| From
Village Healer to Scientist: The History of Natural Product
Chemistry
Rivqa Bina Berger
Whether
we are aware of them or not, natural products are ubiquitous
in our lives. Many pharmaceuticals, pesticides and herbicides,
food additives, and even some plastics are natural products,
or derived from them. So what exactly are natural products?
Although
in theory the term could be used to describe any substance
derived from a micro-organism, plant or animal, it is
usually confined to describing secondary metabolites.1
Natural products have recently become big business, but
people have used them since ancient times.
Natural Products in Ancient Times
Early cultures used specific products to cure specific
diseases. Chances are that the ancient Egyptians had no
idea that the Vitamin A in ox liver was what cured nyctalopia,
but liver was used as a cure for this disease. In ancient
Mesopotamia, Egypt and other countries, a wide variety
of plants, animal products and even stones were used as
treatments for various ailments. These cures were discovered
by trial and error.2
As
early as 800 AD, the Benedictine monks were using many
natural medicines, including the poppy (Papaver somniferum),
which was used to alleviate pain as well as an anaesthetic.
The active ingredient, morphine, was only extracted in
1806… almost 1000 years later. It was marketed by Merck
in 1826. Many other natural products such as quinine,
which was the only effective anti-malarial at the time,
were also isolated in the nineteenth century.3
However, these drugs were also characterised largely by
random experimentation, and many other structures could
not be isolated until much later.
Natural
products in the twentieth Century
The trial and error method of discovering new medicines
continued into the twentieth century. Alexander Fleming,
the British microbiologist who discovered the effects
of some fungi on bacteria, essentially made his discovery
by being careless and not practicing aseptic technique.
He left a Petri dish of Staphylococcus aureus
open when he went on a holiday. It was accidentally contaminated
with Penicillium notatum¸ which inhibited
the growth of the bacteria, apparently by excreting an
antibacterial substance. Chemists Earnest Chain, his Australian
co-worker, Howard Florey, and their team later purified
penicillin and conducted animal and human trials with
it, bringing it to the market in 1941.4
Many
variations of antibiotics exist as a result of research
on improving existing biopharmaceuticals. Photo:
Cheryl
Yau |
Many
secondary metabolites that were
discovered after penicillin in the 1940s and 1950s were
effective antibiotics but too toxic for human use. Some
of these were usefully administered to animals. In the
1960s-70s, research turned to improving yields of existing
biopharmaceuticals,
as well as chemically altering them to reduce their side
effects or improve their activity against micro-organisms.3
As
a result, over 73 different variations of the beta-lactam
antibiotics (including penicillin
and cephalosporins) are available. Of these, 40 varieties
are used to treat human disease in hospitals. The prevalence
of beta-lactam antibiotics, coupled with the ease with
which bacteria can mutate and share genetic information,
has led to widespread resistance to beta-lactam antibiotics.
A famous example of antibiotic resistance in bacteria
is that of Staphylococcus aureus. Golden Staph,
as it is commonly known, causes many problems in hospitals
where bacterial infection spreads rapidly and patients
may be more susceptible to disease than they are usually.5
Natural products today
More recently, the competitive nature of the pharmaceutical
industry in particular has brought natural product chemistry
to a crossroads. Developing new drugs is profitable, and
the pharmaceutical industry is constantly growing. New
innovations such as High Throughput Screening
(HTS), which involves automated, miniaturised assay
techniques, have made it much easier to determine the
potential uses of a new compound. State-of-the-art HTS
machines can test up to 10,000 compounds in one week,
a big improvement on the 10,000 per year that were tested
in the mid-80s.3
These
developments are fantastic both for the pharmaceutical
industry and the consumer. However, the natural product
industry is finding it difficult to keep up with the demand
for new compounds to test. This is pushing the industry
further, as marine biologists, microbiologists, ecologists,
biotechnologists, biochemists and chemists team up to
find new organisms with novel compounds, mainly from previously
untested environments.3 Advances
in biotechnology mean that it is no longer necessary to
collect large amounts of environmental samples in order
to test for a new pharmaceutical. Rather, the sample is
cultured in the laboratory where biotechnologists can
create a clone library. The gene
responsible for the production of the natural product
of interest can then be isolated more easily, and the
natural product itself can be produced in E. coli.6
Ultimately
though, natural product chemistry is still waiting for
a breakthrough that will bring discovery of new compounds
up to speed with the discovery of potential uses for these
compounds.
Glossary
Antibiotics:
secondary metabolites that either kill microbes or hamper
their growth.
Aseptic technique:
maintaining sterility and avoiding contamination of laboratory
instruments and microbial cultures.
Biopharmaceuticals:
Medicines that are made from compounds produced by living
organisms, such as penicillin.
Clone library:
an organism’s DNA is fragmented and copied into a laboratory
organism such as Escherichia coli, allowing for easier
analysis of the original organism’s genes and metabolism.
High Throughput
Screening (HTS): robotic and computerised methods
of testing samples and analysing data, which allow many
samples to be tested in a short amount of time.
Nyctalopia:
night blindness, the inability to see clearly in dim light.
Secondary
metabolites: compounds produced by an organism
that are not essential for its survival but may be useful
to the organism.
References
1. Cannell
RJP (ed). (1998) Natural products isolation. Humana Press,
Totowa, N.J.
2. Porter,
R. (1997) The Greatest Benefit to Mankind: A Medical History
of Humanity from Antiquity to the Present. Harper Collins
Publishers, London.
3. Grabley
S, Thiericke R (eds.) (1999) Drug discovery from nature.
Springer, Berlin.
4. The Nobel
e-Museum: The Discovery of Penicillin, http://www.nobel.se/medicine/educational/penicillin/,
Last modified May 26, 2003
5. Therrien
C, Levesque RC (2000) Molecular basis of antibiotic resistance
and -lactamase inhibition by mechanism-based inactivators:
perspectives and future directions. FEMS Microbiology
Reviews 24: 251-262
6. Lodish
H, Berk A, Zipursky L, Matsudaira P, Baltimore D, Darnell
J (2000) Molecular Cell Biology (4th Ed) WH Freeman and
Company, New York.
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