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The new breed of pharmaceuticals
and Gary Walsh+
+University of Limerick, Limerick
It is no secret that proper nutrition and careful hygiene
are essential for good health. However, it is quite
obvious that these factors alone cannot guarantee
permanent good health over a person's lifetime. Day in,
day out, humans are surrounded by agents (viruses,
bacteria, potentially toxic chemicals, etc.) that can
cause illness and disease (Table 1).
Table 1 The incidence of some diseases
Not only are we vulnerable
to external attackers, we are also susceptible to
internal biological warfare! Inside our cells, the
systems of biochemical reactions that support and
maintain life can sometimes malfunction, thus leading to
disease. Some of this is due to genetic disorders i.e.
errors in segments of DNA (genes) that normally code for
specific proteins. The end result is that the produced
protein may be defective or perhaps missing altogether!
If the protein normally functions as an enzyme, the
consequences may be disastrous. For example, people
deficient in the enzyme phenylalanine hydroxylase suffer
from a disorder called phenylketonuria (PKU). They cannot
degrade an amino acid called phenylalanine, which becomes
toxic for them and this can result in severe brain
damage. In fact, in the past, 1 in every 100 mentally
retarded children suffered from PKU. Today, every
new-born is tested for PKU, and if positive, a carefully
controlled diet (free from phenylalanine) ensures
prevention of mental retardation. A note of interest -
the next time you drink a can of diet Coca-Cola (see p.
34), read the ingredients list. You will see 'Warning:
contains phenylalanine'. For other examples of
defective/missing protein-based disorders, see Table 2.
Table 2 Human
genetic disorders and the responsible defective gene
The search for cures
Since the earliest times, cures have been sought for all
types of diseases. Often, these were discovered quite by
accident. For example, most modern local anaesthetics
(e.g. procaine) were developed based on earlier work in
the late 1880s with an extract from coca leaves
(cocaine). Native American Indians found that chewing
these leaves resulted in numbing of their tongues!
Advances in biomedical research have lead to a better
understanding of diseases, their underlying causes and
how they may be treated more effectively. The vast bulk
of traditional medicines are organic compounds,
manufactured by direct chemical synthesis. Specific
examples include a range of analgesic and
anti-inflammatory agents, anaesthetics, anti-depressants,
immunosuppressants and anti-cancer agents. Some
traditional medicines, such as blood products, are
obtained by direct extraction from biological sources
(Table 3). Such substances are sometimes called
Table 3 Therapeutic agents from biological
||Treatment of blood disorders,
such as haemophilia
||Treatment of diabetes mellitus
||Digestive aids, debriding
agents (i.e. cleansing of wounds)
||Vaccination against specific
||Passive immunisation against
However, as we draw closer
to the beginning of the third millennium, many of the
more exciting modern pharmaceutical agents are produced
by techniques of genetic engineering. These products, the
most notable of which are discussed later (see Table 5),
are termed biopharmaceuticals. Insulin was the first such
biotech-derived protein to become available commercially.
Hence insulin used to treat diabetes may now be produced
by direct extraction from the pancreatic tissue of
slaughterhouse animals, or by genetic engineering in
bacterial cells. About 2% of the population in Europe and
the US are diabetic, and 20% of these are dependent on
regular insulin injections.
The drug development
The drug development process is both time-consuming and
costly. All therapeutic drugs must pass stringent safety
and efficacy trials before they can be 'passed' by
regulatory authorities. On average, a typical drug will
cost a company $150 million to be developed and the
process of getting it successfully from the research lab
onto the pharmacist's shelf typically takes about 12
years. Pharmaceutical companies screen large numbers of
chemical substances as potential drugs. On average, only
1 in 5,000 compounds makes it through the entire
pre-clinical and clinical trial process (Table 4).
Because the success rate is so low, few companies are
keen to pursue such R & D. It has been estimated that
the first 15 years of a new drug's commercial life are
used to recoup the costs incurred during its R & D.
This partially explains why drugs are so expensive.
Table 4 The drug development process.
||In vitro characterisation and
|Phase I clinical
||Safety testing in small number
of healthy volunteers
|Phase II clinical trials
||Efficacy and safety testing in small number
|Phase III clinical trials
||Large-scale triasl in substantial numbers of
Once a substance of
potential therapeutic interest has been identified,
pre-clinical trials are initiated. These tests set out to
characterise the substance and preliminary safety data
are obtained from live animal and cell culture studies.
If initial results are encouraging, clinical trials in
humans are initiated. These appraise the safety and
efficacy of the product. Only drugs that perform
satisfactorily at each phase may proceed to the next one.
Upon completion of the final phase (III), a new drug
application is filed with the relevant regulatory
authority (e.g. the FDA), whose officers then assess all
trial and other pertinent data generated. This can take
up to a further 3 years, at the end of which the
regulatory authority decides whether or not to approve
the drug for sale.
The human pharmaceutical
Most cells in our body work around the clock, many
producing 'defence' biochemicals which function to
protect the body from infectious agents or other
disease-causing substances. Many of these could indeed be
called the body's own pharmaceuticals. For example, in
response to an attack by a viral infection, the body's
immune system kicks into gear and produces small
molecular weight proteins called interferons. They are
thus named because they 'interfere' with viral
replication, thereby putting a halt to the virus' gallop.
Interferons belong to the cytokine family of proteins.
Other members of this family include interleukins and
tumour necrosis factor. Most of these proteins are
produced naturally by certain white blood cells. They
function primarily to stimulate the immune and other
cellular defence mechanisms. Several cytokine
preparations have been found to be effective in the
treatment of various virally-induced conditions (e.g.
hepatitis, AIDS) and certain forms of cancer e.g.
leukaemia. Currently, they are also being assessed in
clinical trials for other conditions, including multiple
sclerosis, asthma and allergies. Other examples of the
body's own 'biopharmaceuticals' include; blood-clotting
factors (used to treat haemophilia), growth hormone (used
to treat dwarfism), and thrombolytic factors, used to
treat heart attacks due to their ability to degrade blood
While the applied
potential of such substances is obvious, most are
produced naturally in such tiny quantities, that
large-scale purification from these natural sources is
simply not practical. The advent of recombinant DNA
technology (genetic engineering) overcomes these problems
of source availability. Production by such means normally
entails transferring the gene which codes for the protein
of interest into a microorganism, or animal cell. The
genetically engineered cell can then produce that
protein. The cells are then grown in fermenters to
facilitate large-scale production of the protein product.
The production of protein-based pharmaceuticals by
genetic engineering has reduced the time required to
produce large amounts of proteins cheaply. The production
of proteins by recombinant DNA technology also eliminates
the possibility of accidental transmission of disease
from infected source material. The very real threat of
such occurrences is illustrated by the number of
haemophiliacs who accidentally contracted AIDS and
hepatitis through infected blood products. The reality is
that haemophiliacs lacking a blood factor (e.g. factor
VIII) can now be administered a recombinant version of
this protein alone, without having to receive blood
preparations from potentially infected material. Remember
that prior to 1981, no blood samples could be screened
for HIV contamination, because the virus had not been
discovered until then. Furthermore, blood donations were
not screened in Ireland for the presence of hepatitis C
until quite recently. The consequences of this has proven
disastrous, as is evidenced by the ongoing Blood Bank
enquiry. How many more viruses are lurking presently (or
in the future), without names, because scientists haven't
yet discovered them!
Several dozen proteins of
medical significance produced by genetic engineering are
now either routinely used (Table 5) or are being tested
in clinical trials, and are likely to be approved for
general medical use soon.
Human life expectancy is at an all-time high. However, it
is an unfortunate fact that ageing brings with it an
increased risk of developing age-related disorders. For
example there are about 53 million sufferers of
rheumatoid arthritis world-wide. Other age-related
disorders include osteoporosis (brittle bone disease) and
neurodegenerative disorders, such as Alzheimers and
Parkinson's disease. All in all, there is an accelerating
demand for pharmaceutical products. It's a big business.
Table 5 Some recombinant biopharmaceuticals which
have been approved for general medical use
|Human growth hormone
|Hepatitis B vaccine
||Vaccine against Hepatitis
|Tissue plasminogen activator
*Year first approved for
sale in Europe
**Estimated world annual sales, $ (millions)
The early 1980s witnessed the birth of hundreds of
'biotech' companies. These were founded, mainly by
scientists, to take commercial advantage of discoveries
in biomedicine. While many of the original companies have
not survived, the world-wide sales value of
biopharmaceuticals was about $5 billion in 1993. The
pharmaceutical industry is still growing rapidly and it
is estimated that within 10 years, its annual sales value
will be in the region of $20-30 billion. This represents
at least 15% of the total pharmaceutical market.
Currently, there are approximately 20 recombinant
biopharmaceutical products approved for sale throughout
various parts of the world and many others are awaiting
regulatory approval. More than 200 proteins of potential
therapeutic use are currently undergoing clinical trials.
It is likely, that by the turn of the century (only 3
years away!), an additional 30-40 biopharmaceuticals will
gain regulatory approval. These drugs will play a major
role in alleviating or curing many of the world's most
prevalent diseases. They will also earn billions of
dollars for the pharmaceutical industry. The future
success of these biotech-derived pharmaceuticals is
assured as we head into the next millennium.
The pharmaceutical sector in Ireland has grown steadily
over the past 30 years and it currently employs over
11,000 people, 30% of whom are graduates. Many
pharmaceutical companies in Ireland manufacture bulk
pharmaceutical ingredients . while others formulate
finished products from such raw materials. Although most
drugs made here are traditional chemical-based
pharmaceuticals, biopharmaceutical products do represent
an important niche activity. The major biopharmaceutical
manufacturers are Schering-Plough (Brinny), see
photographs on p.21, located at Innishannon, Co. Cork,
who manufacture Interferon and Granulocyte-Macrophage
Colony Stimulating Factor (GM-CSF) and Fort Dodge in
Sligo who manufacture animal viruses. (Some photos of
Schering-Plough (Brinny) may be found here.)
Drews, J. (1993) 'Into the 21st century. Biotechnology
and the pharmaceutical industry in the next ten years'
Bio/Technology, 11, 516-520
Walsh, G. (1995) 'Biopharmaceuticals: the body's own
drugs' Biologist, 42, (5) 209- 212.
Walsh, G. (1996) 'Biopharmaceuticals: prospects for the
future' Biologist, 43 (2) 58-60.
Johnson, I., (1984) 'How interferons fight disease'
Scientific American May edn. 40-47.
Balkwill, F. (1988) 'The body's protein weapons' New
Scientist, June 4 (Inside Science report)
Dr. Nancy Shanley lectures
in Biology at Limerick Regional Technical College,
Moylish Park, Limerick and Dr. Gary Walsh lectures in
Biochemistry at the University of Limerick, Limerick.