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In both the pharmaceutical and agrochemical industries, there's a worldwide demand for new substances. Substances can be defined in two ways: From the industrial point of view, they are marketable substances with either a pharmaceutically or agrochemically utilizable profile. From the biological perspective, they show a certain effect in a natural system, e.g., means of defense or marker substances. Conventional substance libraries, which are used for testing systems to find agents, only contain a limited number of fundamentally different types of structures (heterological structures).

The largely unexplored marine world is host to vast resources of new heterological structures and marketable substances. Today, we still only know and understand very few of these marine agents or the underlying processes (see box 1). Of all known 110,000 natural substances, only about 7000 are from marine sources. But among those are very interesting agents such as cephalosporines, which are well established on the market. Medications with antiviral or anti-HIV activities (ara-A, Vidarabin; ara-C, Alexan) are based on arabino-nucleosides, which Bergmann isolated from the Caribbean sponge Cryptotethya crypta in 1950. Just recently, our laboratory Thetis was able to isolate a remarkable lower molecular substance. Its basic structure has been discovered for the first time.

Industrial agent development is cost-intensive and lengthy, and in many cases it is only possible with the collaboration of several scientific disciplines (see box 2). The industries estimate a time frame of about 10 years and a budget up to 900 million DM (about US$410 million) for the process of developing a new substance. During this time, many scientists with various backgrounds and from different disciplines are working together.

Examples of Substances of Marine Origin

  • Pardachirus marmoratus, a plaice species, excretes a milky secretion in case of danger or injury which causes every shark to flee instantly.

  • A chemical communication between the sea anemone Radianthus kuekenthali and the anemone fish that lives in the tentacles. The sea anemone recognizes the fish because of a cocktail of lower molecular substances that are excreted through the fish's skin. The anemone does not consider the fish as food and protects it in exchange for food that the fish brings into this symbiosis.

  • The mollusk Conus textile produces a toxin, the so-called "King Kong peptide," that when applied on prawns leads to male threatening gestures, even against much bigger enemies. These peptides and other proteins are of major interest as substances affecting the central nervous system.

  • Fluorescent or glowing proteins, which are substantial to molecular biology today, were developed from research interest in the phenomenon of glowing marine organisms, such as Aequorea aequorea (a jellyfish) or Noctiluca scintillans (a dinoflagellate).

  • The observation that some macroorganisms like sponges or bryozoes never get overgrown lead to the discovery of antibacterial or tumorstatic substances.

The discovery process begins with marine biologists who focus on systematic taxonomy and physiology. This first step is crucial because without exact species classifications or knowledge about the ecological surroundings it is rather difficult to find specific organisms in the complex marine habitat. Despite genome and genetics, PCR and other modern techniques, the unambiguous classification is extremely important for substance or agent research. A genetic fingerprint is presently not very helpful because of the lack of databases for both marine macro- and microorganisms. Additionally, marine macroorganisms, such as sponges, host different microorganisms to up to 40% of their own weight. So far, little is known about this coexistence, and therefore a genetic fingerprint is more a summary of a multispecies state.

Industrial Agent Development

Providing testing material from natural resources like the ocean.

  • Screening or testing of the organisms' raw material extracts that are composed of a variety of substances under certain pharmacological or agrochemical indications. Generation of positive or false-positive hits. Second testing cycle.

  • Isolation and structural definition of active substance (hit).

  • Determination of toxicity and side effects; first studies on animals (rodents and nonrodents) that may lead to the leading structure.

  • Optimization of the leading structures' pharmacological effects through chemical variations of the molecular structure. Determination of structure-substance and substance-receptor relations with nuclear magnetic resonance or x-ray spectroscopy.

  • Consolidated research on toxicology and pharmacology, which may lead from leading structure to the substance.

  • Testing of the substance in clinical phases I, II, and III.

  • Licensing, clinical phase IV, application observations.

  • Beginning of production and marketing (mostly parallel).

  • In the next phase, natural substance chemists isolate positively indicated substances from tested rare extracts of marine organisms. Analytic chemists define their structure of the active compound with state-of-the-art methods such as nuclear magnetic resonance or x-ray spectroscopy and assign a certain effect in collaboration with toxicologists and pharmacologists. With help of synthetic-deductive chemistry, the effects and side effects of substances are modulated.

    All these described steps of pharmacologically or agrochemically oriented substance research can only be conducted in private industries, especially when given the fact that many steps in industrial development are meant to optimize newly discovered basic principles and therefore are not suitable even for sophisticated master's or doctoral theses.

    On the other hand, there are tremendous opportunities in pure research and possibly, resulting from this, in industrial applications, mainly due to the fact that most areas of the marine habitat are unexplored. As mentioned above, chemical communication or the evolutionary effects of environmental stress are interesting subjects. Which receptors have been developed by organisms to gather information about food, enemies, allies, or slow changes of their environment? What influence does the environment have regarding the genesis or extinction of species, which substances are developed by them to withstand this stress and to survive, how do their primary and secondary metabolite patterns change?

    Marine biotechnologies are currently not only in a dynamic phase of scientific development, they are also becoming more economically important. Coastal countries or national research institutions regard the marine habitat as a major financial source and collect marine macroorganisms in both private and federal institutions to sell them to the industry or public institutions.

    It is now undisputed that the marine habitat contains a vast number of new structures, compounds, and substances. The last few years have somewhat caused a "gold rush" and many substance researchers are trying their luck with the oceans, be it either marine fungi or the industrial growing of marine sponges to produce substances. Some prefer the deep seas, others the coastal waters, in their search for marine microorganisms. Also, using the genome or the proteome might result in new microorganisms through the implementation of biosynthesis cycles. Even nonnatural substances seem possible with methods of biocombination. With a little creativity, industrial applications can be foreseen in many of the results from pure research, resulting in outstanding career possibilities for young scientists.