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5 Opportunities for Medicines The marine ecosystem has been a tremendous resource of novel chemistries, many of which have successfully been translated into or have inspired new medicines. This chapter presents an overview of products that have originated from the marine environment. The presenter cautions that future development of pharmaceutical products may be compromised by ecosystem stressors such as overfishing and selective fishing, and increased ocean acidification and nitrification. CURRENT AND EMERGING OPPORTUNITIES AND CHALLENGES FOR PHARMACEUTICALS FROM THE SEA William H. Gerwick, Ph.D. Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego William H. Gerwick began by noting that the discovery and production of medicines and other natural products is an often overlooked but highly critical ecosystem service and is closely linked to the biodiversity function discussed elsewhere in the workshop. He then outlined the main questions in his discussion about the search for pharmaceuticals from the sea: • Why are new pharmaceuticals needed? • Are oceans a productive source of new medicines? • Are there examples of research and drug discovery from the sea? • Will environmental stressors affect drug discovery from the sea? 75

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76 ECOSYSTEM SERVICES AND HUMAN HEALTH The Need for New Pharmaceuticals Cancer is one of a number of diseases that are ineffectively treated by current medications. Although we see reductions in breast, bronchial, colorectal, lung, stomach, and uterine cancer in women—due to modifi- cations to behavior like smoking, refrigeration of foods, and early screening—there are other cancers that are increasing over time, and currently cancer is the cause of one in four deaths for both men and women (Siegel et al., 2012). There are many other types of diseases that are poorly treated, such as microbial infections. Staphylococcus aureus, for example, has gone from being a highly sensitive strain to an increasingly drug-resistant strain (methicillin-resistant S. aureus that is now encountered in the community as well as in hospitals). It is a danger to population health, and current pharmaceuticals do not work effectively against the infection (Chambers and DeLeo, 2009). New pharmaceuticals are needed to treat these types of resistant organisms, Gerwick said. New methods for their application are needed as well because the same problem will recur if antibiotics continue to be used in the way they have in the past. Also newly emergent diseases, particularly viral diseases, are being transmitted from wild animal populations to human populations and giving rise to various diseases such as AIDS and many others. As humans continue to erode the natural habitat, there will be more contact with wild animals and an increased risk of viral diseases in the wild animal population transmitted to human populations. Pharmaceuticals are derived from diverse sources, Gerwick explained. Of 1,355 new approved drugs spanning the period 1981 to 2010, about 26 percent were derived from natural products. A growing number of pharmaceuticals, about 21 percent, come from biologics or vaccines. Just over half of pharmaceuticals are synthetic drugs, but it can be seen that in many cases the synthetic chemist has looked to nature for an aspect of a molecule and then embedded this special feature into another molecule of synthetic origin, which now has the needed pharmaceutical properties. In this way, a majority of pharmaceuticals are in some sense natural product derivatives or inspired by natural products (Newman and Cragg, 2012).

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OPPORTUNITIES FOR MEDICINES 77 The Oceans Are a Prod s ductive Sourc of New Me ce edicines Th marine env he vironment and its unique l forms, wi their myri d life ith iad colors and shapes and sizes and adaptations to underwater life, have be a o r een a tremmendous reso ource of nov chemistr vel ries, many o which ha of ave successsfully been translated in new med nto dicines. Gerwwick mention ned nine marine natural products, de m l erivatives, or inspired agen approved b nts by the U.S. Food and Drug Admin nistration (FD or Europ DA) pean Medicin nes Agenc (EMEA) (s Figure 5-1). For exam cy see mple, there is a series of pu ure nucleoosides derivin from spon ng nges which h given rise to three ve has e ery useful anticancer ag gents and one antiviral ag ent. Then, there is a pepti e ide used by the cone snail to pr b e rey on fish, which has been used in medica ations for trea atment of chrronic pain tha is no longe responsive to at er opioid These and many other new drugs lo to nature for inspiratio ds. n ook on. Gerwick pointed ou that the suc ut ccess record o marine natu products in of ural this field, namely one drug pe 2,450 com er mpounds, is s times mo six ore producctive than the industry stan ndard (Gerwic and Moore 2012). ck e, FIGUR 5-1 Nine marine natura products, d RE al derivatives, or inspired agen nts approv by the U.S Food and Drug Administ ved S. D tration or Euroopean Medicinnes Agencyy. SOURC Gerwick and Moore, 201 Reprinted w permissio from Elsevie CE: a 12. with on er.

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78 ECOSYSTEM SERVICES AND HUMAN HEALTH Examples of Current Research and Drug Discovery Process Gerwick then turned to one of the current subjects of study at his laboratory—marine cyanobacteria, which are very ancient and very abundant organisms, very rich in structurally diverse bioactive natural products, with a lot of genetic capacity, making them very useful to the laboratory. He stressed that not only is the chemistry of the organism studied and preserved, but also the DNA—science is increasingly moving into the genetics of natural products biosynthesis. Gerwick noted that the process of drug discovery from marine algae and cyanobacteria supports multiple collaborations—in the private sector, in the government, in universities, and internationally. Many important new drugs will be developed through the study of the biosynthetic process. The areas of highest biodiversity—on both land and sea—are concentrated on the tropic belt, where plants and animals are all competing to harvest sunlight and to access nutrients. This very competitive environment seems to encourage the production of biologically active molecules. Gerwick described the collection of cyanobacteria and other organisms from the mangrove swamps in Curaçao, and remarked on the danger of infectious disease the researchers encountered in these places, but stressed that important drugs have resulted from these efforts, including a very powerful anticancer drug. Gerwick described the technical aspects of the biosynthetic processes that go into discovering new natural product structures that are useful in the development of drugs. The team took a cancer cell line assay to guide the isolation of a couple of molecules and, by using their standard techniques, came up with some novel structures, which had exactly the same configuration of epoxy ketones as a class of drug just entered into the market—a very powerful anticancer drug. Then, having created a chemical synthesis for this compound, they were able to use that process to make about 12 additional analogue structures. In studying these molecules, they learned that some had very high potency at killing cancer cells and some were inactive, which demonstrated structure activity relationships in this drug class. Gerwick continued onto a different area of science involving the study of how the compound binds with an enzyme. This particular compound binds in a way unlike any of the other drugs in this class, revealing new ways to interact with the human proteasome, which is a very effective drug target. The human proteasome is a protein degradation “machine” in cells that breaks down proteins. It is a very good target for anticancer

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OPPORTUNITIES FOR MEDICINES 79 therapy, and a targe for many other therapie There is a possible use in et o es. neurollogical disordders, said Geerwick, descr ribing an exp periment using very low concentr l rations of the analogue u e under study, which caus sed neuron to develop neurite proje ns p ections, becooming highly branched. Th his could offer a thera for various conditions such as str apy s roke and spin nal cord innjury. Gerwic suggested that this mol ck lecule class h promise f has for both cancer and the neuroscience e es. Geerwick then described expeditions in Papua, New Guine ea, harvessting cyanobaacteria. The Papuan sampl exhibit an exotic-looking P les n cyclic molecule, which has som very exce w me eptional cytot toxic activitiees, with profound can p ncer cell toxicity. An ex xperiment adm ministering t the compo ound in cance research is showing muc promise. T structure of er ch The the moolecule has in nspired a grea deal of int at terest, Gerwic said, and h ck his researc team is co ch onducting furrther study on the subject He describ n t. bed the meethod for deriiving pure cul ltures of the bbacteria from environmental m sample They were eventually successful in isolating the cyanobacter es. e e ria, and th proceeded to sequence much of th genome of the organism hen d e he f m, finally succeeding in describing the entire bi y g iosynthetic ge cluster (s ene see Figure 5-2). The process is an astonish e hing examp ple of mode ern technoology, which has captured the imaginat tion of many— —this might be a way of harnessi y ing the pow of the ce a pathw wer ell; way toward t the manuf facture of new molecules, Gerwick said w G d. FIGUR 5-2 Apratoxin A cluster annotation and proposed prod assembly. RE a duct SOURC Grindberg et al., 2011. Reprinted with permission. CE: g R

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80 ECOSYSTEM SERVICES AND HUMAN HEALTH How Will Environmental Stressors Affect Our Ability to Discover New Pharmaceuticals from the Sea? Gerwick then moved to environmental stressors and their impact on the discovery of new pharmaceuticals from the sea. He noted several issues, including • overfishing, • selective fishing (removal of apex predators), • nutrient inputs, • climate change in ocean, and • ocean acidification. Human activities have dramatically altered species composition in tropical reefs, said Gerwick, taking as an example the Northern Line Islands (a chain of atolls and islands in the Pacific). The islands get progressively more and more inhabited, going from the uninhabited Kingman reef south to Christmas Island (population of 5,500+). In the north islands, the researchers were surprised to find that the majority of the biomass consisted of large predators, such as snappers, sharks, turtles, and dolphins. Gerwick noted that the expected food pyramid— large amounts of small species on the bottom supporting small amounts of large predators on the top—was turned upside down in this instance. The majority of the biomass in these uninhabited areas was in the large predators: there was little algal biomass, a few herbivorous fish, a few more of the small carnivores, but most of the biomass was resident in the large predators. However, as one goes down toward Christmas Island, the number of large predators grows less and less. There are substantial inputs of nutrients into the ocean from human population at Christmas Island, which correlates directly with increasing cover of algae and decreasing coral cover, leading to a very degraded environment at Christmas Island. However, Gerwick noted that, ironically, this degraded environment supports a rich complement of cyanobacteria—the source of the inspirational molecules that he had discussed earlier (Sandin et al., 2008). Gerwick next touched on the effect of ocean acidification (a product of climate change) on natural products, using the example of an experi- ment studying the production of secondary metabolites in cyanobacteria under different levels of acidification. They hypothesized that ocean acidification may modulate the growth and toxicity, and that such alterations could have substantial environmental impacts, as well as affect drug

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OPPORTUNITIES FOR MEDICINES 81 discovery efforts. They found that as the pH levels became more acidic, there was a destruction of the cellular structures, a decrease in biomass, and a substantial decrease in the production of the natural products they were tracking. Gerwick stressed that this was a small study, and incomplete, but that a preliminary conclusion might be that ocean acidification may decrease growth in natural products production from marine cyanobacteria, thereby decreasing their competitiveness, as well as opportunities for drug discovery. Gerwick closed his presentation by opining that, both historically and currently, nature is the best source of inspiration for the discovery of new pharmaceutical agents, and that turning away from this caused some significant problems in the pharmaceutical pipeline, now remedied by a return to natural products. Further, he stated that the integration of innovative methods in natural products chemistry is enhancing and accelerating our exploration of the chemical and biosynthetic capacities of marine life, and that this is a vigorous and multidisciplinary field which holds great promise. He noted that the marine environment is rapidly changing due to human activities. Further, we have only a fragmentary knowledge of human impacts on the adaptations of marine life to their habitats and, ultimately, their success as species. Our health, he said, as realized through new pharmaceuticals from the sea, is intimately tied to ocean health, and it is in our best interest to maintain it. REFERENCES Chambers, H. F., and F. R. DeLeo. 2009. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nature Reviews Microbiology 7(9):629–641. Gerwick, W. H., and B. H. Moore. 2012. Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chemistry & Biology 19(1):85–98. Grindberg, R. V., T. Ishoey, D. Brinza, E. Esquenazi, R. C. Coates, W. Liu, L. Gerwick, P. C. Dorrestein, P. Pevzner, R. Lasken, and W. H. Gerwick. 2011. Single cell genome amplification accelerates identification of the apratoxin biosynthetic pathway from a complex microbial assemblage. PLoS ONE 6(4):e18565, doi:10.1371/journal.pone.0018565. Newman, D. J., and G. M. Cragg. 2012. Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of Natural Products 75(3):311–335.

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82 ECOSYSTEM SERVICES AND HUMAN HEALTH Sandin, S. A., J. E. Smith, E. E. DeMartini, E. A. Dinsdale, S. D. Donner, A. M. Friedlander, T. Konotchick, M. Malay, J. E. Maragos, D. Obura, O. Pantos, G. Paulay, M. Richie, F. Rohwer, R. E. Schroeder, S. Walsh, J. B. C. Jackson, N. Knowlton, and E. Sala. 2008. Baselines and degradation of coral reefs in the Northern Line Islands. PLoS ONE 3(2):e1548, doi:10.1371/journal.pone.0001548. Siegel, R., D. Naishadham, and A. Jemal. 2012. Cancer statistics, 2012. CA: A Cancer Journal for Clinicians 62(1):10–29.