On the brink of drug discovery

When you think about drug discovery, it’s easy to imagine shiny, white-washed chemistry laboratories with equipment only PhDs in their lab coats would know the names and utilities of. For those on the opposite side of the spectrum, drug discovery only comes to mind when thinking about clinical trials and animal testing. Thinking is in terms of products, not sources. And when we do start thinking about sources, we will find that the most unlikely of creatures offer us the best chances of discovering something that is unique and game-breaking.

This is what we hope to find at our lab at the Marine Science Institute at UP Diliman. The Philippine Mollusk Symbiont International Cooperative Biodiversity Group (PMS-ICBG) is a research program that focuses on biodiversity, drug discovery, biofuels, and basic research aimed at bacterial endosymbionts from mollusks — in particular, members of the superfamily Conoidea (venomous gastropod cone snails) and the bivalve family Teredinidae (an intriguing group of wood-degrading shipworms).

Microbial endosymbionts are bacteria that co-exist within the tissues of their host animals and are known to provide metabolites which act as defense mechanisms that aid their host’s survival. Studying these endosymbionts, we find a larger pool to search for bioactive drugs with potentials against diseases. Currently, no one fully understands why these creatures host these symbionts or why these bacteria produce these compounds, but they are there.

For cone snails that are well defended by a hard shell and venom, it is interesting to note that these snails contain within them bacteria that secrete compounds with antibacterial activity and even anticancer and neuroactive effects. It began with Filipino biochemist Dr. Baldomero Olivera’s fascination with these venom-producing animals. After his discovery of a cone-snail derived toxin, now developed as a clinical painkiller known as Ziconotide, attention was turned to what more the cone snail could offer in terms of pharmaceuticals. This led to the participation of medicinal chemist Eric Schmidt and marine microbiologist Margo Haygood, researchers studying symbiotic associations, and to a 2009 paper of Olivera, Schmidt et al. on the diverse bacteria that were cultivated from the tissues of three different species of cone snails.

From these three cone snails, 229 morphologically distinct bacteria were isolated, and 96 were identified as actinomycetes (a group of bacteria well known for producing bioactive metabolites). Four leads were generated from the DRG (dorsal root ganglion) assay, a neurological assay measuring real-time calcium response of many types of neurons and different receptor types to the bacterial extracts. This protocol is optimized to observe effects that are biased toward interactions with ion channels or receptors closely coupled to ion channels. The fact that these extracts demonstrate neuroactivity shines a torch on the potential of utilizing the bacterial diversity within the cone snail. It was this first study that led to the PMS-ICBG program which aims to isolate bacteria living in the tissues of many more cone snails, to grow the bacteria in the lab and identify the neuroactive compounds they produce.

PMS-ICBG has also brought into the light a rather obscure and inconspicuous animal that has been shown to harbor possible game-changing drug leads. A shipworm is not a worm. It is a bivalve, closely related to clams, but the shells are small and used as a drill, leaving the rest of the body soft and vulnerable to attack. More interesting about it, is that it is cellulolytic. It feeds on wood. Like cone snails, it also harbors a diverse and unusual set of microorganisms, some bacteria that help the shipworm digest the wood, other bacteria that are defensive and display antimicrobial activity.

All this is exciting news for research, as it provides a new source for applications for biofuels, as antibiotics and against pain and cancer. It gives hope for the medical industry to fight against organisms that have developed resistance to current medication.

PMS-ICBG operates under the leadership of Margo Haygood, in association with Schmidt, Olivera, and the addition of marine microbiologist/geneticist Dan Distel, evolutionary biologist/taxonomist Gary Rosenberg, and the MSI’s natural product chemist Gisela Concepcion. Since the program’s inception in 2008, it has produced two pending patents for central nervous system drug applications, 14 research publications, 100 international presentations in different conferences and meetings, and 35 researchers trained both in the US and in the Philippines. From a collection of 1,962 microbial strains isolated and documented, 130 compounds have been identified, 48 of which are new.

It will take years and probably hundreds of compounds before finding one that is clinically relevant in terms of both potency and selectivity and it will take longer before it is developed into a drug. But for now, investigating how these compounds work may help the design of new drugs and the understanding of the molecular mechanisms of their effects on cells. The PMS-ICBG has demonstrated mollusks and their bacterial symbionts as a rich source of novel compounds, and through discovery, this gives value to basic research that explores, documents, and conserves biodiversity.

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Alexis D. Guerrero is a graduate student at the UP Marine Science Institute majoring in Biotechnology. She is a researcher in the PMS-ICBG program where she isolated and cultured microorganisms. Her current research topic is on coral microRNAs under Dr. Cecilia Conaco. E-mail at [email protected].