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REGU L R SSU E

T h e R o g e r R e v e l l e C o m m em o r a t i v e L e c t u r e ~

T h e O c e a n s a n d H u m a n H e a l t h :

T h e D i s c o v e r y a n d D e v e l o p m e n t

o f M a r i n e - D e r i v e d D r u g s

S h i r l e y A . P o m p o n i

H a r b o r B r a n c h O c e a n o g r a p h i c I n s t i t u t i o n F o r t P i e r c e , F l o r id a U S A

I n t r o d u c t i o n

I am honored to have been invited to present the

Second Annual Roger Revelle Commemorative

Lecture. Althou gh I never had the opportu nity to meet

or work with Dr. Revelle, his depth and breadth of

knowledge and scientific investigations have inspired

and challenged oceanographers to interpret the results

of their research in the context of systems, rather than

as isolated phenomena. It is with this challenge in mind

that I will discuss the role of the oceans in human

health, and specifically, challenges in realizing the

potential for the discovery of new, marine-derived

drugs to treat hum an diseases.

N a t u r e a s a S o u r c e o f D r u g s

For thousands of years, man has taken advantage of

nature's ability to produce remedies to treat infection,

inflammation, pain, and many other diseases and ail-

ments. In some parts of the world, natural medicines

are still the only t reatments available.

Scientific research on these eth-

nomedicinal preparations led to the

discovery of purified chemicals,

whose beneficial properties provided

the foundat ion of the current pharma-

ceutical industry. Today, over 50% of

the marketed drug s are either extract-

ed from natural sources or pro duced by synthesis using

natural products as templates or starting materials.

Drugs such as morphine, Taxol', aspirin, penicillin,

vincristine, and cyclosporin are but a few examples of

drugs derived from terrestrial plants and soil microor-

ganisms (Balandrin et al., 1985). The recent emphas is on

alternative medicines by the National Institutes of

Health acknowledges both the history and importance

of natural products in the treatment of diseases.

Based on the success of Bergmann and colleagues in

the late 1950's (Bergmarm and Burke, 1955), which led

d l 'ugs are e ither ex t rac te d f ro m

n a t u r a l s o u r c e s o r p r o d u c e d b y

s y n t h e s i s u s i n g n a t u r a l p r o d u c t s

as t empla te s or s ta r t ing ma ter ia l s .

t o the development of two drugs based on marine

sponge nucleosides (Ara-A for herpes infections and

Ara-C for leukemia) (Baker and Murphy, 1981), as well

as the pioneering research in marine natural products

drug discovery by the Roche Research Institute of

Marine Pharmacology during the mid-19'70s

(McConnell et al., 1994), scientists began to explore the

chemical diversity found in marine organisms and the

potential for discovery of new drugs from the marine

environment. What has become an intense effort in

marine natural products drug discovery by academic,

government, and indus try laboratories, especially in the

past 15 years, is based on a number of facts. The oceans

are a rich source of both biological and chemical diver-

sity. They cover more than 70% of the earth's surface

and contain more than 200,000 described species of

invertebrates and algae (Winston, 1988). It is estimated

that this number is only a small percentage of the total

number of species that are yet to be discovered and

described (Malakoff, 1997). Marine

To d a y, o ve r 50% o f th e m a r ke t e d microorganisms represent the greatest

percentage of undescribed marine

species (Colwell, 1996). A relatively

small number of marine organisms-

primarily algae and invertebrates-has

already yielded thousands of novel

chemical compounds (Ireland et al.,

1993), yet only a small percentage of

these chemicals has been studied for their potential as

useful products. Finally, although there is a major effort

by pharmaceut ical companies in the design of synthetic

chemicals for drug discovery, marine natural products

still provide unusual and unique chemical structures

upon which molecular modeling and chemical synthe-

sis of new drugs can be based.

Presented at the U.S. National Academy qfSciences, Washington D.C on

9 November 2000.

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Why do marine plants, animals, and microbes pro-

duce chemicals that are useful as pharmaceuticals?

Many of them are sessile-attached to the bottom-and

they live in densely populated habitats where competi-

tion for resources, such as space and food, is intense. As

a result, they have evolved a unique inventory of

metabolites used for their defense, reproduction, and

communication (Paul, 1992; Pawlik, 1993; Morse and

Morse, 1991). These metabolites also interact with

receptors and enzymes involved in human disease pro-

cesses. If, for example, a sponge is trying to prevent

another sponge from invading its space, it may produce

a chemical to prevent the other sponge's cells from

growing and dividing. It is not unusual, therefore, that

these same chemicals may also be effective in inhibiting

the uncontrol led growth of cancer cells.

In fact, a major emphasis has been on the discovery of

marine-derived anticancer compounds, due in large part

T A B L E I

A n t i - t u m o r a g e n t s f r o m m a r i n e s o u r c es t h a t a r e c u r r e n t l y l ic e n se d f o r d e v e l o p m e n t

O r g a n i s m M e t a b o l i t e L o c a t io n D i s c o v er e r

Bryozoan: Bryostatin I Gu l f of Cal i fornia Pett it ,

Bugu/a

neritina

Arizona State Univ.

C u r r e n t S t a tu s

In Ph ase 1/11 clinical tria ls in

US/Europe; NC I sponsored t rials.

Sea hare: Do lasta tin 10 Indian Ocea n Pettit,

Dolabella auricularia

Arizona State Univ.

Phase I clinical tr ials in US;

NC I sponsored t rials.

Tunicate: Ecteinascidin 743 Caribbean

Ecteinascidia turbinata

Rinehart, Univ. I l linois Licensed to PharmaM ar S.A.

In Pha se II cl inical tr ials in

Europe and in US.

Tunicate: Dehydro-d idemnin

Aplidium albicans

B [Apl id ine]

Mediterranean

Rinehart, Un iv I ll inois Licensed to PharmaMar S.A.

Gastropod:

Elysia rubefescens

Kahalal ide F Hawai i Scheuer, Univ. Hawai i Licensed to PharmaMar S.A.

Sponge: Discod ermol ide Car ibbean

Discodermia dissoluta

Gunasekera Longley, Licensed to Novar t i s .

H B O I

Sponge: Isohomo-

Lissodendoryx sp. halichondrin B

New Zea land

Mu nro Blunt ; Licensed to PharmaMar S.A.

Univ. Canterbury, N Z

Act inomycete: Thiocoral ine

Micromonospora marina

Mozambique Strait Canedo, Spain Licensed to PharmaMar S.A.

Tunicate: Isogranulatimide

Didemnum granulatum

Atlan t ic [Brazil ] And ersen Bjer inck,

Univ, B ritish

Columbia Brazi l

Licensed to Kinet ik, Canada.

Sponge: Beng amide Fiji

Jaspis sp

Crew s et al . Univ. Synthet ic der ivat ive l icensed

Cal i fornia, Santa Cru z to Nov art is.

Sponge: Hemiasterelins Papua Ne w Guinea Andersen, Univ.

Cymbastella sp. A B Br i tish Co lumb ia

Licensed to Wyeth-Ayerst .

Sponge: Giro l l ine Ne w

Caled onia Pot ier, France

Pseudaxinyssa cantha rella

Licensed to Rhone Poulenc.

Courtesy of Dr. DavidJ. New man ,National nstitutes of Health,National Canc er nstitute, Natural Products Branch.

i i , i i , 1 1 1 , i i , i p i i , ,

Oceanography VoL 14 No. 1/2001

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to the availability of funding to support marine-derived

cancer drug discovery. The National Cancer Institute

(NCI) has led this effort through its programs to support

both single-investigator and multi-institutional natural

products-based, cancer drug discovery research. As a

result, several marine-derived compounds are in pre-

clinical or clinical trials for the treatment of cancer as

shown in Table 1. I will highl ight just a couple.

Ecteinascidin 743, a complex alkaloid derived from

the mangrove tunicate

E c t e i n a s c i d i a t u r b i n a t e

(Wright et

al., 1990; Rinehart et al., 1990) shown in Figure 1 and

licensed by the University of Illinois to PharmaMar

S.A., is in Phase II clinical trials in the U.S. and Europe

for the treatment of cancer. Discodermolide, a polyke-

tide isolated from deep-water sponges of the genus

D i s c o d e r m i a sho wn in Figure 2, inhibits the proliferation

of cancer cells by interfering with the cell's microtubu le

network (ter Haar et al., 1996) as shown in Figure 3.

This compound has been licensed by Harbor Branch

Oceanographic Institution (HBOI) to Novartis

Pharmaceutical Corporation, and is in advanced pre-

clinical trials.

Figure 1. The tunicate, Ecteinascidia urbinata,source of ecteinascidin

743 , is a common inhabitant o f mangrove roots throughout the tropical

western Atlantic region (photo by John Reed, Harbor Branch

Oceanograp hic Institution).

Despite the emphasis on identify ing new anticancer

compounds, marine natural products have also been

found to have other biological activities, including

mediation of the inflammatory response. The pseu-

dopterosins are glycosides derived from the Caribbean

soft coral P s e u d o p t e r o g o r g i a e l i s a b e t h a e (Roussis et al.,

1990). These are in advanced preclinical trials as anti-

inflammat ory and analgesic drugs, and purified

extracts of this soft coral are available commercially as

additives in skin care products. Other marine-derived

compounds, such as the prostaglandins, palytoxin,

calyculin, okadaic acid, and manoalide, to name just a

few, are available commercially as biomedical research

probes that give us valuable insights into understand-

ing and treating human diseases.

There are more than 10,000 scientific publications

related to marine natural products (Munro et al., 1999).

This fact serves to underscore the vast potential of the

oceans as a source of novel chemicals with potential no t

only as pharmaceuticals, but also as nutritional supple-

ments, cosmetics, agrichemicals, molecular probes,

enzymes and fine chemicals shown in Table 2. Algal

products alone form the basis for a multi-billion dollar

industry (Radmer, 1996). Recognizing this potential,

U.S. President Clinton issued a directive to the Secretary

of Commerce on June 12, 2000, requesting recommen-

dations for a national ocean exploration strategy. The

President emphasized consideration of the full array of

benefits the oceans provide, with mechanisms to

ensure that newly discovered organisms or other

resources with medicinal or commercial potential are

identified for possible research and development .

I will, therefore, focus the rest of my lecture on the

challenges facing discovery and development of ne w

marine organisms wi th medicinal potential. These chal-

lenges are t e c h n i c a l , such as exploring new environ-

ments an d developing new platforms, tools, and assays

to discover and test organisms never before studied;

f i n a n c i a l , such as obtaining adequate support for both

exploration and early-phase, high risk discovery

research; and p o l i t i c a l , such as complying with regula-

tions related to the rights of a country to its natural

resources, as well as fair and equitable sharing of tech-

nologies and revenues resulting from commercializa-

tion of produc ts f rom marine resources. Successful dis-

covery and development of marine-derived pharma-

ceuticals will depend, of course, on our ability to

address a number of scientific questions. What organ-

ism produces the bioactive compound, and why? Can

we apply this knowledge to our rapidly increasing

understanding of the human genome and human dis-

ease processes? Are there viable alternatives to prevent

overTexploitation and ensure sustainable use of marine

resources for drug development? Let's examine each of

these challenges.

Figure 2. The sponge, Discodermia dissoluta, ource of discodermolide,

rarely occurs in shallow water, and is more commonly found at depths of

150-250m throughout the tropical western A tlantic region (photo courtesy

of Harbor Branch Oceanographic Institution).

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T A B L E 2

S o m e e x a m p l e s o f c o m m e r c i a l l y a v a il a b le m a r i n e b i o p r o d u c t s a d a p t e d fr o m P o m p o n i , 1 99 9 ).

P r o d u c t

A ra -A

A ra -C

okadaic acid

manoalide

VentD N A

polymerase

Formulaid

(Martek Biosciences,

Columbia , MD)

A equo r i n

Green Fluorescent

Protein (GFP)

phycoery thr in

Resilience (Estae Lauder)

p p l i c a t i o n O r i g i n a l

S o u rce

antiv i ral drug marine sponge,

Cryptotethya cryta

anticancer drug marine sponge,

Cryptotethya cryta

molecular probe:

phosphatase i nh ib i to r

molecular probe:

phospholipase A2 inh ib i to r

polymerase chain

reaction enzyme

fatty acids used as addi t ive

in infant formula nutr i t ional

supplement

bioluminescent

calcium

indicator

repo r te r

gene

conjugated antibodies

used in ELISAs and

f l ow cy tome t ry

marine extract

additive in cosmetics

dinoflagellate

marine sponge,

Luffariella variabilis

deep sea hydro thermal

vent bacter ium

marine microalga

bioluminescent jel lyfish,

Aequora victoria

bioluminescent jel lyfish,

Aequora victoria

red algae

Caribbean gorgonian,

Pseudopterogorgia elisabethae

M e t h o d o f P r o d u c ti o n

microbial fermentation

o f analog

chemical synthesis of analog

cel l cul ture

wi ld harvest of sponge

recombinant protein

cel l cul ture

recombinant p ro te in

recombinant p ro te in

cell cul ture

w i ld harvest of gorgonian

E x p l o r i n g t h e U n k n o w n

Mo s t o f t h e e n v i r o n me n t s e x p l o r e d f o r n o v e l o r g a n -

i s ms c o n t a i n i n g u n i q u e c h e mi c a l s h a v e b e e n t h o s e

a c c e s s i b l e b y S C U B A . A l t h o u g h b i o a c t i v e c o m p o u n d s

h a v e b e e n i d e n t i f i e d f r o m h i g h e r l a t i t u d e s , s u c h a s t h e

f j o r d s o f B r i ti s h Co l u m b i a a n d u n d e r t h e A n t a r c ti c i c e,

t h e g e o g r a p h i c f o c u s o f " b i o d i v e r s i t y p r o s p e c t i n g " h a s

b e e n p r i ma r i l y t h e t r o p ic s . A s i d e f r o m t h e f a c t t h a t i t 's

j u s t mo r e c o mf o r t a b l e t o d i v e i n w a r m w a t e r , t r o p i c a l

s e a s a r e w e l l k n o w n t o b e a r e a s o f h i g h b i o l o g i c a l d i v e r -

s i ty and , t herefo re , l og ica l t a rge t s fo r h igh chemica l

d i v e r si t y . M a r i n e b i o d i v e r s i t y p r o s p e c t o r s h a v e f o c u s e d

o n s h a l l o w w a t e r b e n t h i c e n v i r o n m e n t s - a r e a s t h a t c a n

b e a c c e s s e d w i t h r e l a t iv e e a s e b y s n o r k e l l i n g a n d

S C U B A d iv i n g . C o l l e c ti o n o f s a m p l e s f r o m d e e p e r e n v i-

r o n me n t s h a s b e e n a c c o mp l i s h e d u s i n g c l o s e d - c i r c u i t

r e b r e a t h e r d i v i n g , d r e d g i n g a n d t r a w l i n g , a n d s u b -

me r s i b l e s . T h e f o c u s o f o u r d r u g d i s c o v e r y e x p l o r a t i o n

p r o g r a m a t H a r b o r B r a n ch i s d e e p w a t e r o r g a n i s m s t h a t

l i v e o n t h e c o n t i n e n t a l s h e l v e s a n d s l o p e s a t d e p t h s

f r o m 1 30 to 1 00 0 me t e r s , i .e ., b e y o n d S CU BA d e p t h s ,

u s i n g o u r

Johnson-Sea-Link

m a n n e d s u b m e r s i b l e s .

Su b me r s i b l e s p r o v i d e p l a t f o r ms t h a t e n a b l e u s t o g o

d e e p e r , s t a y l o n g e r, a c c e s s u n u s u a l s i te s t h a t c a n n o t b e

a c c e s s e d u s i n g c o n v e n t i o n a l me t h o d s ( e . g . s t e e p w a l l s ,

r o c k y b o t t o m s , a n d v e n t c o m m u n i t i e s ) , a n d b e m o r e

p r e c i s e a n d s e l e c t i v e i n o u r s a m p l i n g t h a n c o n v e n t i o n a l

d e e p - w a t e r c o l l ec t io n m e t h o d s p e r m i t.

T h e r e i s s ti ll mo s t o f t h e d e e p s e a y e t t o b e e x p l o r e d .

Wi th ra re excep t ions (e .g . t he ana lys i s o f deep sea co res

t o id e n t i f y u n u s u a l m i c r o b e s ) , t h e d e e p s e a b o t t o m, m i d -

w a t e r h a b i t a ts , a n d m o s t o f t h e w o r l d ' s o c e a n s a t d e p t h s

g r e a t e r t h a n t h o s e a c c e s s ib l e b y SC U BA , h a v e n o t y e t

b e e n e x p l o r e d . T h e r e a s o n f o r t hi s d e f i c i e n c y is p r i ma r i -

ly f inanc ia l : oceanograph ic exped i t ions a re expens ive ,

a n d f e d e r a l f u n d i n g t o s u p p o r t s h i p o p e r a t i o n s ( e . g .

U n i v e r s it y - N a t io n a l O c e a n o g r a p h i c L a b o r a t o r y S y s t e m

f lee t sup por t ) i s genera l ly no t a va i l ab le i f t he fo cus o f the

r e s e a r c h i s d r u g d i s c o v e r y . T h e N a t i o n a l S c i e n c e

Fo u n d a t i o n d o e s n o t s p e c if i c a ll y s u p p o r t d r u g d i s c o v -

e r y, a n d t h e N a t i o n a l I n s t i t u te s o f H e a l t h d o e s n o t s u p -

p o r t s h i p o p e r a t i o n s . T h e N a t i o n a l O c e a n i c a n d

A t m o s p h e r i c A d m i n i s t r a t i o n / N a t i o n a l U n d e r s e a

Re s e a r c h P r o g r a m h a s b e e n t h e s i n g l e e x c e p t i o n , h o w -

e v e r , b u d g e t c u t s t o t h a t p r o g r a m d u r i n g t h e p a s t f e w

y e a r s h a v e s e r i o u s l y c u r t a i l e d f u n d i n g f o r o c e a n - g o i n g

r e s e a r c h . I n d u s t r y s u p p o r t f o r o c e a n o g r a p h i c e x p e d i -

t i on s a n d e a r l y - p h a s e d i s c o v e r y r e s e a r c h h a s b e e n l a c k-

Oceanography * VoL 24 No. 1/2001 81

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Figure 3. M CF- 7 hum an breast adenocarcinoma cel ls, v iewed by confocal

microscopy, nuclei (black arrow s); hair-like structures (m icrotubules) w hich

comprise the cytoskeleton (w hi te arrows). A. Untreated canc er cel ls. B.

Fol lowing treatment w i th the ant i-cancer drug, pacl i taxel, nuclei become rag-

mented and the microtubules orm abnormal bundled f i laments. These cel ls

w ill eventually d ie. C. After treatmen t w ith discoderm olide, effects are simi-

lar to pacl itaxel but are much more pronounced. Nuclei are fragmented and

microtubu les are formed into severe needle-like bundled filaments. These

ef fects induce ra pid cel l death (photomicrographs provided by Dr. R oss E.

Longley, H arbor B ranch Oceanographic Inst itut ion) .

ing; some pharmaceutical companies provide matching

funds for less expensive SCUBA collections, but none

provides suppor t for oceanographic expeditions.

The President's Panel on Ocean Exploration, in

responding to the President's directive for a national

ocean exploration strategy (cited above), recommended

the following: R e l e v a n t federal agencies must ensure

support for early phase research by establishing new

programs specifically targeted for research for discov-

eries from the Ocean Exploration Program. In addi tion

to the programs that currently exist to support short-

term, high risk research on the living and non-living

product s of exploration, federal agencies need to

emphasize, prioritize, and fast-track research initia-

tives on these product s of the Ocean Exploration

Program. Private sector involvement is critical.

Although mechanisms exist to support and encourage

partnerships be tween industry, academia, and govern-

ment (e.g. SBIR and STTR programs), these programs

are not oriented to support the early phase research

that is necessary to identify discoveries with commer-

cial potential. Incentives should be provided to

industrial sponsors of high risk, early phase, research.

These incentives should include, but not be limited to,

tax credits, grants and favorable licensing terms

(NOAA, 2000).

P o l i t i c a l C o n s i d e r a t i o n s

The exploration of new geographic areas will

und oub ted ly focus on areas outside of U.S. jurisdiction.

Indeed, since most of the tropical seas-the areas of focus

of most biodiversity prospecting-are under the jurisdic-

tion of other countries, compliance with national and

international regulations regarding access, extraction of

natural resources, and exporting materials has been an

essential element of marine natural products drug dis-

covery to date. Working in a country's territorial waters,

collecting samples and exporting those samples

involves obtaining permits from and coordinating the

interaction of several national and state agencies, e.g.

defense, fisheries, and national parks, to name a few. It

is often a lengthy process, and plans for foreign collec-

tions must be made several months or even years in

advance of the expedition.

Balancing the responsibilities of the stewards of

marine resources with the requests of marine bio-

prospectors is indeed a challenge. Environmental

resource managers are charged with protecting their

resources from overexploitation. Legislators and policy-

makers must decide whether bioprospecting is consis-

tent with their plans for resource management. If they

decide it is, they must draf t and implement policies for

access, use, and deve lopment of the resources.

Still unresolved, for the most part, are issues dealing

with fair and equitable sharing of technologies and rev-

enues related to the discovery and commercialization

of products from marine resources. As a result of the

recommendations of the United Nations Convention

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on Biological Diversity, legislators, bioprospectors, and

environmental resource managers have begun to dis-

cuss what actually does constitute a fair and equitable

sharing. How does one place a value on a resource? If,

for example, a drug was developed based on a chemi-

cal from an organism that is endemic to the country in

which it was collected, should the revenue sharing be

greater than if the organi sm occurs (and was collected)

throughout a geographic region and across jurisdic-

tional boundaries? If the organism is harvested to

provide the materials for clinical development and

commercialization, should the revenue sharing be

greater than if only a few samples were collected to

identify the active compound and subsequent supply

was based on alternative methods? Since the answers

to these questions are usually not known at the time an

agreement must be negotiated to access the resources,

the approach taken to date has been simply to agree

upon a royalty to be paid by the bioprospector to the

country. Expectations for the amount of such a royalty

may sometimes be unrealistic, especially in view of the

fact that pharmaceutical companies will generally

agree to pay royalties of less than 5% of net sales to the

licensor of the chemical. This is (perhaps unfairly)

based on the i ndustry average of $50 to $200 million to

develop a drug, compared with the licensor's costs of

perhaps less than $1 million to collect the organism,

test it for medicinal potential, add value to the com-

pound by characterizing its physical, chemical, and

biological properties, and protect its proprietary value

by pa tenti ng the discovery. Undoub tedly, these consid-

erations arise during nego tiations to determine fair and

equitable sharing between the bioprospector and the

coun try of orig in of the source organism. To be fair, nei-

ther party should be unreasonable in its expectations.

Each party must recognize both the value added to the

resource (and the revenue stream as a result of the

value added), as well as the original, continuing, and

perhaps intangible value of the resource as part of an

ecosystem.

Of course, the chances of a drug being commercial-

ized are very low, and the payoff could be several years

from the original discovery. In the spirit of respect for,

and acknowledgment of the scientific capabilities and

contributions of the source country, alternative scenar-

ios to revenue sharing may include more near-term

benefits, such as support for development of the scien-

tific infrastructure (particularly for developing nations),

training of students, scientist exchange programs, and

technology transfer. These are often key elements in a

revenue- and technology-sharing agreement.

N e w T o o ls fo r D i s c o v e r y

To optimize our chances for identification of marine

resources with medicinal potential, we must use the

best tools for discovery at all stages: exploration of new

locations, collection of organisms never before sampled,

and identification of chemicals with pharmaceutical

potential. Increased sophistication in the tools available

to explore the deep sea has expanded the habitats that

can be sampled and has greatly improved the opportu-

nities for discovery of new species and the chemical

compounds they produce. New and improved

platforms (such as autonomous, remote, and human-

occupied underwater vehicles) to take us farther and

deeper are in development. These platforms need to be

equipped with even more sophisticated and sensitive

tools (e.g. cameras, sensors, and manipulators) to

enable us to identify an organism as new, to assess its

potential for novel chemical constituents, and if possi-

ble, to non-dest ructively remove a sample of the organ-

ism. Tools and sensors that have been developed both

for space exploration and for diagnostic medicine need

to be applied to the study of the inhabitants of our last

frontier on Earth.

Although there exist some specialized tools and

chambers that allow deep water organisms to be main-

tained und er ambient conditions, i.e. high pressure and

low temperature, there is still a need for the develop-

ment of versatile bioreactors that can be deployed and

operated in extreme environments (e.g. hypersaline,

vent, anoxic, and deep sea habitats). Such bioreactors

could be used for collection, at-sea maintenance, and

evaluation of both macroorganisms and microorgan-

isms so that their metabolites could be studied under

physiological conditions that are as similar as possible

to ambient conditions.

Another approach to the identification of new

products is the incorporation of miniaturized biosen-

sors into both collecting tools and bioreactors for rapid,

i n s i t u analysis of marine organisms for bioactive

molecules. A number of miniaturized biosensors and

probes to study human disease processes are in devel-

opment. Adaptation or development of new biosensors

and probes for rapid, in situ screening of marine organ-

isms would involve specialized tools, ideally for non-

destructive sampling and analyses of the target

organisms (Pomponi, 1999). Development of i n s i t u

biosensors would enhance our ability to probe the

expression of metabolites in response to various stimuli,

lead to a better understanding of the role of the sec-

ondary metabolites in nature, and perhaps provide

clues to the potential biomedical utility of these

compounds.

N e w M o d e ls N e w P a r ad i g m s

The biological evaluation of marine-derived extracts

and pure compounds for pharmaceutical development

has been based on assays developed by the pharma-

ceutical industry for high-throughput screening of

large libraries of synthetic compo unds. They measure a

number of end points, such as activation or inhibition

of enzymes or receptors involved in human disease

processes, inhibition of growth of human pathogenic

microorganisms, and toxicity against human cancer

cells (McConnell et al., 1994; Ireland e t al., 1993; Munro

Oceanography VoL 14 No. 1 /200 1 83

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7/10

et al., 1999). As our understanding of the biochemistry

behind a variety of diseases has improved, better meth-

ods have been developed for rapidly determining the

biomedical potential of the metabolites produced by

marine organisms. None of the assays used in major

pharmaceutical drug discovery programs, however,

takes into account the role of marine-derived

compounds in nature, i.e. the i n s i t u biochemical func-

tions of the metabolites, and how

those functions may be applied to the

discovery of new drugs an d probes to

stud y hu man disease processes.

Marine organisms as model sys-

tems offer the potential to understa nd

and develop treatments for disease

based on the normal physiological

role of their secondary metabolites.

For example, the mechanisms of action of the toxins of

C o n u s , the poisonous snail, are well -known (Hopkins et

al., 1995), and are currently being applied to the devel-

opment of new classes of drugs to treat diseases such as

epilepsy.

Marine organisms have already demonstrated their

utility as biomedical models, the results of which have

been applied to understanding normal and disease

processes in human s (Ocean Studies Board, 1999). Can

we continue to apply this knowledge to our rapidly

increasing understanding of the human genome and

hum an disease processes? Or perhaps a more relevant

question is this: can we use our rapidly increasing

understanding of the human genome and human dis-

ease processes to guide our discovery of novel marine-

derived chemicals that can be used against newly

discovered disease targets? Considering the evolution-

ary conservation of molecular signaling pathways, one

can hypothesize that our understanding of molecular

pathways and disease targets in mammalian systems

can help us not on ly to elucidate the ecological roles of

marine-derived metabolites, but can also provide a

more rational approach to the discovery of drugs to

treat a variety of diseases. How does a simple organ-

ism, like a sponge, through which seawater and associ-

ated bacteria, fungi, and viruses constantly flow,

defend itself against microbial infections? How does it

signal its cells to divide rapidly enough to heal a dam-

aged surface in a few hours, or spread out over a

substrate in a matter of days or weeks, yet control this

proliferation so that the sponge itself does not get can-

cer? How, with only a primitive immune system, does

it recognize an invading organism as non-self and

send out chemicals to kill the invading cells, without

killing its own cells? We know so little about these pro-

cesses in the organisms from which we have identified

literally thousands of chemicals with biomedical

potential. Molecular tools and approaches that have

been developed to understand similar processes in

mammalian systems must be applied to understanding

these processes in marine organisms. A multidisci-

plinary approach-involving molecular biologists, phar-

macologists, and chemical ecologists-to discovery of

marine-derived drugs will likely result in the discovery

of unique bioactive chemicals and new ways to address

the treatment of huma n disease.

S u s t a i n a b l e U s e o f M a r i n e R e s o u r c e s

w i t h C o m m e r c i a l P o t e n t i a l

With the enormous potential

C a n w e l~ s e o u r r a p i d l y

i n c r e a s i n g u n d e r s t a n d i n g

o f t h e h u m a n g e n o m e a n d

human d i s e a s e p r o c e s s e s t o

g u i d e o u r d i s c o ve r y o f

n o v e l m a r i n e - d e r i v e d c h e m i c a ls ?

for discovery, development, and mar-

keting of novel marine bioproducts

comes the obligation to develop meth-

ods by which these products can be

supplied in a way that will not disrupt

the ecosystem or deplete the resource.

Supply of most marine-derived com-

pounds is a major limiting factor 15or

further pharmaceutical development. Often, the

metabolite occurs in trace amounts in the organism, and

a st eady source of supply from wi ld ha rvest cannot p~:o-

vide enough of the target compound for preclinical

studies. In general, the natura l abundance of the source

organisms will not support production based on wild

harvest. Unless there is a feasible alternative to harvest-

ing, promising chemicals will remain undeveloped.

Some options for sustainable use of marine resources

are chemical synthesis, controlled harvesting, aquacul-

ture of the source organism, in vitro production through

cell culture of the macroorganism or microorganism

source, and transgenic production. Each of these

options has its advantages and limitations, not all

methods will be applicable to supply of every marine

bioproduct, and most of the biological supply methods

are still in development (Pomponi, 1999). The approach

to be used will be based on a numbe r of factors:

1 . C o m p l e x i t y o f t h e m o l e c u l e: c a n i t b e s y n t h e s i z e d

u s i n g a n i n d u s t r i a l l y f e a s i b l e p r o c e s s ? Chemical

synthesis of a compound gives the pharmaceutical

company ultimat e control in the s upply of materials

for clinical development and eventual marketing of

the drug. Synthetic processes have been published

for many marine bioproducts in development as

pharmaceuticals (Corey et al., 1996; Harried et all.,

1997). Unfortunately, most of these are multi-step

processes that are not amenable to economic, indus-

trial scale synthesis. To overcome this problem,

major research programs are undertaken by the

pharmaceutical industry to identify structurally

similar compounds that are easier to synthesize,

and perhaps even more potent, less toxic, and more

bioavailable than the parent molecule.

2 . A b u n d a n c e o f th e o r g a n i s m i n n at u re : w h a t d o w e

k n o w a b o u t t h e im p a c t o f c o l le c t io n s o n t h e e n v i-

r o n m e n t ? Prior to large-scale wild harvest of an

organism for recovery of a bioproduct, harvesting

feasibility studies should be conducted. These

84 Oceanography VoL 14 No . 1 /200 1

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s h o u l d d e f i n e f a c t o r s s u c h a s t h e s t a n d i n g s t o c k o f

t h e o r g a n i s m, i t s g r o w t h r a t e a n d t h e f a c t o r s t h a t

a f f e c t g r o w t h , a n d t h e e f f e c t s o f h a r v e s t i n g a n d

p o s t - h a r v e s t i n g r e c o v e r y o f t h e t a r g e t o r g a n i s m.

T h e s e i mp a c t d a t a s h o u l d t h e n b e u s e d t o a s s e s s t h e

p o t e n ti a l o f s u p p l y f r o m w i l d h a r v e s t , a n d m a y a l s o

b e u s e f u l i n d e v e l o p i n g m o d e l s f o r a q u a c u l t u r e o f

t h e s o u r c e o r g a n i s m. U n f o r t u n a t e l y , t h i s i s r a r e l y

d o n e . O n e n o t a b l e e x c e p t i o n i s t h e s u r v e y o f t h e

N e w Z e a l a n d s p o n g e,

Lissodendoryx

s p . , w h i c h p r o -

d u c e s t h e h a l i c h o n d r i n s , p o t e n t a n t i t u m o r c o m -

pounds in p rec l in i ca l t r i a l s . The sponge i s res t r i c t ed

i n o c c u r r e n c e t o o n e l o c a l i ty o f f t h e K a i k o u r a

P e n i n s u l a . R e s e a r c h c o n d u c t e d b y B a t t e r sh i ll

( 19 9 8) , d e m o n s t r a t e d t h a t h a r v e s t i n g b y d r e d g i n g

s i g n i f ic a n t l y r e d u c e d t h e s t a n d i n g s t o c k o f t h e

s p o n g e , b u t t h a t t h e p o p u l a t i o n m a y r e c o v e r r a p id -

l y a s a r e s u l t o f a s e x u a l p r o p a g a t i o n o f s p o n g e f r a g -

me n t s d i s p e r s e d a s a r e s u l t o f t h e d r e d g i n g . T h i s

s t u d y s u g g e s t e d t h a t h a r v e s t i n g i s o n l y f e a s i b l e f o r

s ma l l e r q u a n t i t i e s o f t h e s p o n g e .

3 . S o u rce o f t h e co m p o u n d : i s i t m i c r o b i a l l y p r o d u ced ?

A s ig n i fi c an t n u m b e r o f m a r i n e b i o p r o d u c t s w i t h

p h a r ma c e u t i c a l p o t e n t i a l h a v e b e e n i d e n t i f i e d f r o m

h e t e r o tr o p h i c m a r i n e m i c r o o r g a n is m s i s o la t e d f r o m

c o a s t a l s e d i m e n t s ( Fe n ic a l, 1 9 9 3 ; D a v i d s o n , 1 9 9 5 ;

K o b a y a s h i a n d I s h i ba s h i , 1 9 9 3 ) . I n a d d i t io n , s o m e

m a r i n e b i o p r o d u c t s o r i g i n a l l y i s o l a t e d f r o m

m a c r o o r g a n i s m s , s u c h a s s p o n g e s , h a v e b e e n s u b s e -

q u e n t l y d i s c o v e r e d t o b e l o c a l i z e d i n mi c r o b i a l

as soc ia t es (Be wley e t a l ., 1996 ; Senn et t , 2000) . I f

t h e s e mi c r o o r g a n i s ms c a n b e i s o l a t e d a n d c u l t i v a t -

e d , o p t i m i z a t i o n o f p r o d u c t i o n i n ma r i n e m i c r o b i a l

b i o r e a c t o r s c o u l d l e a d t o a n i n d u s t r i a l l y - f e a s i b l e

s u p p l y o p t io n .

I f t h e s o u r c e o f t h e c o m p o u n d i s t h e m a c r o o r -

g a n i s m i t s e l f , d e v e l o p m e n t o f i n v i t ro p r o d u c t i o n

m e t h o d s c o u l d p r o v i d e b u l k s u p p l y o f th e c o m -

p o u n d . R e s e a r c h i n p r o g r e s s i n o u r l a b o r a t o r y

f o c u s e s o n e s t a b l i s h i n g c e l l li n e s o f b i o a c t i v e ma r i n e

i n v e r t e b ra t e s t h a t c a n b e u s e d a s m o d e l s t o s t u d y in

vi tro p r o d u c t i o n o f b i o a c t iv e m e t a b o l it e s a n d t h e

f a c to r s w h i c h c o n t r o l e x p r e s si o n o f p r o d u c t i o n

( Po mp o n i a n d W i l l o u g h b y , 2 0 0 0 ) . T h i s c o u l d u l t i -

m a t e l y l e a d t o

i n v i t r o

p r o d u c t i o n o f m a r i n e

b i o p r o d u c t s . M o r e i m p o r t a n t l y , a n u n d e r s t a n d i n g

o f t h e c e l l u l a r a n d mo l e c u l a r p r o c e s s e s t h a t c o n t r o l

p r o d u c t i o n o f th e s e m e t a b o l i te s c o u l d b e u s e d t o

e n h a n c e c u l t u r e o p t i m i z a t i o n o r t o s t i m u l a t e

p r o d u c t i o n o f " u n n a t u r a l " n a t u r a l p r o d u c t s , i. e.

c h e m i c a l s t h a t t h e o r g a n i s m w o u l d n o t p r o d u c e

u n d e r n o r m a l c o n d i t i o n s , b u t w h i c h m a y b e m o r e

p o t e n t t h a n t h e " n a t u r a l" p r o d u c t .

4 . In s i tu gr ow th cond i t ions : i s aquacu l ture an op t ion

f o r d e e p - w a t e r o r g a n i s m s ? Bo t h i n - t h e - s e a a n d

l a n d - b a s e d a q u a c u l t u r e m e t h o d s h a v e b e e n d e v e l -

o p e d f o r p r o d u c t i o n o f b i o p r o d u c t s f r o m s h a l l o w

w a t e r o r g a n i s m s . C a l B i o M a r i n e T e c h n o l o g i e s

( Ca r l s b a d , Ca l i f o r n i a ) h a s s u c c e s s f u l l y a q u a c u l -

t u r e d t h e b r y o z o a n ,

Bugula ner i t ina ,

t h e s o u r c e o f

t h e a n t i t u m o r c o m p o u n d b r y o s t a t in , a n d

Ecteinascidia turbinata, t h e a s c i d i a n f r o m w h i c h t h e

a n t i t u m o r c o m p o u n d , e c t e i n a s c i d i n 7 4 3 h a s b e e n

i s o l a t e d ( F i g u re 1 ). T h e s e a r e b o t h c o m mo n , s h a l -

l o w - w a t e r o r g a n i s m s f o r w h i c h r e p r o d u c t i o n a n d

g r o w t h h a v e b e e n s t u d i e d , b u t t h e f a c t o r s c o n t r o l -

l in g p r o d u c t i o n o f t h e c o m p o u n d s a r e n o t y e t

c o m p l e t el y k n o w n . T h e N e w Z e a l a n d d e e p w a t e r

s p o n g e ,

Lissodendoryx

sp . , i s t he source o f the an t i -

t u m o r c o m p o u n d s , c a l le d ha l ic h o n d r i ns . T h e

s p o n g e o c c u r s a t 8 5 - 1 0 5 me t e r s d e p t h , b u t h a s b e e n

c u l t u r e d s u c c e s s f u l l y f r o m c u t t i n g s o n l a n t e r n

a r r a y s i n s h a l l o w e r w a t e r , ma i n t a i n i n g p r o d u c t i o n

of the b ioac t ive ha l i chondr ins (Bat t e rsh i l l e t a l . ,

1 9 99 ). T h i s i n d i c a te s t h a t a q u a c u l t u r e o f s o me d e e p

w a t e r s p o n g e s i s f e a s i b l e , h o w e v e r , s p e c i e s f r o m

d e e p e r w a t e r m a y h a v e m o r e c r i t i c a l g r o w t h

r e q u i r e m e n t s , s u c h a s h i g h p r e s s u r e a n d l o w

t e mp e r a t u r e . I n - t h e - s e a a q u a c u l t u r e i s a c o s t e f f e c -

t iv e m e t h o d o f p r o d u c t i o n w i t h o p p o r t u n i t i e s f o r

t e c h n o l o g y t r a n s f e r a n d e c o n o m i c d e v e l o p m e n t i n

t h e s o u r c e c o u n t r y , h o w e v e r , i t ma y n o t a f f o r d t h e

o p p o r t u n i t y f o r c o m p l e t e c o n tr o l o f e n v i ro n m e n t a l

p a r a m e t e r s o r t h e o v e r -e x p r e s s io n o f p r o d u c t i o n o f

t h e c o m p o u n d s . D e v e l o p m e n t o f c l o s e d - sy s t e m

b i o r e a c to r s f o r a q u a c u l tu r e o f b o t h s h a l l o w w a t e r

a n d d e e p w a t e r o r g a n i s ms i s a p a r t i c u l a r l y c h a l -

l e n g i n g o p p o r t u n i t y .

5 . B i o s yn t h e t i c p a t h w a y : i s gen e t ic en g i n eer in g

real

ist ic f o r t h e co m p o u n d ? I f t h e b i o s y n t h e s i s o f t h e

t a r g e t c o m p o u n d i s u n d e r s t o o d , i t m a y b e p o s s i b le

to iden t i fy , i so l a t e , c lone , and express the genes

r e s p o n s i b l e f o r p r o d u c t i o n o f t h e me t a b o l i t e in

a n o t h e r h o s t . I n ma n y c a s e s , o f c o u r s e , b i o s y n t h e s i s

o f t h e p r o d u c t i s n o t k n o w n , o r i t i s a mu l t i - s t e p

p r o c e s s i n v o l v i n g s e v e r a l e n z y ma t i c r e a c t i o n s . Fo r

t h e s e c a s e s , t r a n s g e n i c p r o d u c t i o n i s n o t a t r i v i a l

p r o c e s s . A l t e r n a t i v e l y , c h e mo e n z y ma t i c s y n t h e s i s ,

b y w h i c h m a r i n e b i o p r o d u c t s a r e s y n t h e s i z e d i n

c e l l - f r e e , e n z y me - b a s e d s y s t e ms , o f f e r s a c o mp l e -

m e n t a r y t e c h n i q u e t o

i n v i t ro

a n d t r a n s g e n i c p r o -

d u c t i o n m e t h o d s f o r m a r i n e b i o p r o d u c t s ( K e r r e t

al., 1996).

Summary

T h e O c e a n S t u d i e s B o a r d o f th e U . S . N a t i o n a l

Re s e a r c h Co u n c i l , i n i t s r e v i e w o f t h e o c e a n ' s r o l e i n

h u m a n h e a l t h ( O c e a n S t u d i e s B o a r d , 1 9 9 9 ) , r e c

o m m e n d e d a g r e a t e r f o c u s o n m a r i n e o r g a n i s m s a s

s o u r c e s o f n e w p h a r m a c e u t i c a ls , n e w f u n d i n g i n it ia -

t i v e s to s u p p o r t t h i s e f f o r t i n a l l t h e r a p e u t i c a r e a s - n o t

j u s t c a n c e r - a n d n e w i n t e r d i s c i p l i n a r y r e s e a r c h a n d e d u -

c a t i o n p r o g r a m s t o p r o v i d e i n n o v a t i v e a p p r o a c h e s t o

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m a r i n e b a s e d d r u g d i s co v e r y .

Re c e n t U . S. l e g i s la t i o n a n d e x e c u t i v e d i r e c t i v e s s u p -

p o r t a r e n e w e d e m p h a s i s o n e x p l o r i n g t h e v a s t

u n k n o w n a r e a s o f o u r o c e a n s , d is c o v e r i n g s p e c ie s n e w

t o s c i e n c e , i d e n t i f y i n g ma r i n e r e s o u r c e s w i t h p o t e n t i a l

me d i c i n a l v a l u e , a n d e n s u r i n g t h e p r o t e c t i o n a n d s u s -

t a i n e d u s e d o f th e s e r e so u r c e s . W e n o w h a v e t h e u n i q u e

o p p o r t u n i t y t o c a p i t a l i z e o n n e w t e c h n o l o g i c a l

a d v a n c e s d e v e l o p e d t o e x p lo r e t h e o c e a n s o f E a r th a n d

o t h e r p l a n e t s , r e c e n t d i s c o v e r i e s i n me d i c i n e , mo l e c u l a r

b i o l o g y , a n d ma r i n e b i o t e c h n o l o g y , a n d a g r e a t e r a p p r e -

c i a t io n f o r b e n e f i t s h a r in g a n d t h e v a l u e o f ma r i n e

r e s o u r c e s t o r e a l iz e t h e f u l l p o t e n t i a l o f o u r o c e a n s a n d

h u m a n h e a l t h .

Acknowledgments

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g r a n t s f r o m t h e N a t i o n a l I n s t i t u te s o f H e a l t h . Re s e a r c h

o n s u s t a in a b l e u s e o f m a r i n e r e s o u r c e s w a s f u n d e d b y

t h e N O A A S e a G r a n t M a r i n e B i o t e c h n o l o g y P r o g r a m . I

a c k n o w l e d g e t h e a s s i s t a n c e o f J o h n Re e d , Ro s s L o n g l e y ,

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I g r a t e f u l l y a c k n o w l e d g e t h e N a t i o n a l S c i e n c e

Fo u n d a t i o n , t h e O f f i c e o f N a v a l Re s e a r c h , t h e U n i t e d

S t a t e s G e o l o g i c a l Su r v e y , t h e Sc r i p p s I n s t i t u t i o n o f

O c e a n o g r a p h y , a n d t h e W o o d s H o l e O c e a n o g r a p h i c

I n s t i t u t io n f o r t h e ir s p o n s o r s h i p o f t h is l e c t u r e.

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Dr. RogerRevelle

T h e R o g e r R e v e l l e C o m m e m o r a t i v e L e c t u r e S e r ie s w a s c r e a t e d b y

t he Oce an S t ud i es B oard i n hono r o f the l a t e R oger R eve l l e . The

s peak er s and t op i cs a r e i n t en ded t o h i gh l i gh t t he i m por t an t l i nks

b e t w e e n o c e a n s c i e n c e s a n d p u b l i c p o l i c y fo r a g e n e r a l a u d i e n c e .

The l ec t u re i s he l d an nua l l y a t t he F a l l m e e t i ng o f t he OS B i n

W as h i ng t on , DC , and i s ope n t o t he pub li c . F o r m o re i n fo rm at i on

a b o u t t h e L e c t u r e S e ri e s a n d t h e O c e a n S t u d ie s B o a r d , s e e

h t t p : // w w w 4 . n a t i o n a la c a d e m i e s . o r g / c g e r / o s b . n sf / .

Sponsors:

N a t i o n a l S c ie n c e F o u n d a t i o n

O f f ic e o f N a v a l R e s e a r c h

S c r i p p s I n s ti t u ti o n o f O c e a n o g r a p h y

U.S. Geo l og i ca l S u rv ey

W o o d s H o l e O c e a n o g r a p h i c I n s t i tu t i o n

Oceonography VoL 14 No. 1 /200 1 87