Advancing medicine and treating or preventing chronic illness is tied to the environment in more ways than one. Specifically, working with the overall health of the oceans can lead to opportunities for "bio prospecting" and tapping into underused and under-investigated resources for the benefit of better medicine.

1. Protecting Ocean Regions with Robotics
“How medical breakthroughswillcome fromthe oceanandtransformfuture medicine”
1 INTRODUCTION
1.1 INCREASING BURDEN OF CHRONIC ILLNESS ANDEVER-AGING GLOBAL POPULATION
Withthe ever-agingglobal populationandthe growingburdenof chronicillness,there isanincreased
reliance onthe healthcare system(particularlythe biopharmaceutical industry) inorderorone to
achieve andsustainahigh qualityof life.Accordingtothe WorldHealthOrganization(WHO),the burden
of humandiseaseshave beenrapidlyincreasingfordecadeswiththistrendpredominantlycontributed
by populationgrowthandenvironmental degradation.
1.2 DEFINITION OFMARINE BIOPROSPECTING
Marine bioprospectingisthe searchfornovel compoundsfromnatural sourcesinthe marine
environment.These activitieshave increasedagreatdeal inthe lastfew yearslikelyinpartdue to the
continuedtechnological advancesenablingfurtheroceanicexploration,acknowledgementof the rich
genericdiversityinthe marine biome,aswell asthe pressure fromindustrytoproduce givenvarious
blockbusterdrugsgoingoff patent.Today,about18,000 natural productshave beenreportedfrom
marine organismsbelongingtoabout4,800 namedspecies.The numberof natural productsfrom
marine speciesisgrowingata rate of 4% per year.The increase inthe rate of discoveriesislargelythe
resultof technological advancesinexploringthe oceanandthe geneticdiversityitcontains.Advancesin
technologiesforobservingandsamplingthe deepocean,suchassubmersiblesandremotelyoperated
vehicles(ROVs),have openeduppreviouslyunexploredareastoscientificresearch.Since 1999,the
numberof patentsof geneticmaterial frommarine specieshasincreasedatthe rate of 12% per year.
Marine speciesare abouttwice as likelytoyieldatleastone gene inapatentthantheirterrestrial
counterparts.Bioprospectingtypicallyrequiresthe collectionof averylimitedamountof biomassfor
the initial discovery.Althoughfurthercollectionsmaybe requiredafterapromisingdiscoveryhasbeen
made,bioprospectinggenerallydoesnotinvolve threatstobiodiversitycomparable tothe large biomass
removalsinvolvedinharvestingresourcesforfoodormineral exploitation.
1.3 THE SUCCESSOF NATURAL COMPOUNDS IN DRUG DISCOVERYAND BIOPHARMACEUTICAL BACK
DROP
Biopharmaceuticalsare one of the mostimpressive achievementsof modernscience.Many
biopharmaceuticalsofferhighefficacyandfew side effects.Andthere ismuchmore tocome:radically
newconceptsare makingit to the market,andthe advanceskeepcomingata rapidpace. The successof
natural compoundsindrug discoveryisunparalleled:forantimicrobialandanticancertherapies,for
example,more than70%of newchemical entitiesintroducedduringthe period1981–2002 originated
fromnatural products.Ithas beenestimatedbythe USNational CancerInstitute (NCI)that1% of
samplesfrommarine animalstestedinthe laboratoryreveal anti-tumorpotential (whichcompares
favorablywithjust0.01% of samplesof terrestrial origin).Inthe lastfew decades,advancesin

2. informatics,automationandimagingtechnologyhave made itpossible toscreen100,000s – 1,000,000s
of small moleculesagainstaspecificbiological targetorcellularassayperday,comparedwith10s-100s
of compoundstestedonanimalsovermanymonthspreviously.Growingawarenessof the limitationsof
historicallyvaluableapproaches,andbreakthroughsinroboticstechnologies,suchasthose usedin
separation andstructure determination,have made screeningmixturesof structurallycomplexnatural
productmoleculeseasier,andhave expandedthe potential roleof natural chemical diversityinthe drug
discoveryprocess
2 THEOPPORTUNITY
2.1 AUSTRALIA CONTEXT
Australiaisone of only17 mega-diverse countriesinthe worldandisrenownedforthe uniquenessof its
biota.Australiahasseveral featuresprovingattractive toinvestorsandresearchersinthe natural
productsarea. Thisincludes,notleast,accesstoa diverse andunique biota.More generally,the
featuresof Australiaconducivetoresearchandcommercial activityincludeitsrobustsystemof lawand
stable democraticsystemof government,itsstable andresilienteconomy,transparentandefficient
regulatoryenvironment,comprehensiveintellectual propertyprotectionsandhighscientificand
technological capacity.Australiahasremainedrelativelyisolatedovertime comparedtomostcountries.
Consequently,Australiahasa highproportionof endemicspecies–thatis,speciesnotoccurring
naturallyelsewhere.Forexample,inthe case of mammals,approximately83% are endemictoAustralia.
Australia'sunique marineenvironmentcontainsthe world'slargestareasandhighestdiversityof
tropical and temperate seagrassspeciesandof mangrove species;some of the largestareasof coral
reefs;exceptionallevelsof biodiversityforawide range of marine invertebrates;anditisestimatedthat
around80% of the southernmarine speciesoccurnowhere elseinthe world.Withonly0.3% of the
world'spopulation,Australiacontributes2.5% of the world'smedical researchand2.9% of global
scientificpublications(InvestAustralia,2007, p.6).In 2005, Australiarankedeighthinthe OECDinterms
of the proportionof researchersinthe total laborforce.Thisisabove the OECD average.Ona percapita
basis,Australiahasa researchoutputtwice the OECD average.Intermsof biotechnologyresearch,
Australiahasseveral dedicatedbiotechnologyresearchinstitutes.Australia'sbiotechnologyindustryis
steadilygrowing,withactivityacrossbiotechnologyfieldsincludingbiomedicine,agricultural
biotechnology,industrialbiotechnologyandenvironmentalbiotechnology.The AustralianGovernment
isa staunchadvocate of the domesticpharmaceuticalindustryandhasbeenverysupportive in
implementinginitiativestogrowthissector.By any measure,AustralianGovernmentsupportfor
researchand developmentinthe biopharmaceutical industryhasbeenandlookstocontinue to be
strong.
2.2 MARINE BIOME REMAINS UNTAPPED/UNDER-INVESTIGATED—THUSPROSPECTSFOR NEWAND
MEANINGFUL FINDINGS ARE SIGNIFICANT
Today,biopharmaceuticalsgenerateglobal revenuesof $163 billion,makingupabout20 percentof the
pharma market.It’sbyfar the fastest-growingpartof the industry:biopharma’scurrentannual growth
rate of more than 8 percentisdouble thatof conventional pharma,andgrowthisexpectedtocontinue
at that rate forthe foreseeablefuture.Marine bioprospectinghasthe potential tofurtherdrive these

3. trends.The marine biome remainsuntappedandunderinvestigated,andthus,perfectlypoisedtodrive
bothtopline andbottomline formultiplestakeholdersinthe biopharmavaluechain. Investingin
biotechR&D hasyieldedbetter returnsthanthe pharma-industryaverage.The currentbiologics-
developmentpipeline supportsanoutlookof continuedhealthygrowth.The numberof biotechpatents
appliedforeveryyearhasbeengrowingat25 percentannuallysince 1995. There are currentlymore
than 1,500 biomoleculesundergoingclinicaltrials,andthe successrate forbiologicshassofar beenover
twice thatof small-molecule products,with13 percentof biopharmaproductsthatenterthe Phase I
trial stage goingon to launch.To date, samplingof marine productshasprimarilyoccurredineasy-to-
reach coastal waters.Asa result,97%of natural productsof marine originare fromeukaryoticsources
(organismswithcomplexcells),withspongesaloneaccountingfor38% of the products.However,the
majorityof the Earth's metabolicdiversityresidesinprokaryoticorganisms(single-celledorganismssuch
as bacteria) andover99% of the microbial communityof the oceanremainstobe explored,soitstands
to reasonthat manymore geneticsequencesvaluable forproductsare yetto be discovered.There isa
particularinterestinmarine speciesthatlive inextreme environments,suchashydrothermal ventsand
seamounts(‘extremophiles’).Bythe endof 2007, only10 compoundshadbeenreported fromDeep
Oceanand oceantrench environments,withafurthersevenidentifiedin2010. Fewerthan10 marine
natural productshave so far beenreportedfromhotventbacteria.Furthermore,if we breakdownthe
variousecosystemsof ourseasandoceansand compare the chemical dynamics,coral reefshave
particularlyimpressivepotential.The coralsthatwe see are actuallymade upof coloniesthatbuildup
and thrive inan environmentwherenutrientsare low.Althoughcoral reefsonlyoccupy0.1% of the
world’soceansurface,theyare one of the most diverse ecosystemsonearth,hosting~25% of all marine
species.The focusonthe coral reef ecosystemasatarget place formedicinal purposesisnotanew
concept.Asearlyas the 14th century,coral reefswere aknownsource formedicines.One practice at
that time isthe use of fishgall bladdertotreatvenomousstingsfrommarine organisms.Today,coral
reefshave alreadycontributeditsname inthe pharmaceutical industryasone of the source of
biochemical compoundsfornewdrugsandthe possibilitiesare endless.The opportunitymoving
forwardissubstantial.
2.3 SPECIFIC EXAMPLESOF SUCCESSFUL MARINE BIOPROSPECTING
2.3.1 Aplidin
One of the earlybiochemical compoundsderivedfromthe seaisDidemnin,acompoundisolatedforthe
treatmentof certaincancers.Thiscompoundwasobtainedfromthe tunicate Trididemnumsolidum.
Unfortunately,Didemindidnotsurviveinlaterstagesof itsclinical trials.However,afteraseriesof
furtherexploration,arelative of the formerspecieswasdiscoveredtoposessimilartraits.The tunicate
Aplidiumalbicanspossessesthe compoundAplidin® whichhasa similarstructure withDidemninbutfar
lesstoxic.Aplidinisananti-tumor,anti-viral andimmunosuppressive drugthathas beendemonstrated
to be effective inpancreatic,stomach,bladderandprostate cancers.Afterundergoingseriesof clinical
test,Aplidinwasgrantedthe classificationasanorphan drug thatspecificallytreatsmultiple myeloma
and acute lymphoblasticleukemia.Inthe UnitedStatesalone,there are over45,000 people with
multiple myelomaandanestimated15,000 new casesinthe U.S. eachyear.

4. 2.3.2 Yondelis
Yondelis® wasdevelopedbythe PharmaMar Pharmaceutical Companyandwasreleasedinthe market
in2003. Thiscompoundisnow soldbyZeltiaandJohnsonandJohnson.Yondeliscontainsthe active
substance Trabectedin.Trabectedinisderivedfromcoral reefs.Specificallyfromthe filterfeedingsacs
of the small andimmobile plant-like invertebrate calledseasquirts.Extractsof thisreef associated
specieshasbeenfoundtocontaina treatmentforsoft-tissuesarcomaandovarianneoplasmsarcoma.
Yondeliswasdevelopedasaresultof the National CancerInstitute ScreeningProgramformarine plants
and animals.Seaquirtswere collectedfromreefsof WestIndiesandstudiedinthe laboratoryatthe
Universityof Illinois.The anti-cancerbiosyntheticcompoundwasthendiscoveredtobe embeddedin
the symbioticmicroorganismwithinthe seasquirts.Yondelisisproducedinasemi-syntheticmanner,
afterthe extractsfrom the seasquirtsundergoa patentedchemical process.Thisprocessisless
intrusive andlessdemandingtothe natural marine biome.Moreover,eventhoughthe usage of Yondelis
isonlyfor rare medical conditionssuchassarcoma, there isstill potential forthisproducttoadd a lot of
value tothe livesof patientsandotherstakeholders.More andmore adoptingYondelisintheir
prescribingworkflowforsarcomasandthere are an increasingnumberof patientswhoare sensitive to
medicinescontainingplatinumandYondelisisone of the onlyalternative anti-cancermedicines.
2.3.3 Pro Osteon
There are manyindicationsforabone graft implant(e.g.fusionof the spine,jointsinarmsandlegs,
fracturesor gaps inbonescausedbytrauma or infection,oral surgery).Inatypical bone grafting
procedure,asyntheticmaterial isshapedbythe surgeontofitthe affectedareaof the bone while pins
or screwsare usedto holditinplace.Thismaterial buildsasupportstructure where bone cellscan
interlace,regenerate andheal.ProOsteonImplant500 has a porousmicrostructure where new tissues
and bloodcellscangrow,therebystimulatinggrowthandconnectsfracturedbone segments.
Genericallycalled“Bone VoidFiller”andapprovedbythe FDA in 1992, Pro OsteonImplant500 is
clinicallyproventobe safe,strongandcost effective.Thismaterial issterile,therebyminimizingadverse
reactionsfromthe patient’simmune systemrejectingthe implant. The effectivenessof ProOsteon
Implant500 liesinitssource.It usescoralsfromthe seathat has the same porousinterconnected
structure of a typical bone grafttherebymimickingthe internalstructure of ahuman bone.After
undergoingapatentedchemical process,itconvertsthe coral intohydroxyapatitewhichisamineral and
the chief structural elementof a humanbone.Atthisstage,the implantmaterial isnow also
osteoconductivewhichfacilitatesbone cellstoweave intothe porousstructure. Afterthe procedure
and the healingprocessstarts,the ProOsteonImplantwill eventuallybe coveredandreplacedbybones
creatingthe mendedpartas strongas itwas before.ProOsteonhasgreatdemonstratedefficacyanda
safe side-effectprofile.The companymanufacturingthisproductisprojectingatleast$3 billioninsales
by 2017. What’s more,the productionof ProOsteonisnot completelydependentonfarmingand
extractingcoralsfromtheirnatural habitat.Special techniqueshave beendeveloped,whichrequireonly
a small portionof coral to be extracted,whilethe balance isgrownartificiallyinthe lab—thuspromoting
sustainabilityandstabilityof the marine biome.

5. 3 THECHALLENGES
3.1 HOW TO CONSERVE AND SUSTAINABLY USE MARINE BIOLOGICAL DIVERSITY
Despite the factthat marine bioprospectingisrelativelyunimposingandthe practice doesnotimpose
the sustainabilityriskof variousterrestrial techniques,conservationistsandthe publicstill have some
concerns.For one,verylittle isknownaboutthe conservationstatusof manyspeciesusedassourcesof
marine geneticresources.Further,manyspeciesoccurinvulnerableandfragile ecosystems.Manyare
alsoconcernedwithwhatwe don’tknow inthisrelativelynascentsub-industryatthispoint.For
instance,the effectonecosystemsof removal of marine geneticresourcesispoorlyunderstood.
3.2 FEW NATIONSCAN SUCCESSFULLY DOBIOPROSPECTING ON THEIR OWN
Investmentinmarine biotechnologyisnotwithoutrisk.Samplingatseacosts a minimumof US$ 30,000
perday or US$ 1 millionforamonth.It typicallytakes15years overall,andaninvestmentof upto
US$ 1billion,togofromresearchto commercial product,due tothe fact that many productsfail to
deliveronearlypromises.Asaresultthe fieldis dominatedbyrelativelyfew nations.Patentclaims
associatedwithmarine geneticresources(MGR) originate fromonly31countries.Ninetypercentof
these patentsoriginate from10countries(USA,Germany,Japan,France,UK,Denmark,Belgium,
Netherlands,SwitzerlandandNorway),with70% originatingfromthe US,GermanyandJapan. Despite
the highlevelsof investmentrequiredinR&D,biotechnologyisalucrative andimportantindustry.
3.3 THE CURRENT UNCERTAIN AND UNPREDICTABLE LEGAL AND REGULATORY FRAMEWORK
DISCOURAGESINDUSTRY (I.E.BIOPHARM COMPANIES)FROM INVESTING THEIR EFFORTSINTO
BIOPROSPECTING
The potential of marine bioprospectinghasbecome the subjectof internationalpolicydebate
(particularlyforareasbeyondnational jurisdiction).One central quetioniswhetherthe potential
benefitsfrommarine bioprospectingoughttobe sharedby the entire internationalcommunityoronly
by the Statesor individualcorporationswiththe capacitytoexploitthem.Variousgroupsare lookingat
thisinorder to configure the mostsensible setof policiestobalance the needtopromote innovation
and technological/biopharmaceutical advances,withthe needtomake sure all stakeholdersinthe value
chainare appropriatelycompensated,alongwiththe needtoensure the longevityof these natural
marine habitats. Increasingly,individualnation-statesare establishingpoliciesthatdictate the wayin
whichprotectedmarine habitatsintheirjurisdictionmaybe usedforbioprospectingandotherscientific
and commercial pursuits.
3.4 COSTSOF BIOPHARM/BIOTECH DISCOVERY
There are operational andtechnological challengestobioprospectingandbiopharmaceuticaldiscovery
ingeneral.Reproducinglarge moleculesreliablyatanindustrial scale requiresmanufacturing
capabilitiesof apreviouslyunknownsophistication.Considerthis:amoleculeof aspirinconsistsof 21
atoms.A biopharmaceutical molecule mightcontainanythingfrom2,000 to 25,000 atoms(Exhibit1).
The “machines”that produce recombinanttherapeuticsare geneticallymodifiedlivingcellsthatmustbe
frozenforstorage,thawedwithoutdamage,andmade tothrive inthe unusual environmentof a

6. reactionvessel.The necessarysophisticationcomesatgreatcost.Large-scale biotech-manufacturing
facilitiesrequire$200 millionto$500 millionormore to build,comparedwithsimilar-scalesmall-
molecule facilitiesthatmaycost just$30 millionto$100 million,andtheycantake fourto five yearsto
build.Asthe numberof productsrisesandnew processtechnologiessuchascontinuousmanufacturing
are introduced,the complexityof biopharmaoperationsandthe biopharmasupplychainwill increase.
4 THESOLUTION
4.1 HUMAN/ROBOTICS INTERVENTION
First, activitiesatseainsupportof biotechnologyneedtobe distinguishedfromprocessesinthe
laboratory.Commercial expeditionspurelytocollectmarine geneticresourcesare rare to non-existent.
Typically,samplingisconductedonscientificresearchcruises,orbyusingdowntime onROVsusedin
the offshore oil industry.Ocean-goingresearchvesselsare typicallyownedbynationalresearchbodies
(e.g.China,UK,US, Brazil,Germany,Japan,France,Russia) orcommercial operations,particularlyinthe
offshore oil andgassector.With the advancesinROVs,lessandlessdirecthumandisruptionof the
marine biome isnecessary.LeveragingROV technologyallowsforminimallyinvasive tacticsthatstill
allowsforeffective research/discovery/developmentopportunitieswhile maintainingthe balance inthe
mostfragile of habitats.InvestingandemployingROV technologyisalsosaferforall partiesinvolved.As
the scientificcommunitycontinuestoresearchmore dangerousandless-exploredmarinehabitats,the
riskfor healthandhumansafetyincrease.ROVsdramaticallyreducesthisriskwhilepermittingresearch
and commercial societiestoexplore true frontierregions.Forexample,LiquidRoboticsisaventure-
backedfirmspecializinginthisareawiththeir marquee product,the Wave Glider.The Wave Gliderisan
autonomous,environmentallypoweredocean-goingplatformforgatheringandremotelytransmitting
informationaboutthe ocean.Wave Gliderscollectdataon temperature,winds,humidity,windgusts,
watertemperature,watercolor,andwatercomposition.Theycanalsotake pictures.These robotsare
gatheringa lotof observational dataaboutclimate change,oceanacidification,fisheriesmanagement,
hurricane andtsunami warnings,andexploration — butina greenway.Thistype of technologyapplied
specificallytomarine bioprospectingtofurtherdrive innovationandefficiencyinthisspace.
4.2 HEALTHY PUBLIC-PRIVATE PARTNERSHIPS, CASE-IN-POINT:GRIFFITH/ASTAZENECA PARTNERSHIP
The GriffithUniversity(an AustralianUniversitybasedinthe State of Queensland)/AstraZeneca
Partnershiprepresentsamulti-year,100AUD investmentbyAstraZeneca,hasinvolvedthe screeningof
extractsof floraand fauna byGriffithUniversity’sEskitisInstitute toidentifybioactivemoleculesas
potential leadsforpharmaceutical discoveryanddevelopmentof novel pharmaceuticals.More than
45,000 samplesof regional biota,bothmarine andterrestrial,have beencollectedsince the startof the
partnership.Collectionshave derivedfromseveral jurisdictionswithinAustralia.Thispartnershipshould
alsoserve as a groundedexampletohelpinformfuture intiativesaimedatbalancingthe variousneeds
to ensure effectiveandsafe marine bioprospecting.Thispartnershipdemonstratedthatbioprospecting
partnershipscanyieldconsistentbenefitsforprovidercountriesandforbiodiversityconservationover
time.The collaborative agreementandconsequentinvestmentinQueenslandhasresultedinsignificant
technologytransfer.Aspartof the partnership,AstraZenecaprovidesfundingtoGriffithUniversityto
participate intheirbiodiscoveryandcommercializationefforts.GriffithUniversityinturnpartnerswith

7. domesticandoverseascollectinginstitutionstoundertakebiotacollections,make extractsof samples,
and thenrun these samplesthroughhighthroughputscreens(HTS) againsttargetsprovidedbyandof
therapeuticsinteresttoAZ.Active compoundsare thenidentifiedandisolatedatGriffithUniversityvia
bioassayguided fractionation,andstructuresare elucidatedusingnuclearmagneticresonance
spectroscopy.Benefitsaccruedtothe range of collaboratorsinthe partnership –AstraZeneca,Griffith
University,the QueenslandHerbarium,the QueenslandMuseum, andcompaniesandinstitutionsin
China,India,PapuaNewGuinea,andTasmania.Atthe same time,broaderbenefitswere achievedor
may still emerge forthe State of Queensland,the Australianresearchcommunity,the Australianpublic,
and the international community. RealizedbenefitstoAustraliainclude monetaryremunerationlike
feesforsamples(ortocover the costs of an agreed-uponworkplan) androyalties.Non-monetary
benefitstoAustraliaincludedthe provisionof vehicles,equipment,technology,training,buildingof a
state-of-the-artnatural productdiscoveryunit,andincreasedknowledge of biodiversity.BenefitstoAZ
include the accesstoa huge pipeline of potential blockbusterdrugsthatmayyet serve tobenefit
thousands(if notmillions) of patients. Furthermore,new informationanddatagleanedfromthe
partnershipshave gone towardsinformingmore policyaroundconservationandenvironmental
planningandmanagementthroughoutthe region.Manybestpracticesforsimilarfuture partnerships
can be establishedfromthe AZ/GriffithPartnership.
End Note:
Science hasan opportunitynowunlikeanyothertime inhistorytoadvance mankindutilizingrobotics
for the bettermentof usall.
Todd Kleperis