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Once feared as a green hell, tropical forests are now viewed as paradise
lost. Defenders of the jungle, from biologists and bird-watchers to politicians
and rock stars, now make sweaty pilgrimages to the tropics and return with
prophecies of doom. What, they demand, can be done to save the tropical
forests?

This year, one of the world’s smallest countries will pair up with the
world’s largest drugs company to try something completely different. They
believe they can extract valuable substances from the flora and fauna of
the forest, sell them to the pharmaceuticals industry and, possibly, hold
the bulldozers at bay. Their experiment is called chemical prospecting,
a term usually attributed to Thomas Eisner, professor of biology at Cornell
University in the US. Costa Rica, a Central American country about the size
of Denmark, and Merck & Company of Rahway, New Jersey, are about to
put it to work.

Endowed with one of the world’s most diverse tropical landscapes, Costa
Rica wants to turn itself into a kind of biological OPEC. It would protect
its biota as other countries now do their oil or minerals, sharing it in
return for a portion of the profits from its chemical bounty. Spearheading
the plan is the National Biodiversity Institute (INBio) founded two years
ago in Heredia, in the heart of Costa Rica’s lush, agriculturally rich central
valley. Says Rodrigo Gamez, a plant virologist who runs INBio: ‘We want
to put our biodiversity to work for us. But we want to be perceived as partners,
not as a resource to be exploited.’

The agreement signed last month with Merck is the first of what Gamez
hopes will be several partnerships with drug companies. Merck will provide
$1 million over the next two years, which, along with launch funds from
US and European universities, foundations and govemments, will help to build
INBio into a chemical prospecting business. In return, Merck will acquire
exclusive rights to screen for pharmaceuticals any plant extracts collected
for it by INBio. INBio’s prospecting for industrial clients will dovetail
with its own ambitious 10-year scheme, already under way, to inventory its
entire flora and fauna, the biggest biological project undertaken by any
tropical country .

Costa Rica’s gambit is designed, to make its forests pay for themselves
while the country acquires the technology needed to screen natural compounds
in its own institutions. From now on, says Gamez, ‘we will have absolute
control over who will be allowed to operate in protected areas.’ Biologists
will have to get permits and deliver samples of everything they collect
to INBio. Any profit made on their work must be shared with Costa Rica.
According to Gamez, government officials from several tropical nations have
consulted with him on how to set up similar schemes.

Not all tropical countries, however, are as well placed as Costa Rica
to market their biological resources. With more than one-quarter of its
land protected in some form of reserve or park, Costa Rica is dubbed ‘a
Disneyland for ecotourism’ by other Latin Americans. Income from prospecting
will be used to support the country’s huge conservation programme. Numerous
donors have helped to landscape Costa Rica’s green future. Money has come
from the environment budgets of the MacArthur and Alton Jones Foundations
and the Pew Memorial Trust (all in the US), from the governments of the
US and Sweden as well as that of Costa Rica itself, and from numerous conservation
groups and small private donors. The country has its own flourishing conservation
movement and well established biological research organisations such as
the Fundacion Neotropica based in San Jose.

If Eisner is chemical prospecting’s visionary and Gamez its engineer,
field biologist Dan Janzen is its architect. With over 20 years’ experience
working and living in Costa Rica, mostly in the dry forests of Santa Rosa
National Park, Janzen is the region’s ecological guru. His voluminous research
has traced the life cycle of Santa Rosa’s lepidoptera (of which there are
over 3140 species), seed dispersal of the majestic guanacaste tree via defecating
horses ( ‘A tropical tree that travels by horse’, ¿ìè¶ÌÊÓƵ, 11 June
1987), and the unique and elaborate coevolution of the fig tree with the
fig wasp that pollinates it.

Chemical prospecting will capitalise on an effort Janzen began in the
1980s to create a corps of ‘parataxonomists’. Convinced that those who understand
the biology of the tropics will want to conserve it, Janzen, Gamez and collaborating
scientists are educating the population, especially the youngsters, in tropical
ecology. Costa Rica is fertile territory: 98 per cent of its adult population
is literate, according to government figures.

Parataxonomists on the move

The vanguard of the bioliterate are parataxonomists – farmers, housewives,
bus drivers, former park guards and other lay people who are trained to
become field collectors and paid for their work. After completing a six-month
course covertng botany, entomology and ecology, INBio’s 31 parataxonomists
have moved out into the country’s biological reserves and parks. Splitting
their time between home and a field station, they collect plants and insects.
Every few days, their dried, pinned and boxed collections are driven to
INBio. There, in an airy, high-ceilinged room lined with cases of specimens,
curators preserve them and affix each with a bar-coded label for computer
classification of its genus, species (if known), and where and when it was
found.

Parataxonomist Rodolfo Zuniga is a former farm worker and park guard.
Aged 29, he lives and works in a two-room field station at the edge of the
Carara Biosphere Reserve on Costa Rica’s Pacific coast. Zuniga has been
specialising in insects, particularly the moths, which he snares in a light
trap. ‘I carry a car battery in a sling up into different parts of the forest.
It powers a fluorescent light. Next to the light, I hang a white sheet.’
At about 8 pm and again at about 3 am, braving nocturnal surprises such
as the deadly fer-de-lance and bushmaster vipers, he returns to the site.
The white sheet is covered in insects, which he snares in a bottle laced
with sodium cyanide.

Experience and advice offered by Janzen and visiting researchers from
the Natural History Museum in London, the Smithsonian Institution in Washington
DC, the Missouri Botanical Garden and other scientific centres have taught
parataxonomists such as Zuniga which insects to look for. He prepares the
specimens with naphthalene, mounts them, and regularly drives them back
to INBio on his motorcycle. Like other parataxonomists, Zuniga attends refresher
courses while staying at INBio’s newly built guesthouse.

More types of life inhabit tropical forests than any other habitat.
In a 50-hectare plot on Barro Colorado Island in Panama, botanists found
over 300 species of woody plants with stems more than a centimetre thick
in old-growth forest. The American biologist Edward Wilson found 43 species
of ant in one tree in the Amazon rainforest, about the same number found
in the whole of the British Isles. Costa Rica could have as many as 500
000 species of plants, insects and microorganisms. Arthropods alone number
an estimated 300 000 species, of which only about one-fifth have been described.

Tropical plants are especially well-endowed with chemical defences,
as they must repel so many types of predators. Their armoury includes alkaloids,
such as morphine and nicotine; phenolics and tannins, found in tropical
trees like cecropia and mangrove; cyanogenic glycosides, in passionflowers
and manioc; and terpenoids, found in more than 30 species of plant in Costa
Rica’s dry forest by biologist Stephen Hubbell of Princeton University in
the US. About a quarter of all medical prescriptions in the US are formulations
based on substances from plants or microbes, or are synthetics derived from
such sources. Alkaloids come from flowering plants, notes Eisner, yet only
about 2 per cent of these plants (some 5000 of the estimated total of 250
000 species) have so far been examined for them. Eisner also notes that
insects have never been systematically studied for valuable chemicals. He
won fame for discovering the bombardier beetle’s bizarre ability to defend
itself with a spray of benzoquinones, and he believes insects are an untapped
source of useful compounds.

Costa Rica is home to myriad insects with surprising biochemistries.
Take the bruchid beetle, for example. Janzen, with John Bleiler of the South
Shore Natural Science Center in Norwell, Massachusetts, and Gerald Rosenthal
at the University of Kentucky, found a species of bruchid beetle that eats
a seed, Dioclea megacarpa, which contains L-cavananine, a very toxic amino
acid. The beetles use internal enzymes to detoxify the amino acid and extract
valuable nitrogen from the seed.

Insect behaviour can also help in such discoveries, by leading an observer
to an unusual chemical. If ants turn up their noses at a fallen leaf, or
predators avoid an insect’s egg when it is covered with its mother’s saliva
chemistry is at work. By keeping a lookout for this kind of telltale behaviour,
ecologists can spot interesting compounds. Eisner calls this the ‘biorational’
approach to chemical prospecting, and INBio employs it in training its parataxonomists.

A ‘return to nature’

Interest in botanicals at pharmaceuticals companies ebbed after the
1950s, when fermentation with microorganisms (the source of penicillin)
and synthetic chemistry became more popular. A few drugs companies such
as Merck kept at it, but the work was viewed as laborious and highly speculative.
Now things have changed. Charles McChesney, a natural products chemist at
the University of Mississippi, has watched closely the ‘return to nature’.
‘The synthetic chemists have made the easy molecules,’ he says; now they
must synthesise and investigate some five to ten thousand chemicals to get
one new drug lead. Given the high cost of chemical synthesis, says McChesney,
companies are increasingly inclined to let plants and other organisms do
the synthetic work.

Meanwhile, bio-assays that exploit new molecular techniques – such as
the cloning of genes for receptor molecules, the usual targets for drugs
on the surfaces of cells – are speeding up the process of screening plant
extracts. Using cells engineered to carry a particular type of receptor,
for example researchers can home in on plant extracts that contain compounds
which stimulate or block the receptor. A natural products laboratory, says
Eisner, can now screen thousands of compounds in a week.

Even so, Georg Albers-Schonberg of Merck’s natural products division
is sceptical about chemical prospecting paytn off soon or handsomely. In
the past 25 years, the company has marketed only five drugs discovered by
screening natural extracts, all from microorganisms. So why the contract
with INBio? One reason, says Albers-Schonberg, is the precarious state of
the world’s tropical forests. Merck executives have woken up to the fact
that a vast reservoir of potential drugs is rapidly disappearing, and that
it may be now or never for chemical prospecting. The emergence of faster
screening techniques is another key factor. In the past, Merck has only
dabbled with natural compounds, but it now realises that for a relatively
modest investment it can enter a partnership that could yield thousands
of extracts for screening.

Other organisations are thinking along similar lines. The US National
Cancer Institute in Bethesda, Maryland has created a repository for botanical
specimens and raised its budget for collecting new species of plants and
microorganisms. Last month, the NCI renewed two five-year contracts with
the Missouri and New York botanical gardens in which botanists will collect
specimens for testing as anti-cancer and AIDS treatments. The chemicals
company Monsanto recently signed a contract for several million dollars
with the Missouri garden for three years of collecting. Monsanto calls the
programme ‘bioprospecting’ and is interested in soil microorganisms as well
as plants. Other companies are looking for botanists who can make sense
of tropical flora. ‘We get contacted by an interested drug company every
couple of weeks,’ says Michael Balick, head of the Institute of Economic
Botany at the New York Botanical Garden.

Not everyone agrees on how best to look for new drugs. Eisner and Jansen
prefer to prospect ecologically, learning from the plants, insects and animals
rather than pursuing leads from traditional medicine from indigenous cultures.
‘I would use the whole set of animals out there,’ says Janzen. ‘Humans are
just one animal . . . and they only pick the stuff that doesn’t give them
a stomachache or make them go blind.’ Eisner says that screening methods
are now so fast and automated that it is just as easy to sweep up everything
of interest and test it.

Ethnobotanists such as Balick favour a more pluralistic approach. ‘I
happen to be interested in people . . . as much as the biological organisms
that we interact with.’ He cites the groundwork laid by his mentor at Harvard
University and America’s pre-eminent ethnobotanist, Richard Schultes. On
treks through South America, most notably in the 1930s and 1940s, Schultes
gathered scores of new plant products, not to mention numerous tales that
lent botany an aura of romance and peril.

While collecting plants for the NCI in Honduras and Belize, Balick compared
the number of ‘hits’ – compounds the NCI found worth investigating for action
against the AIDS virus – from two collecting strategies: a random collection
and one based on ‘powerful plants’ used for healing by Don Eligio Panti.
Panti is a curandero, a traditional herbal healer, who practises Mayan medicine
in Belize. Though the sample was small and the findings were preliminary,
Balick says the random collection of 18 plants yielded only one hit, while
the ethnobotanical collection of 20 plants yielded five hits. Balick has
set up a collecting cooperative in Belize that he hopes to use as a model
for other tropical countries.

Of the 121 compounds in the world’s pharmacopoeia that have been derived
from plants, about three-quarters were discovered through ethnobotany, says
Steven King, another Schultes disciple who is now with Shaman Pharmaceuticals,
a company in San Carlos, California. Shaman has begun mining phytochemical
information from the scientific literature as well as talking with American
Indian shamans. The company currently has an antiviral agent in development
and is testing more potential drugs with a research laboratory.

King says Shaman has set up a foundation to channel benefits from drugs
derived from ethnobotanical leads back to the Indian communities from which
they came. Payment may be monetary or in something else of value, such as
medical care. Shaman paid for a doctor to treat people in the Waorani and
Shaur communities in Ecuador, for example, in exchange for ethnobotanical
information.

Conservation International, an environmental group, has also delved
into ethnobotany in a programme with the catchy title of Sorcerer’s Apprentice,
set up by yet another Schultes disciple, Mark Plotkin. The first project
has begun in a corner of the international La Amistad Biosphere Reserve
in the remote Talamanca Mountains of Costa Rica. There, CI held a workshop
with local sukias, or traditional healers, and plans to build facilities
to help the local Bribri people pass on traditional plant knowledge. CI
has similar plans in Ecuador, Guyana and Surinam.

Compensating indigenous groups poses difficult problems. Few Indian
cultures have a word for patent or royalty. ‘International law protects
countries,’ says Jason Clay, head of Cultural Survival, a pressure group
for indigenous peoples. ‘Cultures are consistently left out.’

The NCI is wrestling with the question of ownership as it prepares a
model letter of intent and ‘material transfer agreement’ with collectors
in host countries. The NCI’s preliminary plans would share profits with
governments and their departments. Janet McGowan, a lawyer with Cultural
Survival, is lobbying the NCI to ensure that benefits will reach further,
to those with the original knowledge or those on whose traditional land
valuable plants are discovered.

In the meantime, the NCI is betting on both chemical prospecting and
ethnobotany: it supports Balick in New York as well as the Missouri garden,
which emphasises chemical prospecting. Merck also keeps an eye on what traditional
cultures use. Last year, for example, scientists from Merck published a
paper characterising a potent new anticoagulant. It was derived from the
bark of a tree found in Rondonia, Brazil, known locally as Tike-Ube (Cariniana
domestica). Local Indians have traditionally used the bright-red solution
from the tree bark as poison for their arrows.

* * *

1: COSTA RICA TAKES CONTROL OF ITS BIOLOGICAL ASSETS

Rodrigo Gamez of INBio vows that the days when a drugs company could
make millions from a tropical plant bought for a few dollars are over, at
least in Costa Rica. The story of the Madagascar periwinkle – the source
of vinctistine, a multimillion-dollar cancer drug – is one he hopes will
not be repeated: Madagascar received no royalties.

INBio is a private non-profit organisation with no enforcement powers.
It was created in 1989 with the blessing of former president and Nobel peace
laureate Oscar Arias. Its board includes bank directors, broadcasters and
former government officials as well as leading academics. INBio’s launch
came from the MacArthur Foundation, through Eisner, and its list of backers
reads like a who’s who in international conservation.

Gamez recruited some of Costa Rica’s best scientists, took control of
the country’s largest herbarium (containing some 140 000 specimens) and
modified a sophisticated computer system designed for classifying flora
and fauna. INBio’s assumption of power shook some in what Gamez considers
a sleepy academic community. ‘The people we dealt with, like the national
museum, were horrified at the idea of chemical prospecting,’ he recalls.
‘Their interest was purely in taxonomy.’ But in the end, he notes, they
realised it was a good way to generate money for research.

INBio has begun its inventory of the country’s flora and fauna with
a starting budget of close to $6 million. It plans to spend $3 million yearly
to finish th job in about 10 years, while putting $2 million annually into
an endowment. Income from chemical prospecting will augment that budget,
says Ana Sittenfeld, bead of research and development, as well as pay for
conservation.

Income from valuable plants and insects can be generated in several
ways. One involves Cornell University and the Strathclyde Institute for
Drug Research at the University of Strathclyde in Glasgow, which have formal
agreements to collaborate. INBio or one of its university partners will
test biological extracts of special interest, performing the first bio-assays
of compounds.

For example, INBio and the University of Costa Rica are using cultured
cell lines to test compounds that inhibit bovine leukaemia virus, a retrovirus
that causes tumours in cattle. Those that show some effect are fractioned
and each fraction is tested again. Those with activity then go to Cornell
or Strathclyde, where researchers determine their chemical structures
using nuclear magnetic resonance spectroscopy, mass spectrometry and other
analytical techniques.

If Cornell or Strathclyde or a commercial partner of theirs develops
a patentable product via this route, INBio will receive 60 per cent of royalties.
If the product is based on a significant chemical modification of such a
compound, INBio gets 51 per cent. INBio has drafted several possible arrangements
for drugs companies. The simplest option is something Sittenfeld calls ‘the
lottery’, in which INBio provides several hundred coded compounds. If the
company gets a hit and wants more of one compound, it must agree to share
royalties before the source, whether leaf, bark, fungus, insect or soil
bacterium, is revealed.

Drugs companies may also ask INBio to focus its search. So far, say
INBio scientists, companies appear most interested in compounds that are
effective against inflammation, cancer and fungal infection in humans and
against pests such as nematodes. New antibiotics are also high on the list,
because of growing resistance of the pathogens to existing antibiotics.

Other arrangements in which INBio will pursue its own ‘ecology-driven’
leads for a company would net INBio 51 per cent of royalties. The company
keeps the patent rights; INBio promises to use royalties to help conserve
Costa Rican biological diversity.

The negotiations with Merck took almost a year and were not easy, says
Gamez. Drugs companies need pure, uncontaminated samples, but collecting
flora and fauna is a messy business. Field procedures, extraction techniques
and reagents had to be standardised. Also, says Gamez, chemists had to be
educated. ‘You can’t Just go out and get samples any time. At what period
during a plant’s life cycle is it producing the most compound? Or, if you
want a certain type of larva, you have to wait for the right time of year.

There are logistical headaches as well. If INBio collaborates with more
than one company, it must keep each partner’s samples separate. Then there
is the problem of enforcement, that is, keeping unscrupulous collectors
from purloining a promising product straight from the forest. Furthermore,
a valuable plant species in Costa Rica may occur in other tropical countries
and be available to its client’s competitors. Gamez, while optimtstic, is
also pragmatic: ‘It’s not perfect, but you have to start somewhere.’

* * *

2: OUT OF THE FOREST AND INTO THE BOARDROOM

‘INBio’s plan will make for some unhappy people,’ predicts Dan Janzen,
who spends up to nine months a year in a three-room, tin-roofed house in
Costa Rica’s Santa Rosa National Park. ‘Biologists have had a free ride,’
he says. ‘Those that have been working in Latin America and not turning
anything back into the system have been off-base.’

Janzen says tropical botany may become more like industrial research,
where scientists employed by companies develop and protect their findings
before publishing. ‘The irony is that if people say ‘biodiversity has value’.
. . then it will fall under the social rules that all other things that
have value do. You bargain for it, you hide it, you steal it, you put it
in the bank. It’s no longer the toy of the English rich.’

The fruits of Janzen’s current field work hang in plastic bags clipped
to clotheslines that crisscross his house, whose threshold bears a sign
in Spanish, ‘Closed for Inventory’. He has spent much of the past year in
boardrooms in the US, however, where, along with Cornell’s Tom Eisner, he
negotiated with Merck and other companies on behalf of INBio. ‘It’s like
meeting people from Malaysia,’ he observes. ‘They have their own culture.’

Developing drugs from botanicals is ‘like fishing in a black box,’ says
Janzen. Natural products are less predictable than wholly synthesised compounds.
They may have a very narrow range of effectiveness: that is, one dose has
no effect, while the next higher one is an overdose. Drugs companies also
worry about being sued or nationalised. What is needed, says Janzen, ‘is
a friendly company, one that is willing to set its profit motive to one
side in order to be first in line.’

Costa Ricans, on the other hand, wonder if a drugs company can be trusted
not to synthesise a new drug from a botanical lead while claiming it found
nothing of interest in the forest. INBio will code its samples until a company
shows interest in one compound.

Janzen adds that companies also want to protect their reputations. A
drugs company’s reputation ‘translates as the difference between 2 per cent
sales or 6 per cent. And that can be the whole profit margin for a company.’

Outspoken and blunt, Janzen has little time for those who do their research
in armchairs instead of muddy boots. Costa Ricans studying with him, such
as INBio’s Maria Marta, who directs the parataxonomists supplying Merck
and INBio’s inventory, speak highly of his dedication. ‘He expects you to
work as hard as he does, or he will throw you out. But he is like one of
us, a Costa Rican,’ she says.