Science Spin July 2008

Pharmaceutical treasures to be sought in Irish waters

While almost a third of pharmaceuticals are based on compounds from plants and animals on land, there is a dearth of marine-based drugs by comparison, even though the oceans are the planet's richest habitat. The seas remain largely unexplored, and the creatures that live there are often difficult to collect or cultivate. But, technological advances are changing this, and considering terrestrial organisms have played such a vital role in the advancement of healthcare, what pharmaceutical treasures could be hiding in the oceans?

A new national research programme in marine biodiscovery (the hunt for useful or 'bioactive' compounds in marine organisms) is aiming to find out, whether our oceans do indeed contain useful compounds that could be developed into new drugs. Research in the field is still in its infancy worldwide, with only a handful of marine-derived drugs on the market.

Ziconitide, the synthetic form of a compound extracted from the venom of tropical marine cone snails, is a powerful yet non-addictive painkiller. Zidovudine, the first drug ever approved for the treatment of HIV, is based on compounds extracted from the sponge Tethya crypta more than 40 years ago. But these are the exceptions rather than rule - there are few drugs derived from marine sources.

Research, however, is growing rapidly. "There are quite a number of marine compounds in various stages of clinical trial," said Eoin Sweeney of the Marine Institute. These include ecteinaisdin-743, a compound derived from the Caribbean sea squirt Ectenascidia turbinata, and a potent pharmaceutical that has been effective against drug-resistant tumours in clinical trials. Another compound, aplidine, inhibits enzymes essential to the growth and formation of tumours, and was isolated from the Mediterranean sea squirt Aplidium albicans. "The percentage of marine derived compounds in novel drugs is going to increase markedly," Eoin Sweeney said.

Research

While new drugs are a long-term target of Ireland's Marine Biodiscovery Programme, it aims to benefit other fields too, including functional foods, biomaterials, and bioremediation (the use of organisms to clean up pollution). Eoin Sweeney described the new research venture as a "complex programme, involving everything from marine biology to molecular medicine."

The Department of Communications, Energy and Natural Resources underlined the importance of this emerging research sector when it provided €7.2 million to NUI Galway, University College Cork and Queen's University Belfast for biodiscovery research in September last year under its Beaufort awards scheme. The Marine Institute has also funded three biodiscovery PhD studentships.

One of these projects is being supervised by Dr Christine Loscher, an immunologist at the International Centre for Neurotherapeutics at DCU, whose PhD student is investigating whether extracts from marine sponges and algae exhibit anti-inflammatory properties. "We're growing immune cells from a mouse and exposing them to an inflammatory stimulus, then seeing if the marine extracts can change the cells' response to the stimulation.

At the moment we're working with extracts that have a huge amount of potential," Dr Loscher said, citing arthritis treatment as one possible benefactor of any future breakthroughs. She described the extracts she's working with at the moment as "very crude," but said that as the project progresses, the aim will be to isolate individual molecules with specific biological effects. "What you want is something that is able to increase or decrease what you're interested in, but leave everything else alone. Some of these extracts have very specific effects."

One of the chemists who will be assisting Dr Loscher is UCD's Professor Pat Guiry, another recipient of Marine Institute funding. His work has focused on purifying algal material collected by NUI Galway and separating it into various fractions. One such fraction appears to inhibit potassium ion channels, which play a role in a variety of diseases. "It's still an impure sample, we don't know what the active compound is," Professor Pat Guiry said, "but we know which fraction to target."

If their target compound turns out to be a new one, Prof Pat Guiry said it will at the very least be a 'lead compound' - a starting point for potential drug development.
One of the keys figures behind the biodiscovery programme, Professor Michael Guiry - no relation to Pat - is director of the Martin Ryan Marine Science Institute at NUI Galway. NUIG's Beaufort award of €3.2 million will enable it to appoint specialised biodiscovery researchers, including a principal investigator, two postdoctoral researchers and four PhD students. "That's only the beginning though," Prof Michael Guiry said.

Research at NUIG will focus on looking for new compounds in seaweeds, jellyfish and sponges. "Sponges have been a very rich sources of bioactive compounds," Prof Michael Guiry said, "but we're not sure if they come from the sponge or its associated organisms." Meanwhile, research at UCC will examine exactly how marine organisms produce bioactive compounds, while at QUB the biomedical application of such compounds is the main focus.

Professor Lokesh Joshi will be heading up the biodiscovery programme at NUI Galway. A biologist who has held posts at the University of Arizona and Cornell University, Professor Joshi has previously worked on therapeutic compounds in plants. "The marine environment is Ireland's treasure and the least explored biosphere on the planet. It's our ocean of opportunity," he said. "We ought to look and learn from nature to discover novel biomaterials and biotherapeutics." Professor Joshi said that some marine organisms have "tremendous plasticity and regenerative ability" and that a greater scientific understanding of the molecular mechanisms of how regeneration takes place in such creatures could have potential human applications.

The potential uses of compounds from Irish marine organisms stretch beyond pharmaceuticals though. Mike Guiry mentions one researcher, Dr Pamela Walsh, who has patented a method for using the hard red algal species Corallina in bone replacement therapy. The Irish marine environment is also a potential source of neutraceuticals, foods with health benefits that is - the seaweed Chondrus crispus, full of infection-preventing sugars, is just "one example of many," according to Prof Mike Guiry.

Supply

Biodiscovery, or bioprospecting as it's also known, isn't always popular. There has been a variety of high profile cases in which compounds derived from terrestrial plants have been commercialised without any compensation for indigenous people who had been using the plants medicinally for generations. Such problems won't arise for marine biodiscovery - the biggest challenge is likely to be finding a sustainable supply of biological material. "Some of the species are in very short supply," Prof Mike Guiry acknowledged, adding that sometimes potentially useful species can't even be found again in the vastness of the marine environment.

Indeed, fifteen years passed between the first collection of the deep-water sponge Forcepia - a source of cancer-fighting lasonolide compounds - and its relocation.
As well as this, target compounds are sometimes only present in tiny quantities, and might only be produced in response to certain environmental conditions. Ideally, researchers would be able to produce synthetic versions of natural compounds in the lab, but Prof Mike Guiry concedes that some compounds - he cites those derived from sponges as an example - can simply be too complex for this.

Aquaculture

The marine pharmaceutical company PharmaMar is developing techniques for farming the sea squirt that produces the tumour-fighting ectenaisdin-743 compound. Such harvesting or farming can be difficult or impossible for some species, and only becomes commercially viable once there is high demand for a product. Genetic engineering, by inserting genes responsible for producing useful bioactive compounds into easy-to-grow laboratory species, could be a long-term solution.

Of course the vast majority of bioactive marine compounds won't make it to market. For every new pharmaceutical on the shelves, thousands of other potential drugs will have been abandoned, either because they are too toxic or simply ineffective. But the challenges that lie ahead for marine biodiscovery are just that - surmountable obstacles that research programmes, such as our own biodiscovery research programme, will aim to tackle. There is a literal ocean of potentially useful compounds out there. "The oceans are by far the greatest reservoir of life forms," Eoin Sweeney said, "and we believe it's going to be an interesting mine of resources in the future."

Biodiscovery Programme

"We've been working on the notion of a marine biodiscovery programme with Eoin Sweeney and the Marine Institute for years," said Prof Mike Guiry, "but we've only recently gotten things together." The programme is being co-ordinated by the Marine Institute, and involves researchers in a variety of disciplines at third-level institutions throughout the county, as well as international collaborations with the National Cancer Institute in the United States and the University of London.

The programme is aiming to develop active partnerships across academic institutions and knowledge-based industries to strengthen Ireland's ability to use its marine resources sustainably. If it's to be successful, the programme will require active co-operation among marine biologists, chemists, geneticists, pharmacologists and biomedical scientists. "It's very important we get different types of people to work together," Prof Mike Guiry said.

Eoin Sweeney said that Ireland is ideally suited to such a programme, with its rich marine biodiversity and strong biomedical sector. What are the programme's goals? "We're not hinging the whole programme on having an anti-cancer drug in five years' time," Eoin Sweeney said, citing the fact that drug development is a painstaking process that can take up to 20 years. Prof Mike Guiry explained: "The ultimate idea is to understand how bioactive compounds are made, so we can make them better, and make them in the lab."

In the long term, the programme aims to contribute to the development of new drugs and therapies, to develop and enhance relevant industries, and to make Ireland a world leader in the research, development and commercialisation of marine bioproducts. Prof Mike Guiry believes the programme can help to develop knowledge-based industries in Ireland: "The pharmaceutical and biotech industries are interested in being in places where this sort of research is going on."