Colorado State University
Fort Collins, Colorado 80523
Chemical prospecting has developed recently as an argument for preserving
biodiversity.а The idea is that in biodiversity lies unknown molecules and genes
that have potential uses such as drugs for human diseases.а The development of the
anti-cancer drug taxol from the Pacific Yew tree (Taxus brevifolia) in the United
States is discussed as an example of the process of chemical prospecting. By
examining the history and current status of taxol, positive and negative aspects of
chemical prospecting are considered.
Most people would agree that biodiversity is important and are concerned with its
rapid rate of destruction. However, it appears that often it is difficult to justify
exactly why biodiversity is so valuable.а Why not slash and burn the rainforest for
agricultural purposes? What is the value in the biodiversity found in a healthy
rainforest ecosystem? One argument that strives to put a value on that diversity is
based on the molecular and genetic potential it represents.а Specifically, as
sources of future drugs and chemicals that have unlimited potential to further
mankind.а In recent literature, Tom Eisner has given this line of reasoning the name
"chemical prospecting" (1,2).
Chemical prospecting is a multi-step process that begins by screening organisms for
molecules or genes for a particular function, often potential sources of drugs to
treat diseases.а Once a natural product has been identified as useful, at least some
of the source organism is collected for further study.а This natural product then
has value to pharmaceutical companies because it can be developed into a marketable
drug either made directly from the source organism, or by synthetic processes.а This
monetary windfall from the drugs then leads to money that will be reinvested into
conservation of the original benefactor, biodiversity (1).
While rainforests are often the focus of biodiversity discussions, a superb
illustration of the process of chemical prospecting is on-going in the United
States.а The story involves a tree of little appreciation and the powerful anti-
cancer agent found in its bark.а The tree is the Pacific Yew (Taxus brevifolia) and
the drug is a diterpenoid named taxol.а The discovery and development of taxol for
the treatment of cancer warrants an in depth look, not only for illustrating how
chemical prospecting works, but also how it doesn't work.
Discovery of Taxol
Taxol was discovered through a prospecting venture begun in the 1960s by the
National Cancer Institute (NCI) in cooperation with the US Department of
Agriculture. These agencies began screening plant tissues in North America for anti-
tumor activity in the hope of discovering new treatments for cancer (3). In 1962,
tissues from the Pacific yew tree were collected by USDA workers and sent in for
analysis.а The initial screening showed extracts from the yew to have cytotoxicity
activity against human cancer cells (3).а This success caught the attention of the
NCI and the yew extracts were targeted for more intensive research at one of the
NCI's research institutions.
A research team led by Dr. Wani at the Research Triangle Institute received the yew
assignment and began to isolate the active compound.а This process was begun by
water-chloroform fractionation of bark extracts directed by bioassay results (4).а
The primary bioassay used to detect activity in the fractions was a test against
leukemia cells (4).а Once the compound in the active fraction had been isolated, Dr.
Wani's team began to determine the structure of the compound.а Mass spectrometry
showed the molecular weight of the compound to be 853.а X-ray analysis was then used
to determine the structure of the molecule.а However, this was not possible on the
entire molecule, and it had to be cleaved by base catalyzed methanolysis into
subunits that could be identified with x-rays (3,4).а The final structure was
completed with alkaline oxidation with MnO2 to define the structure of the molecule
named Taxol (3) (Fig. 1). In 1971, Wani et al. published their results on taxol as
the first molecule at that time with a taxane ring to have anti-cancer activity (4).
Despite this achievement, NCI then lowered the priority in continuing research on
taxol (3).а The compound was difficult to obtain because it is present in relatively
low concentrations in the bark of the Yew tree, (.5 g for 12 kg of bark) and the
anti- leukemic activity was not considered dramatic enough to warrant continued
research (3). Taxol research then remained stalled until 1977.а Around this time it
was realized that the leukemia bioassay used to asses taxol's effectiveness was
relevant towards human leukemia, but was not a good test for activity against solid
tumors.а Another bioassay that had also been used by Wani's group on melanoma cells
(solid tumors) had much more dramatic positive results and this stimulated interest
in taxol again and led to its development (3).
Development of Taxol: the supply problem
The research on taxol then proceeded on two fronts, one to determine how taxol
worked and the other to determine its effectiveness in cancer patients.а By the late
1970s, the mechanism of taxol was known to be enhancement of microtubule
polymerization such that the dividing cells were stalled in the G-2 phase and do not
depolymerize (5,7). Clinical trials then proceeded through the 1980s on various
forms of cancer.а Specifically, taxol has proven to be effective against ovarian,
breast, lung, head and neck, and esophageal cancers (7).а The use of taxol has been
approved by the Food and Drug administration for use in treatment of two of these
cancers, ovarian and breast (7).
Due to the success in clinical trials, the NCI offered the right to develop the
drug competitively to drug companies.а In 1991, the company Bristol-Meyers Squibb
(BMS) won this right (3).а Since the source for taxol was the Pacific Yew tree, BMS
and the NCI entered into an alliance with the US Forest Service and the Bureau of
Land Management, the two agencies who had access and control of the yew tree supply
on public lands (8).а The initial step in this process was to determine the supply
of yew bark in the US.а Even though the yew tree ranges along the west coast of
North America from British Columbia to California with inland populations in Idaho
and Montana, relatively little was known about its abundance.а T. brevifolia had
previously been considered unimportant economically and therefore no money had been
invested by government agencies to record any information on the tree (8).
The obvious economic potential of a cancer treatment then stimulated research on the
Pacific yew.а An Environmental Impact Statement prepared by the US Forest Service
identified several roles of the yew in its environment.а Specifically, habitat for
the spotted owl, winter food for large herbivores and microhabitat for invertebrates
were identified (8).а It is not surprising that the yew tree is important to many
different aspects of the environment, as most organisms are tightly intertwined
within their respective ecosystems.
Harvest of the Pacific Yew may have proceeded unabated, despite its role in the
forest ecosystem, if not for one problem.а The concentration of taxol in the bark of
the tree is extremely low.а A 100 year old tree might yield 3kg of bark which
provides enough taxol for one 300mg dose (6).а By 1991, harvest of bark was up to
around 425,000kg, at 3kg a tree that is over 100,000 trees that year (8).а The
public became justly concerned at such harvest since bark cannot be harvested
without killing the tree.а This concern in part stimulated the passage of the 1992
Yew Act which stated that there should be a "sustainable harvest" that provided for
the long term viability of the yew tree but still provided enough taxol for Bristol-
Meyers Squibb (8).
Such determinations are difficult to make, what BMS requires for its research may
overlap significantly with what may be considered a "sustainable harvest".а
Furthermore, it is interesting that the Environmental Impact Statement was not
completed until 1993, a year after the Yew Act was passed.а Thisа casts doubt on how
"sustainable harvest" was defined when the basic ecology of the tree had not yet
been determined.а In addition, as the figures from 1991 harvest indicate,
significant amounts of bark were being harvested without any knowledge as to how
that might impact the environment.а The policy of taxol collection appeared to be
driven immediately by demand and environmental concerns were an afterthought.а This
clearly demonstrates one difficulty with natural products prospecting, in that the
enthusiasm for a new treatment can preclude any consideration of the effects of
collection. The very biodiversity that was defended to provide the drug initially
was degraded.а For example, along with the yew trees may have gone an equally
important invertebrate, that depended on the yew tree's habitat, with unknown
medicinal properties in its own right.
Solutions to the Supply Problem:а alternative sources of taxol
In defense of the prospectors developing taxol, it was readily apparent to them that
long term use of taxol was going to require an alternate, probably synthetic, source
of the drug.а Unfortunately, the complex structure of this molecule does not lend
itself to simple or rapid synthesis.а Only recently (1994), has the total synthesis
of taxol been reported (9).а This synthesis is summarized in Figure 2 to illustrate
the complexity of this process.а Although this synthesis was a formidable
achievement, reviews by other workers do not support this as a practical or
economical way to dramatically increase the supply of taxol (3,6).
One way to circumvent this problem is with a semi-synthesis starting with a more
readily available precursor.а This is currently being investigated with the
precursors baccatin III and 10-deacetylbaccatin III which are isolated from the
needles.а These compounds can be found in several Taxus spp. which alleviates some
of the pressure on T. brevifolia (3,10).а However,а taxanes isolated from the
needles degrade more rapidly than taxol from the bark, which can be stored for
longer periods of time due to its increased stability (11).
Yet another possible solution to the supply problem is developing plant cell
cultures to produce taxol.а Progress in this area has not been rapid because taxol
is difficult to generate in this way.а A primary difficulty is the relatively slow
growth of plant cells, but research continues to overcome this (12).а Apparently,
this line of research may be more advanced than is widely known because it is
believed that corporate developments may be withheld until success is achieved (10).
One unique potential supply of taxol has arisen through work of Gary Strobel and his
lab (13,14,15).а They have identified an endophytic fungi of the yew tree, Taxomyces
andreanae, that produces taxol when grown in culture.а Similar to the other
synthetic methods, the production by the fungi at this time does not represent a
rapid or significantly large supply of taxol.а As with the others, time and
continued research may correct this.
Implied, if not directly stated, in the reasoning for chemical prospecting is the
idea that diverse organisms are needed only for the initial suggestion for a drug.а
After discovery, mass production of the drug can be accomplished artificially to
reduce the burden on the environment (11).а The difficulty in doing so with taxol
demonstrates the flaw in this assumption.а Furthermore, there is no reason to expect
that taxol is the exception and not the rule.а Cragg and Snader from NCI summarized
the taxol supply problem in 1991 (11), and stated that it should not be assumed that
large scale production of natural products is possible since these molecules tend to
be complex and challenging to synthesize in part due to a high degree of chirality.а
In addition, each new synthetic version of a drug must undergo its own approval from
the FDA which can take 1-2 years.а Such delays mean that in the meanwhile, the
natural source of a drug must continue to be tapped.а They also note in 30 years no
synthetic source has been developed for the anti- cancer drugs vinblastine and
vincristine which are still harvested from their original plant source (11).а Thus
far, taxol in not much different, it has been 25 years since the discovery of taxol
and no large scale, synthetic method has been developed.
Considerations of "Chemical Prospecting"
So then the saga of taxol remains stymied for the moment in the supply issue.а
Research on the drug, for its function, effectiveness and synthesis continues and
the promising results against solid tumor cells appears to ensure continued interest
in developing the drug.а Not having a large supply for the general public certainly
does not mean chemical prospecting has failed, it is merely stalled. Therefore, does
the development of taxol indicate a success such that future prospecting should go
on? Or does it show potential pitfalls in the argument for preserving biodiversity
for future prospecting?
Potential trouble spots have already been mentioned in the review of taxol.а For
example, the immediate exploitation of the source organism before any impact of
collection has been assessed.а Also, that it cannot be assumed that all natural
products lend themselves efficiently to synthetic techniques.а While these and other
practical matters are of concern, scrutiny of chemical prospecting on a
philosophical level raises other issues.
A recurring theme in Eisner's papers (1,2) is the value in biodiversity because of
these potential cures and treatments for human disease.а Eisner does acknowledge
that species have worth other than chemical potential(2), but he does not expand on
these. This implies that other measures of value are not sufficient to defend
biodiversity.а Therefore, the assumption within this argument is that intrinsically,
biodiversity has no value.а This is demonstrated with taxol explicitly.а The yew
tree was considered so unimportant that it was ignored in surveys done by the US
Forest Service and the Bureau of Land Management over the last century.а When taxol
became important the agencies had no idea even how many trees there were.а
Furthermore, when timber was clearcut, the policy was to burn yew trees along with
other scraps and waste (8). This changed when taxol was discovered and the yew tree
now had value, economically and medically.а Logging practices shifted from wasting
yews as trash to developing management techniques for "sustainable yield".а So it
seems chemical prospecting saved the yew tree and some of the biodiversity
associated with it.а However, it may also be said that chemical prospecting furthers
the attitude that the destruction of a species is wrong only if it has some economic
value or potential.а So biodiversity is still left with no inherent value, and
therefore is still difficult to defend.
Somewhere along the way Western culture placed humans well above all other animals
and consequently above all other organisms.а This disregard for 'lower' organisms
makes it difficult to use and not abuse biodiversity. A critical response to
chemical prospecting by Downes and Wold noted this tendency of "industrial
societies" to destroy biodiversity through its use, unlike indigenous peoples who
use biodiversity within its boundaries (17).а Steven J. Gould expresses this
phenomenon as a "picket fence around Homo sapiens" that rests on the beliefs that
"humans have not only transcended the ordinary forces of nature, but all that came
before was...a preparation for out eventual appearance" (16).а It is a philosophy
deeply entrenched in policy, especially in conservation issues.а It is this
elevation that enables people to assume they have the intelligence and capability to
'manage' biodiversity.а The environmental impact statement drawn up for the Pacific
Yew tree carried an implicit assumption that there was one set of the right
guidelines that would enable a "sustainable yield" such that all parties would be
satisfied and the forest would be in ecological balance.
It may be argued that the goal of sustainable yield is not to be perfect, but to do
the least damage.а If so, then the idea of chemical prospecting as an argument for
preservation is flawed.а If it is not possible to avoid altering an ecosystem to
collect a newly discovered drug then how is the biodiversity of the system to be
maintained?а It would seem the purpose of chemical prospecting is to preserve
biodiversity until something useful is found.а The further loss of biodiversity in
the harvest of the useful organism is secondary.
Another flaw with using prospecting to defend biodiversity is that it is short
sighted in its vision.а The main loss of biodiversity is through loss of habitat for
an expanding human population and its perceived needs.а Eisner even recognizes this
when he writes "human expansionist demands can be expected to wreak environmental
deterioration and biotic destruction well into the next century"(2). If this
expansion is due in part to improved life expectancy and infant survival due to
modern medicine, prospecting potentially feeds the destruction of biodiversity.а For
example, ovarian cancer, against which taxol is particularily effective, is the
fourth highest cause of death in American women (7).а Eliminating this could
contribute further to an ever-expanding human population.а Stepping back a bit,
suppose large areas of northwestern forests were set aside as reserves of
biodiversity due to the example set by taxol.а The new drugs developed from these
reserves might lower mortality rates and thus the population would increase. Where
is this increased population going to live?а With what resources are they going to
sustain themselves? From what forests are they going to get wood to build houses?а
The problem with maintaining biodiversity is largely habitat destruction from
expanding human populations. Developing drugs to further this expansion means in the
distant future biodiversity will be harder to defend due to prospecting, not easier.
Despite this, preservation of biodiversity is not hopeless. Clearly, for the short
term, the potential of biodiversity for life-saving drugs is appealing and may stall
current destruction of areas like the Amazon rainforest.а Legislation may also
provide temporary fixes, but later generations can always rewrite laws when they
really need all the timber in previously designated wilderness areas. Chemical
prospecting needs to be considered for the long term and in a global context.а Plans
need to be made for harvesting source organisms to maintain biodiversity and for the
ultimate implications of those products on global population growth.а Furthermore,
there must be a realization that biodiversity has intrinsic value that is not
measured solely in immediate human benefits.а Only this kind of fundamental shift in
how biodiversity is valued will provide lasting protection far into the future.
1. Eisner, T. and E.A. Beiring. 1994. Biotic exploration fund- protecting
biodiversity through chemical prospecting.а BioScience 44(2):95-98.
2. Eisner, T. 1991. Chemical prospecting: A proposal for action. pgs. 196-202 in
F.H. Bormann and S.R. Kellert eds. Ecology, Economics, Ethics-the broken circle.
Yale University Press, New Haven.
3. Wall, M.E. and M.C. Wani. 1995. Paclitaxel: from discovery to clinic.а pgs 18-30
in G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane Anticancer Agents:
basic science and current status. ACS Symposium Series 583, Washington D.C.
4. Wani, M.C., H.L. Taylor, M.E. Wall, P. Coggon and A.T. McPhail. 1971. Plant
antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and
antitumor agent from Taxus brevifolia. J. of Am. Chem. Soc. 93(9): 2325-2327.
5. Schiff, P.B.. J. Fant and S.B. Horwitz. 1979. Promotion of microtubule assembly
in virto by taxol. Nature 277:665-667.
6. Horwitz, S.B. 1994. How to make taxol from scratch. Nature 367: 593-594.
7.Holmes, F.A., A.P. Kedelka, J.J. Kavanagh, M.H. Huber, J.A. Ajani and V. Vlaero.
1995. Current status of clinical trials with paclitaxel and docetaxel. pgs 31-57 in
G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane Anticancer Agents: basic
science and current status. ACS Symposium Series 583, Washington D.C.
8. Campbell, S.J. and S.A. Whitney. 1995. The pacific yew environmental impact
statement. pgs. 58-71 in G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane
Anticancer Agents: basic science and current status. ACS Symposium Series 583,
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Claiborne, J. Renaud, E.A. Couladouros, K. Paulvannan and E.J. Sorensen. 1994. Total
synthesis of taxol. Nature 367:630-634.
10. Suffness, M. 1995. Overview of paclitaxel research: progress on many fronts. pgs
1-17 in G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane Anticancer
Agents: basic science and current status. ACS Symposium Series 583, Washington D.C.
11. Cragg, G.M. and K.M. Snader. 1991. Taxol: the supply issue. Cancer Cells 3(6):
а12. Ketchum, R.E.B., D.M. Gibson and L. Greenspan Gallo. 1995. Media optimization
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and Organ Culture 42: 185-193.
13. Strobel, G.A., A. Stierle and F. van Kuijk. 1992. Factors influencing the in
vitro production of radiolabeled taxol by Pacific yew, Taxus brevifolia. Plant Sci.
14. Stierle, A., G. Strobel and D. Stierle. 1993. Taxol and taxane production by
Taxomyces andreanae, and endophytic fungus of pacific yew. Science 260: 214-216.
15. Stierle, A., G. Strobel and D. Stierle. 1995. The search for a taxol-producing
microorgansim among the endophytic fungi of the pacific yew, Taxus brevifolia. J. of
Natural Prod. 58(9): 1315- 1324.
16. Gould, S.J. 1980. In the midst of life. pgs. 134-144 in The Panda's Thumb: more
reflections on natural history. W.W. Norton and Company, New York.
17. Downes, D.R. and C. Wold. 1994. Biodiversity prospecting: rules of the game.
BioScience 44(6): 381-383.аааааааааааааааааааааааааааааааааааааааа