THE OCEANS AND HUMAN HEALTH Marine BY WILLIAM FENICA Pharmaceuticals Past,Present, and Future
110 Oceanography Vol. 19, No. 2, June 2006 Marine Pharmaceuticals Past, Present, and Future THE OCEANS AND HUMAN HEALTH BY WILLIAM FENICAL 110 Oceanography Vol. 19, No. 2, June 2006 Th is article has been published in Oceanography, Volume 19, Number 2, a quarterly journal of Th e Oceanography Society. Copyright 2006 by Th e Oceanography Society. All rights reserved. Permission is granted to copy this article for use in teaching and research. Republication, systemmatic reproduction, or collective redistirbution of any portion of this article by photocopy machine, reposting, or other means is permitted only with the approval of Th e Oceanography Society. Send all correspondence to: info@tos.org or Th e Oceanography Society, PO Box 1931, Rockville, MD 20849-1931, USA
BENEFICIAL ROLE OF THE OCEANS? the salicylates [aspirin])were utilized in single-ingredient for- In this issue of Oceanography,the majority of the papers pre mulations(i.e"drugs").As time passed,these molecules be- sented focus on the harmful health effects of the oceans cre- came the foundation of the new discipline of organic chemis- ated by oceanic events,anthropogenic influences,and harmful try.The developing pharmaceutical industries evolved to focus marine life.These are important issues that dramatically affect their efforts on purifying new drugs from these traditional eth human health,but at the same time this view does not reflect nomedicines(Therapeutic Research Faculty,2006). the fact that we are just now realizing some of the health-re The discovery of penicillin in the late 190s by Alexander lated benefits from the oceans.Comprising 34 of the 36 Phyla Fleming was perhaps the single most important medical dis- of life,marine ecosystems are indeed our last genetic diversity covery in modern times.This,and subsequent discoveries by and biotechnological frontier terrestrial systems possessony Selman Waksman(ie.,actinomycin and other antibiotics)and 17 Phyla.We have much to learn. other researchers,changed how drugs were discovered and Humankind has explored and explo oited the terrestrial envi- how Nature was explored (Berdy,005).The pharmaceuti ronment for more than 3000 years,leading to the examination cal industry,worldwide,quickly evolved by embracing these of almost every possible resource on land.In the future,similar findings,and subsequently discovered hundreds of"wonder explorations of the world's oceans,using modern chemical and drugs"that had the capability to cure pneumonia and almost molecular genetic technologies,will uncover a rich treasure all bacterial infectious diseases.These natural"wonder drugs chest of new medicinal products,cosmetics,foods,industrial saved millions of lives during and after World War II.and gav chemicals,and new,environment-friendly industrial processes. us the false sense that the great plagues of the past(c.g..chol- As we have benefited from life on land,it is reasonable to pre- era)would never again be seen (see Laws case study,this issue). dict that the next few decades will be filled with new discoveries More than 120 antibiotics,anticancer agents,and other thera- from our greatest untapped resource,the world's oceans.In this peutics originally derived from microorganisms that are found short synopsis,I will attempt,admittedly in a non-comprehen- nsoil are still prescribed today sive way,to summarize the past and current status of marine medicine,and to emphasize the important role the oceans will DISCOVERY OF THE OCEANS IN THE 1960s- play in human medicine in the decades to come THE PAST It is interesting to note that,historically,the oceans were rarely NATURAL PRODUCTS AND THE TREATMENT considered as a likely soure for natural medicines.In souther OF HUMAN DISEASE China,a poorly described marine ethnomedicine evolved,but More than 3000 years ago,early societies recognized that the this approach was not generally seen elsewhere.Despite biolo- diversity of plant lifearound them could be used for the treat- gists exploring life in the oceans in the ment of human illness.Natural "preparations,"in the form the linkage of medicine and marine biodiversity was never of teas or salves derived from plants,were commonly used to made.Even in more modern times,the pharmaceutical indus treat pain,infections,gastrointestinal maladies,inflammation, tries made little effort to examine life in the sea.This is under cancer,and many other common illnesses.Traditional healers standable because the ocean was virtually unknown,and diffi evolved who were consulted to treat illness,and the knowledge cult and dangerous to explore,while new drugs from terrestria of these individuals was passed down to understudies or ap- plants,and later soil microorganisms,were plentiful. prentices who continue to practice todayToday,for economic Asa consequence,the enormous resources of the oceans lay as well as traditional reasons,much of the developing world dormant until the mid to late 1960s when small groups of or. still relies on natural medicines(e.g.,ethnomedicines or tradi- ganic chemists in the United States,Europe,and Japan begar tional medicines)for the treatment of human disease to collect,extract,and chemically explore the diversity of ma Over time,the"active ingredients"from traditional medi- rine life.Pioneers like Paul Scheuer and Richard Moore in the cines were chemically purified,and during theand United States,Luigi Minale and Ernesto Fattorusso in Italy,and 2cnturies some of these drugs (morphie,unne, a small group of Japanese researchers(who were already the Oceanography I Vol 19.No.June 2006 111
Oceanography Vol. 19, No. 2, June 2006 111 BENEFICIAL ROLE OF THE OCEANS? In this issue of Oceanography, the majority of the papers presented focus on the harmful health effects of the oceans created by oceanic events, anthropogenic infl uences, and harmful marine life. These are important issues that dramatically affect human health, but at the same time this view does not refl ect the fact that we are just now realizing some of the health-related benefi ts from the oceans. Comprising 34 of the 36 Phyla of life, marine ecosystems are indeed our last genetic diversity and biotechnological frontier; terrestrial systems possess only 17 Phyla. We have much to learn. Humankind has explored and exploited the terrestrial environment for more than 3000 years, leading to the examination of almost every possible resource on land. In the future, similar explorations of the world’s oceans, using modern chemical and molecular genetic technologies, will uncover a rich treasure chest of new medicinal products, cosmetics, foods, industrial chemicals, and new, environment-friendly industrial processes. As we have benefi ted from life on land, it is reasonable to predict that the next few decades will be fi lled with new discoveries from our greatest untapped resource, the world’s oceans. In this short synopsis, I will attempt, admittedly in a non-comprehensive way, to summarize the past and current status of marine medicine, and to emphasize the important role the oceans will play in human medicine in the decades to come. NATUR AL PRODUCTS AND THE TREATMENT OF HUMAN DISEASE More than 3000 years ago, early societies recognized that the diversity of plant life around them could be used for the treatment of human illness. Natural “preparations,” in the form of teas or salves derived from plants, were commonly used to treat pain, infections, gastrointestinal maladies, infl ammation, cancer, and many other common illnesses. Traditional healers evolved who were consulted to treat illness, and the knowledge of these individuals was passed down to understudies or apprentices who continue to practice today. Today, for economic as well as traditional reasons, much of the developing world still relies on natural medicines (e.g., ethnomedicines or traditional medicines) for the treatment of human disease. Over time, the “active ingredients” from traditional medicines were chemically purifi ed, and during the 19th and 20th centuries some of these drugs (e.g., morphine, quinine, the salicylates [aspirin]) were utilized in single-ingredient formulations (i.e., “drugs”). As time passed, these molecules became the foundation of the new discipline of organic chemistry. The developing pharmaceutical industries evolved to focus their efforts on purifying new drugs from these traditional ethnomedicines (Therapeutic Research Faculty, 2006). The discovery of penicillin in the late 1920s by Alexander Fleming was perhaps the single most important medical discovery in modern times. This, and subsequent discoveries by Selman Waksman (i.e., actinomycin and other antibiotics) and other researchers, changed how drugs were discovered and how Nature was explored (Bérdy, 2005). The pharmaceutical industry, worldwide, quickly evolved by embracing these fi ndings, and subsequently discovered hundreds of “wonder drugs” that had the capability to cure pneumonia and almost all bacterial infectious diseases. These natural “wonder drugs” saved millions of lives during and after World War II, and gave us the false sense that the great plagues of the past (e.g., cholera) would never again be seen (see Laws case study, this issue). More than 120 antibiotics, anticancer agents, and other therapeutics originally derived from microorganisms that are found in soil are still prescribed today. DISCOVERY OF THE OCEANS IN THE 1960s THE PAST It is interesting to note that, historically, the oceans were rarely considered as a likely source for natural medicines. In southern China, a poorly described marine ethnomedicine evolved, but this approach was not generally seen elsewhere. Despite biologists exploring life in the oceans in the 18th and 19th centuries, the linkage of medicine and marine biodiversity was never made. Even in more modern times, the pharmaceutical industries made little effort to examine life in the sea. This is understandable because the ocean was virtually unknown, and diffi - cult and dangerous to explore, while new drugs from terrestrial plants, and later soil microorganisms, were plentiful. As a consequence, the enormous resources of the oceans lay dormant until the mid to late 1960s when small groups of organic chemists in the United States, Europe, and Japan began to collect, extract, and chemically explore the diversity of marine life. Pioneers like Paul Scheuer and Richard Moore in the United States, Luigi Minale and Ernesto Fattorusso in Italy, and a small group of Japanese researchers (who were already the Oceanography Vol. 19, No. 2, June 2006 111
leaders in marine toxin research),began marine organisms.Their goal was to carbonimidic dichlorides(Wratten and to examine sponges,marine algac,and fully comprehend the sources of these Faulkner,1977)and molecules of un- other unfamiliar forms of marine life molecules and the extent to which these precedented size and complexity,such as To their great surprise.new molecules new compounds were different from the polvether toxin brevetoxin-B (Lin et of unprecedented types were found those produced by terrestrial plants and al,1981),were isolated and identified (Faulkner.2000a.2000b).The struc- microorganisms.Chemical structures The new field of marine natural prod- tures of entirely new chemical entities were found that pletely changed the ucts chemistry had been initiated with a which challenged accepted biosynthetic foundations of natural-product biosyn- resounding success understanding,were published at an im- thesis.Perhaps to be kDected.the halo- In the beginning,financial support pressive rate.These pioneering chemical gens(i.e.,iodi and chlorine, to expand this entirely new and explor researchers.who were amateur biolo- but not fluorine)were found to play atory science was yery difficult to obtain gists at best,found that marine animals prominent roles, ly a ent Ocean scientists asked why this was be- possessed a rich new chemistry that had in complex molecule but also by act- ing done?But the chemists,who were never been seen before.It then became ng as reactants(in halocyclization reac- largely not trained as marine scientists clear that the oceans were indeed a new tions,for example)to create entirely new and exciting resource (Figure 1). classes of terpenoids and other structure William Fenical (wfenical@ucsdedu)is classes of bioactive molecules(Figure 2). Director Center for Marine Biotechnolog THE "EXPLORATORY DECADE' In a mere ten-year span,the complex- and Biomedicine and Professor of Ocean During the 1970s,small groups of chem- ity of terpenoid biosynthesis was more ography.Scripps Institution of Oceanogra- ists continued to explore the amazing than doubled!Molecules possessing un phy,University of California San Diego,La diversity of novel molecules present in precedented functional groups such as Jolla,CA,USA. nderwater photo e and plan Figure 2.The widely distributed red seaweed Laurencia was the first to b ognized as a robust sourc per square meter. ing enzymes.Laurinterol (shown)was the first brominated terpene to be olated(1968】 112 Occanography I Vol 19,No.2.June 2006
112 Oceanography Vol. 19, No. 2, June 2006 Figure 2. Th e widely distributed red seaweed Laurencia was the fi rst to be recognized as a robust source for halogenated natural products. Th is and related seaweeds produce a diversity of halogenated compounds (some with 5–6 bromine and chlorine atoms) by processes involving halogenating enzymes. Laurinterol (shown) was the fi rst brominated terpene to be isolated (1968). leaders in marine toxin research), began to examine sponges, marine algae, and other unfamiliar forms of marine life. To their great surprise, new molecules of unprecedented types were found (Faulkner, 2000a, 2000b). The structures of entirely new chemical entities, which challenged accepted biosynthetic understanding, were published at an impressive rate. These pioneering chemical researchers, who were amateur biologists at best, found that marine animals possessed a rich new chemistry that had never been seen before. It then became clear that the oceans were indeed a new and exciting resource (Figure 1). THE “EXPLOR ATORY DECADE” During the 1970s, small groups of chemists continued to explore the amazing diversity of novel molecules present in marine organisms. Their goal was to fully comprehend the sources of these molecules and the extent to which these new compounds were different from those produced by terrestrial plants and microorganisms. Chemical structures were found that completely changed the foundations of natural-product biosynthesis. Perhaps to be expected, the halogens (i.e., iodine, bromine, and chlorine, but not fl uorine) were found to play prominent roles, not only as substituents in complex molecules, but also by acting as reactants (in halocyclization reactions, for example) to create entirely new classes of terpenoids and other structure classes of bioactive molecules (Figure 2). In a mere ten-year span, the complexity of terpenoid biosynthesis was more than doubled! Molecules possessing unprecedented functional groups such as carbonimidic dichlorides (Wratten and Faulkner, 1977) and molecules of unprecedented size and complexity, such as the polyether toxin brevetoxin-B (Lin et al., 1981), were isolated and identifi ed. The new fi eld of marine natural products chemistry had been initiated with a resounding success. In the beginning, fi nancial support to expand this entirely new and exploratory science was very diffi cult to obtain. Ocean scientists asked why this was being done? But the chemists, who were largely not trained as marine scientists, William Fenical (wfenical@ucsd.edu) is Director, Center for Marine Biotechnology and Biomedicine and Professor of Oceanography, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA. Figure 1. Close-up underwater photograph of the invertebrate and plant diversity typically observed on coral reefs. Diversity can reach 1000 species per square meter
knew that they had uncovered an amaz- ingly complex new science,one that would ultimately explain much of the ecology of marine life.In the funding arena,the National Sea Grant Program (United States)was a clear exception. The founders of this program,who had the wisdom to envision the discovery of marine drugs,were rewarded by the huge successes that were subsequently achieved.Later,the Divisions of Chem- istry and Ocean Sciences at the U.S National Science Foundation became involyed,showing an interest in this new and developing field of study.No one knew where this was going,but ev- eryone saw the potential for the future. Beginning in the early 1980s,a new component of marine ecology."marine chemical ecology,"was established by small group of scientists who used this chemical knowledge base to demon- strate that bioactive molecules produced e 3.The C sea whip.Pseudo by(mainly)soft-bodied marine plants ins (shov wn)which po and animals are the foundation of ar Lauder,in collaboration with California Sea Grant researchers,developed these agents as skin care ad- elaborate strategy of chemical defense and communication in the ocean(Hay 1996,2002). COULD THESE MOLECULES BE DRUGS?CONNECTIONS continued to be seen. a marine source.During this same pe- WITH INDUSTRY AND With the help of Estee Lauder scien riod,both the National Cancer Institute PHARMACOLOGY tists,Sea Grant researchers in Califor (NCI)and many researchers began to see On the basis of the recognized "prom- nia developed a new skin-care additive the promise of the marine environment ise of the sea,"many researchers in the “pseudopterosins”from the Caribbean in the treatment of cancer.The NCI had mid to late 1980s began to see how the sea whip Pseudopterogorgia elisabethae undertaken a screening program ten complex chemistry from the marine en- (Figure 3)(Look et al,986).This prod- vears earlier,and they were finding that vironment could be applied to improv- uct,still in use today,dramatically reduc marine samples provided the highest ing human health.Academic researchers es the allergenic responses of skin lotions botential for anticancer drug discovery probed industry,seeking collaborations to some individuals and provides strong Evidence that this would utimately bea and approached the national Institutes anti-inflammatory properties.This successful endeavor came from the sub of Health (NIH)to support these devel product was perhaps the first cinically equent isolation of a broad structural oping studies.Although slow,successes validated"cosmeceutical"derived from diversity of more than 500 molecules Occanography I Vol 19.No.2.June 2006 113
Oceanography Vol. 19, No. 2, June 2006 113 knew that they had uncovered an amazingly complex new science, one that would ultimately explain much of the ecology of marine life. In the funding arena, the National Sea Grant Program (United States) was a clear exception. The founders of this program, who had the wisdom to envision the discovery of marine drugs, were rewarded by the huge successes that were subsequently achieved. Later, the Divisions of Chemistry and Ocean Sciences at the U.S. National Science Foundation became involved, showing an interest in this new and developing fi eld of study. No one knew where this was going, but everyone saw the potential for the future. Beginning in the early 1980s, a new component of marine ecology, “marine chemical ecology,” was established by a small group of scientists who used this chemical knowledge base to demonstrate that bioactive molecules produced by (mainly) soft-bodied marine plants and animals are the foundation of an elaborate strategy of chemical defense and communication in the ocean (Hay, 1996, 2002). COULD THESE MOLECULES BE DRUGS? CONNECTIONS WITH INDUSTRY AND PHARMACOLOGY On the basis of the recognized “promise of the sea,” many researchers in the mid to late 1980s began to see how the complex chemistry from the marine environment could be applied to improving human health. Academic researchers probed industry, seeking collaborations, and approached the National Institutes of Health (NIH) to support these developing studies. Although slow, successes continued to be seen. With the help of Estee Lauder scientists, Sea Grant researchers in California developed a new skin-care additive “pseudopterosins” from the Caribbean sea whip Pseudopterogorgia elisabethae (Figure 3) (Look et al., 1986). This product, still in use today, dramatically reduces the allergenic responses of skin lotions to some individuals and provides strong anti-infl ammatory properties. This product was perhaps the fi rst clinically validated “cosmeceutical” derived from a marine source. During this same period, both the National Cancer Institute (NCI) and many researchers began to see the promise of the marine environment in the treatment of cancer. The NCI had undertaken a screening program ten years earlier, and they were fi nding that marine samples provided the highest potential for anticancer drug discovery. Evidence that this would ultimately be a successful endeavor came from the subsequent isolation of a broad structural diversity of more than 500 molecules Figure 3. Th e Caribbean sea whip, Pseudopterogorgia elisabethae (Gorgonaceae), contains the pseudopterosins (shown) which possess potent topical anti-allergenic and anti-infl ammatory properties. Estee Lauder, in collaboration with California Sea Grant researchers, developed these agents as skin care additives. Th e fi rst application was in their “Resilience” cosmetic line. Photo courtesy V.J. Paul, Smithsonian Institution Marine Laboratory, Fort Pierce, Florida
that had the ability to inhibit the growth mind,society now places exceptionally oceans best serve human medicine? of cancer cells at sub-micromolar con strong demands on drug safety and ef- Over the past ten years,the oceans centrations.These highly bioactive mol- ficacy.As a consequence,many of the have provided exciting medical dis- ecules came mainly from sponges,ascid- drugs developed in past years would not coveries that are now yielding drugs ians,and bryozoans,classes of marine survive today's high-level expectations. The first marine drug wasZiconotid invertebrates that are now recognized Drug resistance in the treatment of can- (Pralt),a potent pain medication as the most chemically prolific of all the cer and infectious diseases isemerging that was developed based upon knowl- marine animal groups(Figure 4). at a frightening rate,just when the phar- edge of the highly toxic small peptide maccutical industries are turning away 0-conotoxin mVIlA extracted from the DISCOVERIES AND from some of these areas,only to focus venomous gastropod mollusk Conus successes-cuRrent their attention on the development of magus (Figure 5)(Olivera et al,1987). Many natural products were developed "block-buster drugs"(sales in excess of Ziconotide,a potent calcium channel into medicines in the mid 20 century. $2 billion)in therapeutic areas requiring blocker,is the only drug in this class of but the challenges and difficulties to do chronic treatment over a lifetime.Ex- agents that provides relief from severe so now have dramatically changed.In plorations for new anti-infective agents, neurogenic pain.Although this is the the 214 century,we live in a more com- especially antibacterial drugs,have all first marine drug generally recognized, plex world in which diseases are comple but ceased.Given these new realities, in the 1950s,Werner Bergman and resistant to cures.With the past in how can the biomedical potential of the in marine sterol chemistry,isolated two Figure4.An underwater photo of theascidian Ecteinasdi turbinata grow (shown)a powerful anticancer agent currently in advanced rials. is currenty marketed for intense pain under the trade are in ake City.Utah. 114 Oceaography I Vol 19,No..June 2006
114 Oceanography Vol. 19, No. 2, June 2006 that had the ability to inhibit the growth of cancer cells at sub-micromolar concentrations. These highly bioactive molecules came mainly from sponges, ascidians, and bryozoans, classes of marine invertebrates that are now recognized as the most chemically prolifi c of all the marine animal groups (Figure 4). DISCOVERIES AND SUCCESSESCURRENT Many natural products were developed into medicines in the mid 20th century, but the challenges and diffi culties to do so now have dramatically changed. In the 21st century, we live in a more complex world in which diseases are complex and resistant to cures. With the past in mind, society now places exceptionally strong demands on drug safety and ef- fi cacy. As a consequence, many of the drugs developed in past years would not survive today’s high-level expectations. Drug resistance in the treatment of cancer and infectious diseases is emerging at a frightening rate, just when the pharmaceutical industries are turning away from some of these areas, only to focus their attention on the development of “block-buster drugs” (sales in excess of $2 billion) in therapeutic areas requiring chronic treatment over a lifetime. Explorations for new anti-infective agents, especially antibacterial drugs, have all but ceased. Given these new realities, how can the biomedical potential of the oceans best serve human medicine? Over the past ten years, the oceans have provided exciting medical discoveries that are now yielding drugs. The fi rst marine drug was Ziconotide (Pralt™), a potent pain medication that was developed based upon knowledge of the highly toxic small peptide ω-conotoxin MVIIA extracted from the venomous gastropod mollusk Conus magus (Figure 5) (Olivera et al., 1987). Ziconotide, a potent calcium channel blocker, is the only drug in this class of agents that provides relief from severe neurogenic pain. Although this is the fi rst marine drug generally recognized, in the 1950s, Werner Bergman, a pioneer in marine sterol chemistry, isolated two Figure 4. An underwater photo of the ascidian, Ecteinascidia turbinata, growing on hanging mangrove prop roots. Th is animal contains ecteinascidin 743 (shown), a powerful anticancer agent currently in advanced clinical trials. Figure 5. Th e cone snail, Conus magus, produces the potent analgesic peptide ω-conotoxin MVIIA (or ziconotide, shown). A synthetic version of this peptide is currently marketed for intense neurogenic pain under the trade name Prialt™. Mollusks of the genus Conus produce numerous highly bioactive peptides that are in clinical trials for pain relief and treatment of asthma and Alzheimer’s Disease. Photo courtesy B. Olivera, University of Utah, Salt Lake City, Utah