Marine sponges are a rich source of bioactive compounds, which have the potential to provide future medicines. Since biological production is particularly needed for early drug development, the main challenge is to establish generic techniques for small-scale production of marine organisms.
Screening for bioactive sponges in sponges began in the mid-20th century. Bergman and Feeney isolated some of the first nucleosides from the Caribbean sponge Cryptotethya crypta in 1949. These nucleosides appeared to have antiviral properties and synthesis of these nucleosides resulted in the production of Ara-A (active against herpes) and Ara-C (effective in leukaemia treatment). As a result, Roche Research Institute of Marine Pharmacology started pioneering research in marine natural product drug discovery in the mid-1970s and scientists began to explore the chemical diversity found in marine organisms and its potential for drug discovery (Pomponi, 2001). More than 20,000 novel, marine-derived chemicals have been discovered since 1965, of which hundreds have potential pharmaceutical applications (Blunt et al., 2009). Marine sponges have continuously been the most prolific source of newly discovered bioactive compounds, with more than 7,000 sponge-derived, novel molecules (Blunt et al., 2009). Table 1.1 lists sponge-derived metabolites that have advanced to clinical trials.
Despite their enormous biotechnological potential, only few marine natural products have been successfully developed into products for the market. A major obstacle for the development of these products has been the lack of sufficient supply of biological material. Although controlled chemical synthesis of the bioactive molecules (or their analogues) is the preferred production method for pharmaceutical application, material obtained from natural sources is often needed for the first part of the drug development process. This is due to the fact that most bioactive natural compounds are chemically complex structures that cannot be synthesized easily. For example, to produce the anticancer compound halichondrin B, over 30 synthesis steps are needed. Investments in establishing a synthesis route for complex molecules are usually not done until the potency of the compound concerned has been sufficiently proven (i.e. after completion of preclinical development studies or even after phase 2 clinical trials). This means that for all studies up to phase 1 or 2 clinical trials material has to be obtained from natural sources. Since many of the marine-derived compounds are found in nature in minute quantities tons or thousands of tons of fresh material may be needed to supply sufficient amounts. It is obvious that such large quantities of biomass can never be harvested from nature without risking serious damage or even the extinction of the respective species. Culture of marine organisms that produce the bioactive compounds may overcome the supply issue (e.g. Dumdei et al., 1998, Mendola, 2003, Mendola et al., 2005), but at present, many marine organisms are considered unculturable. This paradox (early drug development being dependent on biological production methods that do not exist), which is often referred to as “The Supply Issue” (e.g. Osinga et al., 1998, Munro et al., 1999, Faulkner, 2000, Fusetani, 2000), emphasizes the need to establish appropriate culture techniques. Since biological production is particularly needed for early drug development, the main challenge for marine biotechnologists is to establish generic techniques for efficient, small to medium scale production of large numbers of marine organisms.
Depending on the product of interest, different cultivation approaches may be applied to achieve the supply of sufficient quantities of sponge-derived, bioactive compounds. When product concentrations are high inside the sponge or if the sponge itself is the product (e.g., bath sponges), cultivation of adult sponges is most likely the best option (Sipkema et al., 2005b). However, many secondary metabolites are present only at low concentrations. In this case the amount of sponge biomass required is simply too high and to obtain a proper production system first the product concentrations have to be increased. The use of in vitro cell cultures may then be the method of choice. In these cultures, culture conditions can be controlled and can be manipulated to obtain elevated product concentrations. Also other biotechnological approaches, like metabolic engineering or random mutagenesis can be used to increase the productivity. In other cases, when the compound of interest is actually produced by a microbial symbiont of the sponge, the sponge may not be needed at all and the production system would consist of only the symbiont, if of course it is possible to culture the symbionts separately. If this is not possible or if the compound is partly synthesized by the sponge and partly by the symbiont, some kind of co-culture may be required. Thus, different molecules will require different production system and it is therefore important to have a versatile set of cultivation tools.
With BluePharmTrain we aim to contribute to solving the supply problem by developing new ways to unlock the biochemicals produced by sponges.