Plumbing the depths: PharmaSea's search for new drugs

The World Health Organization fears a “post-antibiotic era”, where common infections and minor injuries can kill. “Far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century,” the organisation said in its April report on microbial resistance.

While there are efforts to tackle this problem from economic and educational angles, some researchers are turning to the world’s oceans in the search for new drug candidates.

According to the Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, at the University of California, San Diego, many marine organisms are host to exotic compounds the molecular structures of which are completely different from those found in land plants and animals, and trigger different mechanisms in the human body.

Over the last three decades, the government-funded California Sea Grant has discovered potential treatments for inflammatory diseases and cancer, and the EU has funded similar work in its Framework Programmes and forthcoming Horizon2020 innovation programme.

Finding these new compounds is only half the battle, as they must then be developed into viable drug candidates. This is where the PharmaSea project steps in.

PharmaSea’s objective is to identify the best drug leads from the many molecules that are discovered under the sea, and in the most efficient way possible.

“There are lots of unexpected and unusual molecules and microbial genomes available from the sea and in extreme environments,” says Meredith Lloyd-Evans, one of the dissemination partners in the PharmaSea project.

“Previous projects have looked at those, generated them and then got stuck, because there are still bottlenecks when trying to move interesting molecules through to industrial use.”

PharmaSea is working to combat these bottlenecks by accelerating the culturing process, so that marine molecules can be cultured and manufactured on an industrial scale, and speeding up molecule screening and analysis, so that researchers can be confident that the project’s new finds haven’t been recorded elsewhere.

It aims to deliver one or two drug candidates to pharmaceutical companies for further development by the end of the four-year project.

The challenge is finding the molecules that hold the most potential for usefulness, and making them more appealing to industry as viable candidates for product development, Lloyd-Evans explains.

“The samples have to be validated in a way that makes them more attractive to the pharmaceutical, cosmetics, biomaterials or food companies.

“You have to have some data available that will de-risk the enormous cost that established industries have taking molecules forward.”

Sorting the catch

The potential of marine-derived compounds for use in pharmaceutical and cosmeceutical products has long been known. In the 1980s, an anti-inflammatory compound called pseudopterosin was isolated from a sea fan, and later patented and licensed to cosmetics company Estée Lauder, which used it in a range of skin creams.

California Sea Grant isolated manoalide, an anti-inflammatory agent, from a sea sponge, and it was patented by the University of California and licensed to Allergan, a company that was developing a treatment for the skin condition psoriasis.

While it was later abandoned as a drug candidate, manoalide was developed as a commercial reagent for studies on an enzyme that has been linked to causing inflammation and pain.

These projects have generated a healthy number of new compounds, but Lloyd-Evans says that the most important task is filtering out the best candidates.

This applies especially to conditions such as epilepsy or depression where new compound discoveries are uncommon. “Finding molecules that could be effective in whatever models there are currently for neurodegenerative disease would be a positive step as it’s an important area that isn’t being properly addressed,” he says.

PharmaSea is also looking for potential candidates for inflammation and diseases of the central nervous system.

To ensure its finds haven’t previously been discovered by other projects, PharmaSea has a team of experts who can identify and screen the molecules in different circumstances, and employs partners who compare the molecules with other structures using computers.

It is working to automate, or semi-automate, this process.

“To check your discovery isn’t the same as something else in an existing library of chemical structures, you need to know quite a range of things about the molecule’s structure, and how it behaves, by performing different laboratory-based analyses,” Lloyd-Evans explains.

PharmaSea’s consortium of partners was brought together for its screening and data-mining skills. It includes companies engaged in information management as well as research groups.

“This ensures that it becomes easy to compare our information about our molecules with information that is in libraries and other culture collections,” he adds.

Going deeper

Many of the compounds with therapeutic potential have been sourced from invertebrates that live in extreme environments, thousands of metres under the sea. It’s these extreme environments that give the compounds their relative novelty.

"all the consortium partners have access to anything generated in the course of the project, while the project is going on, for a royalty-free licence."

“Deep ocean trenches are islands of diversity in which evolution may have progressed differently,” says Marcel Jaspars, PharmaSea’s project leader.

“The work on microorganisms from deep trenches shows they are indeed different. The chemistry derived from these, though limited in scope, shows high novelty.”

Although we have a good understanding of the benefits of the compounds they produce, the challenge of physically reaching them remains. However, this challenge does present opportunities for creating some IP.

“With the deep sea, the difficulty is getting to it,” says Lloyd-Evans.

“Even if you have an ocean-going boat, you still need some kind of sampling mechanisms that will get you down to depths of as much as 5,000 metres.”

One of PharmaSea’s partners, Deep Tek, is working on a streamlined device for deep sea sediment and material sampling.

“That would be a significant technical advance and certainly something that we would want to exploit.

“We would sell it to other expeditions and expeditionary boats because it would be a good adjunct to the kit those boats have to carry.”

End game

The PharmaSea project started just under two years ago, launching in October 2012, and it’s now looking for partners that would be responsible for directly developing the molecules the project finds and exploiting them in a clinical context.

“We’ve managed to get funding for early stage, pre-clinical evaluation and validation,” says Lloyd-Evans.

“Because the project partners have been chosen to include small-to-medium-sized entities (SMEs) and applied researchers, we can then take exciting molecules to a stage where they can be moved into full-stage clinical development.”

PharmaSea has a consortium agreement in place, so that all concerned parties will know how to deal with the project’s commercially exploitable outcomes, such as patent-eligible subject matter like new molecules, biomaterials or medical treatments, at the end of the project.

“The general rule here is that all the consortium partners have access to anything generated in the course of the project, while the project is going on, for a royalty-free licence. Other than that it’s up for discussion between the partners,” he explains.

With another two years to go, PharmaSea is also planning to invite a group of end users to get involved; they will be granted first access to information about the project’s results. It also has an internal group that will discuss how to handle IP produced by the project.

“The options are to encourage patenting, to encourage free access, or to encourage creation of a package of information and potential patentable IP that might be licensable through the end user group if they decide to do it,” Lloyd-Evans says.

One idea is to put together suites of molecules, packaged with an amount of screening information, and make those available to researchers.

While PharmaSea has generated many unique molecules, Lloyd-Evans says that patenting isn’t necessarily the “first line of attack with IP”.

The project now has some definite outputs, and it’s time to start bringing the group together to decide what to do with it, he says.

“Part of my job will be to write a technical brief for the things we have produced so we can distribute them to our community and elsewhere to raise interest in the outputs and see what happens.

“Effectively that would be an IP clearinghouse-type activity,” he says.

With a wealth of interesting molecules lurking in the oceans that cover about 70 percent of the world’s surface, we could be on the brink of a surge in marine organism discovery.

This can only be a good thing, as the need for new medicines is nowhere near being fulfilled, although it remains to be seen what the best approach will be for protecting, while making available, these products where there is such a strong, urgent global need.