Nature’s
Way - The Case For, Against Natural Therapeutics
Published
in Mass High Tech Vol. 22, Issue 16
By: Trevor P. Castor
Arguing
the case for and against natural therapeutics is like arguing
the case for and against food, oxygen and water. These are
all necessary for our very existence, yet all must be taken
in moderation and balance. Out of proportion, we can be
readily poisoned by excess or too little oxygen; similarly,
too little food results in starvation while obesity can
lead to cancers, heart diseases and other chronic illnesses.
So too with natural pharmaceuticals and herbal dietary supplements
that I call quality-of-life medicines.
Prior to the discovery, development and use of antimicrobial
agents, morbidity and mortality from bacterial infections
were significant. In the early 20th century, the three leading
causes of death were pneumonia, tuberculosis and enteritis.
These three infections were responsible for 40percent of
all deaths, and the lifespan of the average American was
only 49 years.
The introduction and commercial use of antimicrobial agents
has significantly advanced the fight against bacterial infection.
However, the emergence of multiple-drug resistant bacteria
is reversing their effectiveness.
The major antibiotics in clinical use were discovered by
screening terrestrial microorganisms, primarily actinomycetes
that appear to have a Darwinian propensity to produce antimicrobials
against human pathogens.
Over the past decade, however, the discovery rate of new
antibiotics has decreased. At this time, re-discovery rate
for the terrestrial environment is estimated to be greater
than 90 percent.
In contrast, the marine environment represents a relatively
unexplored resource for the discovery of new anti-infectives.
The extreme diversity of the marine environment with respect
to salinity, temperature, pressure and nutritional availability
provides an environment that selects for a high level of
genetic and molecular diversity.
Marine microorganisms are therefore likely to be a good
and almost untapped source for new antimicrobials against
resistant bacteria as well as antivirals against new and
re-emerging viruses such as the SARS coronavirus, West Nile
virus, HIV, influenza and smallpox.
Pathogenic viruses, often generated as a result of rainforest
deforestation and habitat occupation by man that caused
these pathogens to jump species, have rapidly emerged as
one of this century’s major health threats. These
threats are readily magnified by high-speed modern transportation
systems, the ability of these pathogens to rapidly mutate
as well as the potential for man-instituted bioterrorism.
Terra firma has already provided and will continue to provide
a number of human therapeutics, from aspirin to paclitaxel,
the active ingredient in the potent anticancer drug, Taxol?.
Paclitaxel,
discovered in the latter part of the 20th century from the
stunted North American yew, Taxus brevifolia, in the Pacific
Northwest, works by preventing cells from subdividing and
has proven to be a potent anticancer drug and more recently,
with stents, a powerful arteriosclerosis agent.
Aspirin, derived in the early 1900’s from the lowly
willow weed used by North American Indians for pain and
other maladies, has found niche applications with a number
of different disease states including arthritis, heart disease
and cancer.
Over the last three decades and covering all diseases, countries
and sources, 52 percent of the 1,031 new chemical entities
(NCEs), 60 percent of anticancer drugs and 71 percent of
anti-infectives approved by regulatory authorities were
based on natural products isolated from terrestrial plants
and microorganisms, according to the National Cancer Institute.
Despite these statistics, many pharmaceutical companies
have eliminated or significantly downsized their natural
products research over the last two decades. This shift
was made to explore the promise of high-throughput screening
of mass-produced combinatorial libraries against the many
disease targets that have been developed as a result of
the explosion of biologic and genetic information, and the
sequencing of the human genome.
This shift has not resulted in the expected surge in productivity
in the discovery pipeline. Last year, the U.S. Food and
Drug Administration approved only 21 NCEs, marking a steady
decline since a peak of 53 in 1996. This decline in productivity
is, in part, caused by the shift from screening natural
products molecules that have been honed by millions of years
of evolutionary development to screening simple organic
structures that can be readily manipulated by combinatorial
chemistry.
This shift was primarily driven by the identification of
many disease targets. However, the difficulties of rapidly
preparing natural products for screening, the high numbers
of false positives and negatives in sensitive enzymatic
and molecular screens, the time-consuming tasks of identifying
bioactive compounds combined with the difficulties associated
with large-scale manufacturing provided the rationale for
this shift.
In the last two decades, technologies have been developed
by instrumentation companies to address the tasks of analysis
and structural elucidation of bioactive compounds and new
chemical entities.
In the past decade, researchers have addressed some of the
remaining critical issues of natural products drug discovery
by developing supercritical fluid technologies for the rapid
preparation of partially purified natural product mixtures
that minimize false positives and negatives in sensitive
biological screens. Concurrently, we have also developed
supercritical fluid technologies for the scalable and cost-effective
manufacturing of rare and complex natural product molecules.
More recently, after the passage of the Dietary Education,
Health and Safety Act (DSHEA) by Congress in 1994, suppliers
were allowed to provide herbal dietary supplements, based
on structure and function, to the consuming public without
having to embark on rigorous clinical trials and FDA approval.
The prevailing wisdom, at that time, was that these products
have been around for centuries and that they were both safe
and effective, at least based on anecdotal evidence.
Ephedra, recently banned by the FDA, has proven this prevailing
wisdom false. Indeed, there have been significant problems
with herbal products in the marketplace in terms of standardization,
batch-to-batch reproducibility, safety and efficacy. There
is thus an urgent need for responsible manufacturers to
take the high science road to standardize these products,
vouch for their batch-to-batch reproducibility, and conduct
scientific studies to establish safety, efficacy and dosing
regimens.
At the turn of the last century, the average American lifespan
was roughly 78 years and the new health threats are cancers,
infectious pathogens and heart disease, some of which can
be contained and/or ameliorated by health maintenance and
disease prevention utilizing natural therapeutics.
Indeed, with careful titration of our natural environment,
we may be able to push the boundaries of life expectancy
and quality-of-life in the 21st century.
Trevor P. Castor is CEO of Aphios Corp., a Woburn-based
biopharmaceutical company that is developing enhanced natural
therapeutics.
