The Pharmaceutical Journal
Vol 268 No 7197 p655-656
11 May 2002

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Bermuda Biological Station for Research (www.bbsr.edu)

How scientists are persuading the oceans to give up their secrets

Biopharmaceutical companies over the past decade have funded many research programmes around the world to initiate the mammoth task of searching and analysing what bioactive substances are in the seas.

The Bermuda Biological Station for Research (BBSR) is just one such site. The BBSR has access to a range of marine environments within easy reach, ie, inshore, ocean floor, shallow and deep sea. However it has targeted specific sites and species to hunt for potential medicines.

Biodiversity

Like many researchers, the BBRS focuses on a place with huge biodiversity — the coral reefs that surround Bermuda. The reasoning is that here is an environment where organisms are faced with a diverse and concentrated number of predators, competitors and prey. This means that they are under more evolutionary threat.

Dr Hank Trapido-Rosenthal, a molecular biologist at the BBSR explains: "The coral reef is the aquatic equivalent of the rain forest — a place where biodiversity is at its highest and least understood. There are a lot of chemical interactions between the organisms and there is a lot of potential for important drug discovery."

The BBSR has focused on sponges (eg, Dysidea etheria, Pseudoceratina crassa, Chondrilla nucula), which are primitive multicellular invertebrates. "They are soft organisms that are fleshy and they cannot run away, so why have they not been eaten into extinction?" asks Dr Trapido-Rosenthal. "The consensus among marine biologists is that sponges and their symbionts (bacteria that live in symbiosis in or on them) are talented in the arts of chemical warfare. When a predatory fish takes a bite they load it with toxins or noxious compounds. The fish has an intensive learning experience and as a result the sponge does not get gobbled up into oblivion."

In addition a sponge filters about 10,000 quarts of sea water per hour. As it filters a lot of bacteria will settle in the sponge. Whether the chemicals that protect the sponges are secondary metabolites or are produced by symbiotic bacteria is unknown. But the hope is that some of these biologically active molecules are of use.

However, there are problems that biopharmaceutical companies and their partners have had to address. Scientific research is slow and tedious. Given the size of the area being studied (70 per cent of the earth's surface) and the ambiguous aims of the work, these programmes may appear, well, a drop in the ocean. As such, biopharmaceutical companies and other sponsors could well find it an expensive waste of time.

Environmental concerns

There is also environmental concern. Dredging up large areas of seabed or "trimming" back the coral reefs as they screen thousands of samples for that one blockbuster molecule is not socially acceptable and could be politically and commercially dangerous. Even when an interesting find has been discovered there may be the question of enough of a supply to undertake any significant reasonable large-scale research. Take, for example, bryostatin-1. This compound was isolated from a bryozoan (Bugula nerita) or "moss animal" that forms moss-like colonies of interconnected individuals on rocks, wharfs and ship hulls. Bryostatin-1 is now in phase II human trials at several places in the United States as an anticancer drug. The problem is that, should it eventually be approved, it would remain costly and rare. At present, researchers need 14 tons of harvested Bugula to produce half an ounce of bryostatin-1. Another possibility is to synthesise it, or a similar chemical, but it is complex and therefore likely to be expensive produced by that route, too. In the meantime, obtaining enough is a stumbling block.

Contract

That is where the BBSR's contract with Diversa Corporation is of interest. "There has been a shift in emphasis in the past few years," explains Sandra Zielke, a biotechnologist at the BBSR. "In the past a marine microbe would be isolated and then cultivated to see what interesting chemicals are produced. This was slow. Now we skip this stage. Rather than taking marine samples and then culturing them to see what the different microbes produce, the BBSR takes mixed uncultured samples, with unknown properties and extracts the DNA, as whole genes or DNA fragments. There is no particular regard from what organisms the DNA is from." The BBSR takes the mixed DNA samples from the sponges and send them to its partners Diversa.

Diversa, based in San Diego, California, uses what it terms "ultra high-throughput" screening methods on the samples supplied from Bermuda. Diversa ligates the DNA fragments to a vector and brings this into the host cell. The host cell is usually a fast growing microbe that can easily be cultivated, eg, Escherichia coli. These recombinant DNA samples are then stored in gene expression libraries and also, if they contain larger pieces, multi-gene pathway libraries. They are then screened for bioactive molecules using robotics and bioinformatics (a confluence of biology, computational and information sciences).

Diversa says it can screen up to a billion recombinant DNA samples a day. Any bioactive molecules produced can then be tested for usefulness, including in vitro, for pharmaceuticals. By disregarding the source of the DNA this ultra high-throughput method should speed up the process of searching the marine world for useful molecules. Diversa suggests that it may, also, uncover valuable DNA from rare microbes or recessive genes that would otherwise be unlikely to be captured. Since less than 1 per cent of micro-organisms in nature can be cultured in laboratories, this strategy permits a way of researching them, even if just to extract their DNA while not knowing from what organism it came.

Tranquil

The expression "ultra high-throughput" may well suit a large biotech company yet it seems ill fitting with the rather more tranquil environment of the BBSR. The pace of life in Bermuda appears more placid. Also the romance of knowing the source of natural chemicals may be lost.

This is not science for science's sake. However, using this method it is possible to carry out screening using only small samples. By extracting small samples of DNA for analysis there is no need for mass extraction of organisms from their natural habitats. This reduces damage to delicate ecosystems.

It is to be hoped, then, in the future, that the charm of places such as Bermuda will still be there and marine habitats be protected, while we will have the benefits of useful biochemicals and pharmaceuticals that have originated from the sea.

Mr Deeney is a pharmacist in Bermuda

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