Sunday, February 23, 2014

Oceans, bacteria, and the quest for new drugs



A marine sponge of the genus Theonella. Photo by Nick Hobgood.
We rely on natural products in medicine: the vast majority of pharmaceutical drugs are thus of plant or microbial origin. (The purely synthetic drugs, which have no counterparts in the environment, are the exception rather than the rule.) To name potent examples of natural products, take antibiotics (discovered in fungi and bacteria), the anti-malaria drug artemisinin (isolated from sweet wormwood) or simply aspirin (salicylic acid is present in willow bark). Many people, I think, forget about this, as they oppose a so-called ‘natural’ medicine to a ‘chemical’ medicine (the pills you get from your doctor). 

It is not easy to find new active compounds, however, and much more difficult to test them and turn them into a real medicine. The situation doesn’t look that good, notably because of the high increase of antibiotic-resistant strains of bacteria, and the paucity of new drugs available. A natural environment that has long been recognized as a promising source of new chemicals is the largest on Earth—oceans—, and many researchers are mining the sea in search of new organisms and their specific biochemical abilities. For instance, the research project PharmaSea, funded by the European Union, was launched in 2013 with the goal of discovering new microbial organisms that could be the source of useful chemicals for medicine or industry. This team of academics and industry researchers plan to explore the deep bottom of the sea, looking for environments that are poorly known and potentially harbor interesting organisms. Here’s an excerpt from the project website:

Marine organisms that live more than 6,000 meters below the sea level are considered to be an interesting source of novel bioactive compounds as they survive under extreme conditions. "Trenches are separated from each other and represent islands of diversity. They are not connected to each other and life has evolved differently in each one", explains Marcel Jaspars [PharmaSea project leader]. “

PharmaSea is an ambitious project, and it may not be easy at all to get many new products out of it, but the goal has to be praised, as we surely are in need of new biochemicals, particularly new antibiotics.


Another exciting example of ocean biodiscovery was recently published in the journal Nature. It is the collaboration of research groups in Japan, Germany, USA and Switzerland, and led by Jörn Piel, professor in the Institute of Microbiology at ETH Zürich. (A summary of the findings was published on the ETH News website.) This team of scientists is interested in a species of marine sponge, Theonella swinhoei, which is known to produce many bioactive compounds (notably polytheonamides). The sponge, however, is not producing these chemicals itself; instead, symbiotic microorganisms are doing the job. It’s worth knowing that most sponge species live in close association with a large consortium of many diverse bacteria (not unlike the bacterial flora in our gut), and that most of these bacteria are unknown to us and can’t even be grown in the laboratory. 
Example of a bioactive compound from Theonella: Theonellamide F, a fungicide.

The group of Prof. Piel identified a new group of bacteria, living in symbiosis with Theonella swinhoei, which is responsible for the synthesis of most bioactive compounds in the sponge; they proposed a new genus name (Entotheonella) and even a new taxon (Tectomicrobia) to characterize these microorganisms. Many advanced techniques were necessary for this breakthrough, including single-cell genome analysis. 

The discovery of a new potent drug producer, as exciting as it is, is far from the end of the story. One major issue is to extract enough material to pursue clinical trials, something not easy with marine sponges, which at present cannot be cultivated. What is more, most of these compounds are too complex to be synthesized chemically. But if we could harness the biochemical ability of the sponge microorganisms, outside of their host, this would offer an alternative. That, unfortunately, is not guaranteed to work, as microorganisms grown in pure cultures in the lab often behave unpredictably (in that case, that could be by stopping the production of bioactive compounds). A third route exists: using bioengineering technology to transfer Entotheonella’s ability to produce bioactive compounds in other, more amenable microorganisms (say, yeast or E. coli). In other words, it’s still a long way to the development of useful drugs from sponge microbes. But, at least, there is a way.

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