Blue biotechnology

A watery goldmine for “biotech”

From fish in polar seas to bacteria in hydrothermal springs, some sea creatures live in conditions which make it hard for us to believe their survival possible. Their resistance under exceptional conditions, such as strong salinity or extreme temperatures, or their ability to produce toxic substances, is intriguing researchers from Marine Genomics(1), a network of European excellence. Slowly but surely, biotechnology researchers are taking an interest in these astonishing natural phenomena, which can provide us with numerous benefits, from new medicines for cancer and revolutionary antibiotics to biodegradable plastics.

Close-up on the  fronds of the red alga Chondrus  crispus as they are attacked by microbes,the algae can be real factories of by-products oxidised from fatty acids, that could be  used as medicines. ©CNRS/Photothèque/Odile Richard Close-up on the fronds of the red alga Chondrus crispus as they are attacked by microbes,the algae can be real factories of by-products oxidised from fatty acids, that could be used as medicines. ©CNRS/Photothèque/Odile Richard
Fauna from the cold  waters of the North Atlantic, growing in a protected marine zone, studied by MarBEF researchers. The Gadus morhua breaks away from the bottom of a white coral (Lophelia pertusa) and orange  coral (Paragorgia arborea), at a depth of 200m, north of Norway. ©Institute of Marine  Research (IMR) Fauna from the cold waters of the North Atlantic, growing in a protected marine zone, studied by MarBEF researchers. The Gadus morhua breaks away from the bottom of a white coral (Lophelia pertusa) and orange coral (Paragorgia arborea), at a depth of 200m, north of Norway. ©Institute of Marine Research (IMR)

“Certain organisms survive in extreme depths, with little or no oxygen, or resisting extreme temperatures,” notes Mike Thorndyke, leader of the Evolution, Development and Diversity node within the Marine Genomics network. “How do these creatures manage under such conditions? How do they cope with the dramatic depths, temperatures and pressure? We are trying to find out, as their metabolisms could offer discoveries that would be of use to everyone, including in the field of human health. The enzymes of these organisms are of more interest than those usually used as, for example, we could use them in very saline solutions and at extreme temperatures.”

Extremophiles

Take the case of fish swimming in the polar seas. Why don’t they freeze? Thirty years of relentless research has finally revealed the secret of their resistance to the icy waters. A team of Canadian biologists has demonstrated that “anti-freeze” proteins, ten times more active than those previously known, fix to ice crystals to stop them growing: a property that could be very useful in the field of medicine, in particular for organ storage or for cryosurgery, a technique which consists of destroying tumour cells by freezing them.

Or consider the bacterium Desulfotalea, resistant to the cold since it grows in sub-zero temperatures on the seabed. By using the enzymes of this bacterium instead of their mesophilic counterparts (which can only grow at moderate temperatures), industries involving food processing or washing processes could save significant amounts of energy.

At the other end of the spectrum, the bacterium Pyrococcus abyssi lives in hot marine springs and maintains an optimal enzymic activity at temperatures of 80-110º C. The biochemical nature of its enzymes could be a key tool intechnologies in the future to recombine DNA. Certain enzymes have already been put to commercial use: the DNA polymerase I, isolated from the thermophile bacterium. Thermus aquaticus works in polymerase chain reactions (PCRs) to manufacture huge numbers of genes for in vitro research.

The list of marine products useful in bio - technology is growing steadily and includes a range of proteins, lipids and “cazymes”, enzymes capable of converting complex carbo - hydrates to produce green fuel. Other bacteria are involved in the breakdown of polymers, a process which scientists at Ifremer, the French Research Institute for Exploitation of the Sea, are using to produce entirely biodegradable plastic. “Finding micro-organisms capable of resisting very high temperatures, or surviving in extreme conditions, should lead to revolutionary industrial applications,” explains Philippe Goulletquer, National Coordinator of Marine and Coastal Biodiversity at Ifremer. “That’s why biodiversity is fundamental to biotechnology.”

Chemical warfare

It is not only the habitats of some marine organisms that have led them to acquire valuable qualities, but also the way in which they spend their time. These “couch potatoes” of the deep combine a sedentary lifestyle with a soft body, necessitating a chemical means of defence from predators. They have therefore evolved the ability to synthesise toxic compounds, or to obtain them from marine micro-organisms.

Particularly powerful, since they need to be effective in water, and as diverse as the microscopic flora and fauna that produce them, these natural products are of great interest to scientists. They provide a huge reservoir of substances that could be used, for example, to develop new treatments for infectious diseases or cancer. Over 16 000 new compounds of this type have been isolated from organisms like sponges, ascidians and seaweeds.

Genetic diversity

In Europe, the Marine Genomics network is helping to discover new metabolites. “We sequence DNA fragments to measure genetic diversity in different sites along European coasts, but also elsewhere, like in the Antarctic. It’s important to allow us to study extremophiles, those organisms living in extreme conditions,” explains Mike Thorndyke. The network is constructing large databases which support research into biotechnology, like the development of antibiotics from DNA fragments, the creation of micro-conductor chips and the mass production in bioreactors of rare marine bioproducts, such as growth hormone.

Director of the Center for Marine Biotechnology and Biomedicine in San Diego, (USA), William Fennical is among the pioneers discovering new anti-cancerous molecules in the sea. Having left the invertebrate field to turn tomicro-organisms, Fennical and his team discovered numerous actinomycete species in the benthic deep, despite the received wisdom that there were none in the sea. In 2003, these researchers demonstrated that Salinosporamide A, a compound isolated from one of these actinomycetes, was able to bind to a tumour and inhibit its growth. It is now in clinical trials for multiple myeloma, a cancer of the blood.

A research odyssey

“Despite these promising applications, research related to marine organisms and the seas’ vast potential is greatly lacking. The seas offer riches that we need to take advantage of, before they disappear,” underlines Mike Thorndyke. The pharmaceutical industry lacks interest in this type of research, particularly because of legal uncertainty and a problem of availability: it is difficult to apply traditional methods of testing and developmentfor a compound produced in tiny quantities by a sponge that lives hundreds of metres down. But, thanks to a few sea enthusiasts, the “biotech” odyssey is running its course. For the last 20 years, the biotechnology company PharmaMar (ES) has been investigating potential anti-cancer properties of the marine products discovered by academics as well as by its own explorers. Some 40 000 organisms and marine products likely to offer therapeutic potential have already been recorded by the Spanish company, and six of these are in clinical trials.

In the future, researchers will find it easier to experiment on hard-to-reach abyssal creatures. They will be able to grow the useful substances in the laboratory, since they do not always come from the marine organisms but from associated bacteria. Another option is to isolate the gene responsible for synthesising the compound and “grafting” it onto an organism that is easier to handle. Either way, these developments cannot take place withoutinvestments, both private and public. As part of this, the European Commission’s Green Paper on maritime policy suggests the creation of “Blue Investment Funds”.

Charlotte Brookes

  1. Financed by the Commission with €10 million over four and a half years.
  2. Commission Green Paper: Towards a future maritime policy for the Union: a European vision of the oceans and seas (7 June 2006).

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Blooming with energy

Producing green energy from a sea lettuce, Ulva lactuta, is the challenge taken on by a team of Danish researchers at the National Institute of Environmental Research (NERI-DMU). While the study on the production of bioethanol produced by this green alga is still in its early stages, early outcomes are promising: the sea lettuce produces 700 times more biomass per hectare than a traditional wheat field. The Ulva and other similar species are very widespread in most regions of the world, particularly in eurotrophic zones where their abundance threatens local  ecosystems: an environmental problem that the harvesting of algae and their transformation into bio-fuel  could resolve. And the production platforms planned in Denmark will help to use up surplus CO2 produced by electricity and by fertilisers. Who could ask for more?



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Medicines fished from the seas

Ecteinascidia turbinate: this sea squirt from the Caribbean or the Mediterranean makes an anti-cancer compound, Yondelis (PharmaMar).

Actinomycetes: with its active ingredient extracted from the actinomycete bacterium Micromonospora marina, the anti-tumour drug Thicoraline is under development by PharmaMar.

Bugula neritina: this cosmopolitan marine bryozoan lives in symbiosis with a bacterium able to secrete an active biomolecule, bryostatin. This acts as a deterrent to predator fish, but is also known for having properties against cancer of the kidney and the pancreas, and non-Hodgkin’s leukemia, melanomas and lymphomas. It is currently in clinical trials.

Cyanobacteria: scytonemin is a yellow-green unltraviolet sunscreen pigment present in this aquatic blue-green algae and may be used to develop inhibitors for use as antiproliferative and anti-inflammatory drugs.

Aplidium albicans: this invertebrate has enabled the company PharmaMar to isolate a marine anti-cancer agent, Aplidin, currently in its trial phase.

Sharks: sharks are particularly unaffected by cancer, largely thanks to squalamine, a molecule present in the liver. This could be used to fight against certain brain tumours.

Japanese sponge: KRN 7000 is not a natural product but it consists of a series of compounds extracted from a Japanese sponge, Agelas mauritianus. Tested on mice, it has been proven to work against tumours, particularly colon cancer.

Conus magus: this cone snail paralyses its prey using a poison-tipped barb. The poison is a painkiller many times more potent than morphine and is now on the market as Prialt.

Nemerte worm: GST 21 is the first molecule of marine origin that has been tested for the treatment of  Alzheimer’s.

Marthasterias glacialis: the Roscovotine molecule has been extracted from this spiny starfish by Dr. Laurent Meijer from the National Centre for Scientific (CNRS) at Roscoff, France. In blocking cancerous cells without  affecting healthy ones, it is a potential chemical weapon against cancer.



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