Thus far marine, or blue biotech is an also ran next to its pharmaceutical, industrial and agricultural cousins. But last week Pharmamar, Europe’s leader in marine drug discovery and development submitted a new cancer treatment for approval, signalling a turning tide in the commercial prospects of marine biotechnology.
Oceans cover about 70 percent of the earth and are home to thousands or possibly millions of species of plants and animals. But while plant and animal life on land is well documented, much of life in the seas remains uncharted territory.
They may all be wet, but there is a huge variety of marine habitats – from hot water vents to polar ice, and tidal rock pools to high pressure environments in the abyssal deeps. And now it transpires that microbial diversity in the oceans may be up to 100 times greater than previously estimated.
Earlier this week scientists from the US, Spain and the Netherlands reported that using new DNA sequencing tools they had discovered more than 20,000 kinds of bacteria in a litre of sea water. “This observation blows away all previous estimates of bacterial diversity in the ocean,” said one of the researchers, Mitchell Sogin, director of the Marine Biology Laboratory at Woods Hole, Massachusetts.
“We are learning through DNA technologies that the number of marine organisms invisible to the eye exceeds all expectations, and their diversity is much greater than we could have imagined.”
In parallel, this has generated a diversity of biochemistry that is unmatched and distinct from that found on land. Microbes, in particular, embody massive biological and chemical diversity, yet they are largely unclassified. While to date 5,000 microbial species have been formally identified, this study - which is part of the Census of Marine Life, a ten-year global attempt to catalogue diversity in the oceans - shows that barely scratches the surface.
Huge potential markets
The potential markets for compounds originating at sea – in the pharmaceutical, cosmetic, nutritional supplement and agrichemical industries - are worth billions of dollars. But the industry remains in its infancy. While potential stirs in the depths, investors have hardly dipped their toes into marine biotechnology.
“Blue biotech gives us an enormous opportunity with potential huge rewards. On the one hand, we are building on existing markets for direct extraction from sea organisms of products already worth several billion dollars,” says Meredith Lloyd-Evans, the managing director of BioBridge Ltd, a biotechnology consultancy, and manager of the UK government’s biosciences portal, Bioscience for Business Knowledge Transfer Network, which includes a focus on transferring marine sciences research to industrial partners.
On the other hand says Lloyd-Evans the sea is full of untapped bioactives that could be used to treat diseases from cancer to obesity. But to date, he says there has been very little venture capital investing in the blue biotech sector, with most money in the field still coming from government grants.
Examples of existing products include, agar, alginates, carrageenan and other marine hydrocolloids; fucoidans, chitosan and glucosamine; astaxanthin and other carotenoids. For instance, Germany-based start-up BlueBioTech International GmbH, based near Hamburg, cultivates micro-algae for commercial and scientific uses at its research centre in Buesum on the North Sea. It produces Spirulina through a joint venture in China and expects to have Euros 6 to 12 million in sales in 2006, says Friedhelm Mienert, head of communications.
Another start-up, Aquapharm Bio-discovery Ltd, aims to replace synthetically produced compounds used in animal feed with naturally bio-manufactured marine natural products. In mid 2005 the company received £1.25 million GBP in a funding package from the Scottish Enterprise Co-Investment Fund, which included a small supplement from angel investors.
Aquapharm was the first company to locate at the European Centre for Marine Biotechnology in Oban, Scotland. Andrew Spragg, CEO says, “Being here has given us access to sampling missions and key academic expertise in marine biotech.”
“We believe we have a process in the lab that could allow us to manufacture antioxidants cheaper than those that are chemically synthesised,” Spragg says. Aquapharm, which has applied for four patents and has one at an advanced stage, continues to seek investment.
Accessing biological diversity at sea
While everyone agrees the sea is full of interesting biologically active compounds, until now, the problem has been how to access this diversity in a systematic way. Pharmamar’s approach is based on collecting and screening thousands of marine compounds, and using interesting ones as the model for synthetic derivatives. The company, owned by Zeltia Group, has submitted more than 500 patent applications and has six compounds in clinical trials.
The lead product, Yondelis was originally isolated from a marine invertebrate, Ecteinascidia turbinate. It has a distinct mechanism of action, binding to the minor grove of DNA and interrupting the cell cycle.
Pharmamar’s techniques highlight one of the main obstacles in the way of commercialising marine compounds – it is difficult to isolate and synthesise them. Harvesting from the wild source is unlikely to be a suitable basis for investment, and to date attempts to use aquaculture have not been successful. For example, marine sponges are a rich source of compounds, but they are very difficult to cultivate. Another confounding factor is that many biologically active compounds found in marine organisms are actually generated by symbiotic micro-organisms. And because of the extreme environments in which many microbes are found they are notoriously difficult to culture in the lab.
“The difficulty of synthesis is often cited as the main obstacle to investing in and exploiting otherwise bioactive compounds,” Paul Long, of the School of Pharmacy at the University of London, UK, told the Fourth International Symposium on Marine Biology, held in Greifswald, Germany in June.
But now he said, conventional bioprocessing techniques can be applied to compounds originally identified in marine environments
One of the keys to unlocking marine diversity is the use of metagenomics, in which rather than identifying individual species, researchers hunt for DNA sequences encoding novel chemicals. Once a gene of interest is singled out it can be cloned and used in conventional bioprocessing systems in which the gene is inserted into a microbial or mammalian cell line for use in an industrial scale fermentation process.
Long and his colleagues are working currently on developing a platform technology for cloning and expressing genes that generate compounds of interest.
Similarly, scientists at the Institute of Bioprocess Engineering at the University of Erlangen-Nuremberg, Germany have devised a process for generating anti-viral compounds they have discovered in the microalgae Arthrospira platensis. The group has found compounds that are active against a range of viruses, including herpes and HIV, and are currently investigating their mechanism of action.
Researchers at the University of Tubingen, Germany and the universities of Kent and Newcastle, UK, have developed a culture-based bioprospecting strategy, in which they ‘dereplicate’ micro organisms to avoid redundancy, and then grow the remaining micro organisms in a range of fermentation conditions. Chemical profiles are then defined and checked against chemical databases and novel or rare metabolites are screened for biological activity.
From this they have uncovered compounds from sea sediments that have a novel mode of action against the hospital-acquired infection MRSA. These compounds are now being taken forward by Actinomics Ltd, a spin-out from Newcastle University.
Meanwhile researchers at the German Centre for Biotechnology in Braunschweig are applying metagenomics to look for biocatalysts, including amylases, esterases and cellulases for industrial applications.
Arcadio García de Castro, business development and licensing manager at Pharmamar, says high-content screening technologies or new ways to tap the genetic diversity of marine life is the next big trend in blue biotech.
“I feel there is little value added in offering microbial collections. A company can only expect to get funding by entering the arena of drug discovery and development, and by establishing strategic alliances with companies with complementary expertise.”
Many new applications to come
Lloyd-Evans believes that in future there will be a wide range of applications of marine biotechnology. They include using marine viruses to control bacterial diseases; taking advantage of the novel chemical cycling abilities of sea microbes to disable greenhouse gases and reduce ozone-damaging compounds; generating hydrogen for fuel cells and creating photosynthesis and energy-trapping.
“The list is only limited by our vision and imagination and, of course, the funding available to turn microbial activity into technological reality. In many ways this wealth of opportunity has always presented a big challenge - to discover and focus on the leads that will really make a difference.”
“But we now have the tools to streamline screening, selection and validation. This translational focus is the key to success in realising the wealth of the seas.”
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