Protecting Ocean Regions with Robotics“How medical breakthroughs will come from the ocean and transform future medicine”

1 INTRODUCTION

1.1 INCREASING BURDEN OF CHRONIC ILLNESS AND EVER-AGING GLOBAL POPULATION

With the ever-aging global population and the growing burden of chronic illness, there is an increased reliance on the healthcare system (particularly the biopharmaceutical industry) in order or one to achieve and sustain a high quality of life. According to the World Health Organization (WHO), the burden of human diseases have been rapidly increasing for decades with this trend predominantly contributed by population growth and environmental degradation.

1.2 DEFINITION OF MARINE BIOPROSPECTINGMarine bioprospecting is the search for novel compounds from natural sources in the marine environment. These activities have increased a great deal in the last few years likely in part due to the continued technological advances enabling further oceanic exploration, acknowledgement of the rich generic diversity in the marine biome, as well as the pressure from industry to produce given various blockbuster drugs going off patent. Today, about 18,000 natural products have been reported from marine organisms belonging to about 4,800 named species. The number of natural products from marine species is growing at a rate of 4% per year. The increase in the rate of discoveries is largely the result of technological advances in exploring the ocean and the genetic diversity it contains. Advances in technologies for observing and sampling the deep ocean, such as submersibles and remotely operated vehicles (ROVs), have opened up previously unexplored areas to scientific research. Since 1999, the number of patents of genetic material from marine species has increased at the rate of 12% per year. Marine species are about twice as likely to yield at least one gene in a patent than their terrestrial counterparts. Bioprospecting typically requires the collection of a very limited amount of biomass for the initial discovery. Although further collections may be required after a promising discovery has been made, bioprospecting generally does not involve threats to biodiversity comparable to the large biomass removals involved in harvesting resources for food or mineral exploitation.

1.3 THE SUCCESS OF NATURAL COMPOUNDS IN DRUG DISCOVERY AND BIOPHARMACEUTICAL BACK DROP

Biopharmaceuticals are one of the most impressive achievements of modern science. Many biopharmaceuticals offer high efficacy and few side effects. And there is much more to come: radically new concepts are making it to the market, and the advances keep coming at a rapid pace. The success of natural compounds in drug discovery is unparalleled: for antimicrobial and anticancer therapies, for example, more than 70% of new chemical entities introduced during the period 1981–2002 originated

from natural products. It has been estimated by the US National Cancer Institute (NCI) that 1% of samples from marine animals tested in the laboratory reveal anti-tumor potential (which compares favorably with just 0.01% of samples of terrestrial origin). In the last few decades, advances in informatics, automation and imaging technology have made it possible to screen 100,000s – 1,000,000s of small molecules against a specific biological target or cellular assay per day, compared with 10s-100s of compounds tested on animals over many months previously. Growing awareness of the limitations of historically valuable approaches, and breakthroughs in robotics technologies, such as those used in separation and structure determination, have made screening mixtures of structurally complex natural product molecules easier, and have expanded the potential role of natural chemical diversity in the drug discovery process

2 THE OPPORTUNITY

2.1 AUSTRALIA CONTEXT Australia is one of only 17 mega-diverse countries in the world and is renowned for the uniqueness of its biota. Australia has several features proving attractive to investors and researchers in the natural products area. This includes, not least, access to a diverse and unique biota. More generally, the features of Australia conducive to research and commercial activity include its robust system of law and stable democratic system of government, its stable and resilient economy, transparent and efficient regulatory environment, comprehensive intellectual property protections and high scientific and technological capacity. Australia has remained relatively isolated over time compared to most countries. Consequently, Australia has a high proportion of endemic species – that is, species not occurring naturally elsewhere. For example, in the case of mammals, approximately 83% are endemic to Australia. Australia's unique marine environment contains the world's largest areas and highest diversity of tropical and temperate seagrass species and of mangrove species; some of the largest areas of coral reefs; exceptional levels of biodiversity for a wide range of marine invertebrates; and it is estimated that around 80% of the southern marine species occur nowhere else in the world. With only 0.3% of the world's population, Australia contributes 2.5% of the world's medical research and 2.9% of global scientific publications (Invest Australia, 2007, p.6). In 2005, Australia ranked eighth in the OECD in terms of the proportion of researchers in the total labor force. This is above the OECD average. On a per capita basis, Australia has a research output twice the OECD average. In terms of biotechnology research, Australia has several dedicated biotechnology research institutes. Australia's biotechnology industry is steadily growing, with activity across biotechnology fields including biomedicine, agricultural biotechnology, industrial biotechnology and environmental biotechnology. The Australian Government is a staunch advocate of the domestic pharmaceutical industry and has been very supportive in implementing initiatives to grow this sector. By any measure, Australian Government support for research and development in the biopharmaceutical industry has been and looks to continue to be strong.

2.2 MARINE BIOME REMAINS UNTAPPED/UNDER-INVESTIGATED—THUS PROSPECTS FOR NEW AND MEANINGFUL FINDINGS ARE SIGNIFICANT

Today, biopharmaceuticals generate global revenues of $163 billion, making up about 20 percent of the pharma market. It’s by far the fastest-growing part of the industry: biopharma’s current annual growth rate of more than 8 percent is double that of conventional pharma, and growth is expected to continue at that rate for the foreseeable future. Marine bioprospecting has the potential to further drive these trends. The marine biome remains untapped and underinvestigated, and thus, perfectly poised to drive both topline and bottom line for multiple stakeholders in the biopharma value chain. Investing in biotech R&D has yielded better returns than the pharma-industry average. The current biologics-development pipeline supports an outlook of continued healthy growth. The number of biotech patents applied for every year has been growing at 25 percent annually since 1995. There are currently more than 1,500 biomolecules undergoing clinical trials, and the success rate for biologics has so far been over twice that of small-molecule products, with 13 percent of biopharma products that enter the Phase I trial stage going on to launch. To date, sampling of marine products has primarily occurred in easy-to-reach coastal waters. As a result, 97% of natural products of marine origin are from eukaryotic sources (organisms with complex cells), with sponges alone accounting for 38% of the products. However, the majority of the Earth's metabolic diversity resides in prokaryotic organisms (single-celled organisms such as bacteria) and over 99% of the microbial community of the ocean remains to be explored, so it stands to reason that many more genetic sequences valuable for products are yet to be discovered. There is a particular interest in marine species that live in extreme environments, such as hydrothermal vents and seamounts (‘extremophiles’). By the end of 2007, only 10 compounds had been reported from Deep Ocean and ocean trench environments, with a further seven identified in 2010. Fewer than 10 marine natural products have so far been reported from hot vent bacteria. Furthermore, if we break down the various ecosystems of our seas and oceans and compare the chemical dynamics, coral reefs have particularly impressive potential. The corals that we see are actually made up of colonies that build up and thrive in an environment where nutrients are low. Although coral reefs only occupy 0.1% of the world’s ocean surface, they are one of the most diverse ecosystems on earth, hosting ~25% of all marine species. The focus on the coral reef ecosystem as a target place for medicinal purposes is not a new concept. As early as the 14th century, coral reefs were a known source for medicines. One practice at that time is the use of fish gall bladder to treat venomous stings from marine organisms. Today, coral reefs have already contributed its name in the pharmaceutical industry as one of the source of biochemical compounds for new drugs and the possibilities are endless. The opportunity moving forward is substantial.

2.3 SPECIFIC EXAMPLES OF SUCCESSFUL MARINE BIOPROSPECTING

2.3.1 AplidinOne of the early biochemical compounds derived from the sea is Didemnin, a compound isolated for the treatment of certain cancers. This compound was obtained from the tunicate Trididemnum solidum. Unfortunately, Didemin did not survive in later stages of its clinical trials. However, after a series of further exploration, a relative of the former species was discovered to poses similar traits. The tunicate Aplidium albicans possesses the compound Aplidin® which has a similar structure with Didemnin but far less toxic. Aplidin is an anti-tumor, anti-viral and immunosuppressive drug that has been demonstrated

to be effective in pancreatic, stomach, bladder and prostate cancers. After undergoing series of clinical test, Aplidin was granted the classification as an orphan drug that specifically treats multiple myeloma and acute lymphoblastic leukemia. In the United States alone, there are over 45,000 people with multiple myeloma and an estimated 15,000 new cases in the U.S. each year.

2.3.2 YondelisYondelis® was developed by the PharmaMar Pharmaceutical Company and was released in the market in 2003. This compound is now sold by Zeltia and Johnson and Johnson. Yondelis contains the active substance Trabectedin. Trabectedin is derived from coral reefs. Specifically from the filter feeding sacs of the small and immobile plant-like invertebrate called sea squirts. Extracts of this reef associated species has been found to contain a treatment for soft-tissue sarcoma and ovarian neoplasm sarcoma. Yondelis was developed as a result of the National Cancer Institute Screening Program for marine plants and animals. Sea quirts were collected from reefs of West Indies and studied in the laboratory at the University of Illinois. The anti-cancer biosynthetic compound was then discovered to be embedded in the symbiotic microorganism within the sea squirts. Yondelis is produced in a semi-synthetic manner, after the extracts from the sea squirts undergo a patented chemical process. This process is less intrusive and less demanding to the natural marine biome. Moreover, even though the usage of Yondelis is only for rare medical conditions such as sarcoma, there is still potential for this product to add a lot of value to the lives of patients and other stakeholders. More and more adopting Yondelis in their prescribing workflow for sarcomas and there are an increasing number of patients who are sensitive to medicines containing platinum and Yondelis is one of the only alternative anti-cancer medicines.

2.3.3 Pro OsteonThere are many indications for a bone graft implant (e.g. fusion of the spine, joints in arms and legs, fractures or gaps in bones caused by trauma or infection, oral surgery). In a typical bone grafting procedure, a synthetic material is shaped by the surgeon to fit the affected area of the bone while pins or screws are used to hold it in place. This material builds a support structure where bone cells can interlace, regenerate and heal. Pro Osteon Implant 500 has a porous microstructure where new tissues and blood cells can grow, thereby stimulating growth and connects fractured bone segments. Generically called “Bone Void Filler” and approved by the FDA in 1992, Pro Osteon Implant 500 is clinically proven to be safe, strong and cost effective. This material is sterile, thereby minimizing adverse reactions from the patient’s immune system rejecting the implant. The effectiveness of Pro Osteon Implant 500 lies in its source. It uses corals from the sea that has the same porous interconnected structure of a typical bone graft thereby mimicking the internal structure of a human bone. After undergoing a patented chemical process, it converts the coral into hydroxyapatite which is a mineral and the chief structural element of a human bone. At this stage, the implant material is now also osteoconductive which facilitates bone cells to weave into the porous structure. After the procedure and the healing process starts, the Pro Osteon Implant will eventually be covered and replaced by bones creating the mended part as strong as it was before. Pro Osteon has great demonstrated efficacy and a safe side-effect profile. The company manufacturing this product is projecting at least $3 billion in sales by 2017. What’s more, the production of Pro Osteon is not completely dependent on farming and extracting corals from their natural habitat. Special techniques have been developed, which require only a small portion of coral to be extracted, while the balance is grown artificially in the lab—thus promoting sustainability and stability of the marine biome.

3 THE CHALLENGES

3.1 HOW TO CONSERVE AND SUSTAINABLY USE MARINE BIOLOGICAL DIVERSITY

Despite the fact that marine bioprospecting is relatively unimposing and the practice does not impose the sustainability risk of various terrestrial techniques, conservationists and the public still have some concerns. For one, very little is known about the conservation status of many species used as sources of marine genetic resources. Further, many species occur in vulnerable and fragile ecosystems. Many are also concerned with what we don’t know in this relatively nascent sub-industry at this point. For instance, the effect on ecosystems of removal of marine genetic resources is poorly understood.

3.2 FEW NATIONS CAN SUCCESSFULLY DO BIOPROSPECTING ON THEIR OWN

Investment in marine biotechnology is not without risk. Sampling at sea costs a minimum of US$ 30,000 per day or US$ 1 million for a month. It typically takes 15 years overall, and an investment of up to US$ 1billion, to go from research to commercial product, due to the fact that many products fail to deliver on early promises. As a result the field is dominated by relatively few nations. Patent claims associated with marine genetic resources (MGR) originate from only 31 countries. Ninety per cent of these patents originate from 10 countries (USA, Germany, Japan, France, UK, Denmark, Belgium, Netherlands, Switzerland and Norway), with 70% originating from the US, Germany and Japan. Despite the high levels of investment required in R&D, biotechnology is a lucrative and important industry.

3.3 THE CURRENT UNCERTAIN AND UNPREDICTABLE LEGAL AND REGULATORY FRAMEWORK DISCOURAGES INDUSTRY (I.E. BIOPHARM COMPANIES) FROM INVESTING THEIR EFFORTS INTO BIOPROSPECTING

The potential of marine bioprospecting has become the subject of international policy debate (particularly for areas beyond national jurisdiction). One central quetion is whether the potential benefits from marine bioprospecting ought to be shared by the entire international community or only by the States or individual corporations with the capacity to exploit them. Various groups are looking at this in order to configure the most sensible set of policies to balance the need to promote innovation and technological/biopharmaceutical advances, with the need to make sure all stakeholders in the value chain are appropriately compensated, along with the need to ensure the longevity of these natural marine habitats. Increasingly, individual nation-states are establishing policies that dictate the way in which protected marine habitats in their jurisdiction may be used for bioprospecting and other scientific and commercial pursuits.

3.4 COSTS OF BIOPHARM/BIOTECH DISCOVERY There are operational and technological challenges to bioprospecting and biopharmaceutical discovery in general. Reproducing large molecules reliably at an industrial scale requires manufacturing capabilities of a previously unknown sophistication. Consider this: a molecule of aspirin consists of 21

atoms. A biopharmaceutical molecule might contain anything from 2,000 to 25,000 atoms (Exhibit 1). The “machines” that produce recombinant therapeutics are genetically modified living cells that must be frozen for storage, thawed without damage, and made to thrive in the unusual environment of a reaction vessel. The necessary sophistication comes at great cost. Large-scale biotech-manufacturing facilities require $200 million to $500 million or more to build, compared with similar-scale small-molecule facilities that may cost just $30 million to $100 million, and they can take four to five years to build. As the number of products rises and new process technologies such as continuous manufacturing are introduced, the complexity of biopharma operations and the biopharma supply chain will increase.

4 THE SOLUTION

4.1 HUMAN/ROBOTICS INTERVENTION First, activities at sea in support of biotechnology need to be distinguished from processes in the laboratory. Commercial expeditions purely to collect marine genetic resources are rare to non-existent. Typically, sampling is conducted on scientific research cruises, or by using downtime on ROVs used in the offshore oil industry. Ocean-going research vessels are typically owned by national research bodies (e.g. China, UK, US, Brazil, Germany, Japan, France, Russia) or commercial operations, particularly in the offshore oil and gas sector. With the advances in ROVs, less and less direct human disruption of the marine biome is necessary. Leveraging ROV technology allows for minimally invasive tactics that still allows for effective research/discovery/development opportunities while maintaining the balance in the most fragile of habitats. Investing and employing ROV technology is also safer for all parties involved. As the scientific community continues to research more dangerous and less-explored marine habitats, the risk for health and human safety increase. ROVs dramatically reduces this risk while permitting research and commercial societies to explore true frontier regions. For example, Liquid Robotics is a venture-backed firm specializing in this area with their marquee product, the Wave Glider. The Wave Glider is an autonomous, environmentally powered ocean-going platform for gathering and remotely transmitting information about the ocean. Wave Gliders collect data on temperature, winds, humidity, wind gusts, water temperature, water color, and water composition. They can also take pictures. These robots are gathering a lot of observational data about climate change, ocean acidification, fisheries management, hurricane and tsunami warnings, and exploration — but in a green way. This type of technology applied specifically to marine bioprospecting to further drive innovation and efficiency in this space.

4.2 HEALTHY PUBLIC-PRIVATE PARTNERSHIPS, CASE-IN-POINT: GRIFFITH/ASTAZENECA PARTNERSHIP

The Griffith University (an Australian University based in the State of Queensland)/AstraZeneca Partnership represents a multi-year, 100 AUD investment by AstraZeneca, has involved the screening of extracts of flora and fauna by Griffith University’s Eskitis Institute to identify bioactive molecules as potential leads for pharmaceutical discovery and development of novel pharmaceuticals. More than 45,000 samples of regional biota, both marine and terrestrial, have been collected since the start of the partnership. Collections have derived from several jurisdictions within Australia. This partnership should also serve as a grounded example to help inform future intiatives aimed at balancing the various needs to ensure effective and safe marine bioprospecting. This partnership demonstrated that bioprospecting

partnerships can yield consistent benefits for provider countries and for biodiversity conservation over time. The collaborative agreement and consequent investment in Queensland has resulted in significant technology transfer. As part of the partnership, AstraZeneca provides funding to Griffith University to participate in their biodiscovery and commercialization efforts. Griffith University in turn partners with domestic and overseas collecting institutions to undertake biota collections, make extracts of samples, and then run these samples through high throughput screens (HTS) against targets provided by and of therapeutics interest to AZ. Active compounds are then identified and isolated at Griffith University via bioassay guided fractionation, and structures are elucidated using nuclear magnetic resonance spectroscopy. Benefits accrued to the range of collaborators in the partnership – Astra Zeneca, Griffith University, the Queensland Herbarium, the Queensland Museum, and companies and institutions in China, India, Papua New Guinea, and Tasmania. At the same time, broader benefits were achieved or may still emerge for the State of Queensland, the Australian research community, the Australian public, and the international community. Realized benefits to Australia include monetary remuneration like fees for samples (or to cover the costs of an agreed-upon workplan) and royalties. Non-monetary benefits to Australia included the provision of vehicles, equipment, technology, training, building of a state-of-the-art natural product discovery unit, and increased knowledge of biodiversity. Benefits to AZ include the access to a huge pipeline of potential blockbuster drugs that may yet serve to benefit thousands (if not millions) of patients. Furthermore, new information and data gleaned from the partnerships have gone towards informing more policy around conservation and environmental planning and management throughout the region. Many best practices for similar future partnerships can be established from the AZ/Griffith Partnership.

End Note:

Science has an opportunity now unlike any other time in history to advance mankind utilizing robotics for the betterment of us all.

Todd Kleperis