes, hypertension, athero-
sclerosis, asthma, depression, cancer and HIV/
AIDS.
Difficulties of herbal medicines: inadequate
standardisation.
Nutraceuticals: foods purported to contain sub-
stances pharmacologically beneficial.
No food and drug laws in USA specifically relate
to herbal remedies.
References to related technology
Biotechnology
Ernst & Young. Annual regional biotechnology
reviews.Oxford,UK:OxfordBusinessPublications.
Bioscience Engineering: BBSRC review of bio-
chem eng. (1999) Swindon, UK: (British) Bio-
technology & Biological Sciences Research
Council.
Building long-term capability. (1996). Ottawa:
Canadian Human Resources Study in Bio-
technology Human Resources Development
Canada.
Leading in the next millennium. (1998). Ottawa:
Rept of the National Biotechnology Advisory
Committee Industry Canada.
Annual reports of the NRC Biotech Research Inst.
Ottawa: National Research Council of Canada.
Biotechnology: opportunities & constraints.
(1985). Ottawa: Intl Devt Res Centre (IDRC-
MR 110e).
European Union Council Directives on bio-
technology. Rue de la Loi 200, B-1049, Brussels:
EU.
Good Manufacturing Practice, Position Statement
on Genetic Modifications. British Inst of Food Sci
and Tech, London: EU.
Ismael Seraglio & Persley G J. Promethean Sci-
ence: Agriculture, Biotechnology, Environment.
CGIAR, World Bank, Washington DC.
Ernst & Young. Focus on fundamentals: the bio-
technology report. Ernst & Young L L P, NY.
European Commission. Life sciences and bio-
technology: A strategy for Europe. E C Public-
ations, Luxembourg.
Doyle, John J & Persley G J. Enabling safe use of
biotechnology: EDS Series No 10. (1996). World
Bank, Washington DC.
FAO/WHO. Strategies for assessing the safety of
foods produced by biotechnology. (1991). FAO,
Rome.
IFST(UK). Guide to food biotechnology. (1996).
Inst Food Sci and Tech, UK.
J of Pharmagenomics. Advanster Commu-
nicatiosn. Edison, NJ.
Biotech journals
Biotechnology & Bioengineering. NJ: John Wiley.
Enzyme & Microbiology Technology. Elsevier
Press.
Trends in Biotechnology. Elsevier.
Biochemical Engineering Journal. John Wiley.
Journal of Chemical Technology & Biotechnology.
Elsevier Science Press.
Food & Bioproducts Processing. Transactions of
the Institute of Chemical Engineers UK.
J Biotechnology. Elsevier.
Bioprocess & Biosystems Engineering. Springer.
Biotechnology Progress. American Chemists’
Society.
BioCanada 2000. Montreal: Montreal Business
Magazines.
Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 17

16. Historical
Gribbin, J. (2002). Science: a history. Penguin
Books, UK.
Mees, C.E.K. (1947). The path of science. New
York: John Wiley.
Boorstin, D.J. (1998). The seekers. New York:
Random House.
Boorstin, D.J. (1993). The creators. New York:
Vintage Books, Random House.
Boorstin, D.J. (1985). The discoverers. New
York: Vintage Books, Random House.
Rose, S. (1976). The chemistry of life. UK:
Penguin Books.
Dixon, B. (1976). What is science for? UK:
Penguin Books.
Jacob, H.E. (1954). Sechstausend Jahre Brot.
Hamburg: Rowohit Verlag GMBH.
Corran, H.S. (1975). A history of brewing. Lon-
don: David and Charles.
Walton, J., Barondess, J.A., & Lock, S. (Eds.).
(1994). The Oxford medical companion. Oxford
University Press.
Duffin, J. (1999). History of medicine. University
of Toronto Press.
Porter, R.W. (1997). The greatest benefit to
mankind: a medical history of humanity. New
York: W.W. Norton & Co.
Bynum, W.F., & Porter, R. (Eds.). (1993).
Companion encyclopaedia of the history of medi-
cine. London: Routledge.
Sonnedekker, G. (Ed.). (1976). Kremers and
Urdang’s history of pharmacy Philadelphia:
Lippincott.
De Burgh, W.G. (1947). The legacy of the ancient
world. London: McDonalds & Evans.
Tacitus, Cornelius. (1956). The annals of Imperial
Rome. Penguin Classics.
Livius, Titus. (1960). The early history of Rome.
Penguin Classics.
Tannahill, Reay. (1973). Food in history. New
York: Stein & Day.
Root, Waverly. (1980). Food. New York: Simon
& Shuster.
Porter, R., & Teich, M. (Eds.). Drugs and
narcotics in history. Cambridge University Press.
Magner, L.N. (1994). A history of the life
sciences. New York: M. Dekker.
Porkert, M., & Ullmann, C. Chinese medicine: its
history, philosophy and practice. New York: W.
Morrow.
By this author: Joseph H Hulse
Science, Agriculture and Food Security. (1995).
National Research Council of Canada.
Ethical issues in biotechnologies and interna-
tional trade. (2002). Journal of Chemistry, Tech-
nology and Biotechnology, 77, 607.
Opportunities for industrial bioengineers. (2001).
Food Science and Technology, 15, 34; Opportu-
nities for industrial bioengineers. (2002). Food
Science and Technology, 16, 34.
Biotechnologies: new homes for an old dilemma.
(1984). Journal of the Canadian Institute of Food
Science and Technology, 17(3), iii.
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