Sponges and humans... alike in many ways

In November 2010, a new drug for cancer named Halaven (generic name eribulin mesylate) was approved by the US FDA (Food and Drug Administration). Halaven was shown to extend the life of patients with metastatic breast cancer who had developed resistance to today’s leading anticancer drugs Paclitaxel (Taxol) and Doxorubicin. Halaven was the result of decades of challenging intensive research at Japanese and US universities, the US National Cancer Institute and the Japanese pharmaceutical company EISAI.

Halaven kills human cancer cells by blocking mitosis (cell division). Mitosis requires the movement of microtubules — which are part of the structural network of the cell’s cytoplasm. Microtubules move as their component proteins called tubulins continuously assemble and disassemble until the cell divides into two daughter cells. (All cell biology students would know this.) By binding tightly to tubulin, Halaven inhibits tubulin assembly and microtubule dynamics.

Halaven is a large “small molecule” drug. It has a molecular weight of 826.0 (729.9 for the free base) which is high compared to most drugs (MW ~300-400).  It is a macro-cyclic structure (meaning it contains a large ring) with many small rings containing oxygen groups (therefore capable of strong polar interactions) and it has 18 asymmetric or chiral carbon centers (implying it is a constricted, specific 3D structure).   To a chemist, this means that Halaven is a complex chemical structure and is very difficult to synthesize. Unless a compound can be produced in large quantities, it cannot become a drug. Large quantities are needed to test a drug lead all the way to clinical trials. EISAI’s synthetic chemists succeeded in synthesizing Halaven in ~60 steps (~60 organic chemistry reactions) — a major breakthrough for what was considered the most challenging drug synthesis ever undertaken by EISAI.

Where did EISAI get this drug lead? From a sponge named Halichondria okadai commonly found in the Pacific coast of Japan. The Japanese scientists who first studied this sponge discovered a much larger, highly toxic compound which they named halichondrin B. Medicinal chemists and pharmacologists later figured out through SAR (structure activity relationship) studies that only a part of the structure of halichondrin B was needed to kill cancer cells. This became the basis for designing and fully synthesizing Halaven. 

How long have sponges been producing cytotoxic compounds such as halichondrin B? For hundreds of millions of years. Why do sponges produce these molecules? We don’t really know for sure, but we think that being soft, sedentary, physically defenseless creatures, sponges had to evolve a chemical arsenal to defend themselves against predators, to compete for space and nutrients in the coral reef by inhibiting the growth of their neighbors, and to regulate their own growth. In all, to survive successfully in the sea for all this time.

Last week Cecilia Conaco shared with us in Star Science her fascination with sponges and showed how we can actually trace the evolution of these primeval animals to modern animals, through the cellular and biomolecular structures they possess. The international team she worked with was surprised to see that sponges share nearly 70 percent of their genes with humans. I share this fascination for sponges with Cecilia. I realize how smart sponges are, having prototype structures for synapses, and am in awe of this wonder of Nature. I think of sponges as my oldest ancestors, being the earliest, most primitive metazoans (multicellular animals) that lived as early as the Pre-Cambrian period (~>600 million years ago).

At the UP Marine Science Institute, we have studied sponges for many years, isolating compounds that act on different cellular and molecular targets involved in cancer. Most remarkable is a blue Xestospongia sp. sponge that produces renieramycins which are among the most potent compounds ever isolated from sponges. Like Halaven, the renieramycins have a complex 3D structure. By binding to the minor groove of DNA, Renieramycin M inhibits DNA replication and kills cancer cells. When we combined Renieramycin M with Paclitaxel or with Doxorubicin, the killing was even better. This tells us that drugs can act in synergy, and combination therapy is a good strategy for reducing doses of drugs and their toxic side effects on normal cells.

Lately, we have been isolating microorganisms that live in sponges. It is likely that many compounds found in sponges are produced by their “micro-biome.” We are able to culture some of these microorganisms in fermentors or bioreactors in the laboratory, which means that we are able to produce anticancer or antimicrobial compounds without having to collect large quantities of the sponge.

I can think of many more projects on sponges to do — mostly on sponge proteins — if only we had the resources, researchers and graduate students we need. When one breaks apart sponge tissue and disperses sponge cells, after some period, the sponge cells re-aggregate. Sponges have lectins (carbohydrate-binding proteins) lodged on their surfaces that are involved in cell-cell recognition and aggregation. Some lectins have antimicrobial properties, others stimulate stem cell growth and proliferation. Sponge cell types are few; one is the archaeocyte — a stem cell which transforms or differentiates to a specific cell type depending on the needs of the sponge. Archaeocytes could serve as good models to study human stem cells.

When sponges take up water, their volume increases more than ten-fold. There must be highly elastic sponge proteins that we could make use of. Sponges have siliceous (silica) spicules as their skeleton. Imagine how silica is deposited on to the organic material (biosilica) by an enzyme called silicatein that the silicon nanotechnology industry could learn from. The type of sponge known as glass sponges that live in deep waters, have the highest content of siliceous spicules. Glass sponges produce better fiber optics materials than synthetic fiber optics.

If we want to understand sponges better, imagine ourselves as sponges living a long time in the ocean. If we want to culture a marine microorganism (MMO) from a sponge, let’s think like that MMO living in the sponge. The fascination and learning would be endless. We would be bridging the gap between humans and sponges and the rest of nature, learning that we are all alike — in many ways.

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GP Concepcion is a professor of the Marine Science Institute, University of the Philippines Diliman where she teaches graduate courses and leads marine-biodiscovery projects and biomedical research. She is an academician of the National Academy of Science and Technology. She is currently the vice president for academic affairs of the UP System. E-mail at [email protected].