Active substances from marine creatures
Source of healing since ancient timesFor thousands of years people have believed in the healing power of the sea. As the Greek dramatist Euripides says in one of his plays about Iphigenia, “The sea washes away the stains and wounds of the world”. The ancient Egyptians and Greeks examined the effects of seawater on human health. They credited the sea and the substances it contained with healing properties. Marine products have for centuries been an integral part of folk medicine all around the world. For example, sea salt has traditionally been used to treat skin diseases, and algae to treat parasitic worms.
In 1867 the French doctor La Bonnardière introduced the classical thalassotherapy (seawater therapy) and climatotherapy to Europe, reinforcing people’s belief in the therapeutic properties of the sea. However, mythologizing these powers has also brought forth irrational fruit – the notion that eating turtle eggs or shark fins increases virility, for instance. Unscrupulous businesses have exploited this superstition and are contributing to the decimation of numerous animal species.
High-tech equipment seeks out promising moleculesModern biomolecular and genetic techniques now make it possible to identify promising marine substances very rapidly. We have long known that the oceans are awash with unfamiliar bioactive substances that have healing or other beneficial properties. In many cases researchers have been able to ascertain the roles played by certain substances within the living organisms – the immune system for instance – and to explain the biochemical processes that occur. They believe that many new agents will be found in the sea and in marine organisms in future, since the oceans are home to millions of plants, animals and bacterial strains. Today there are approximately 10,000 known natural substances, most of which were isolated from marine organisms over the past 20 years. New technology such as nuclear magnetic resonance, which can be used to identify and analyse unknown molecules, even if the organism contains only a trace of them, has made the search much easier. More research is now being conducted on the ocean floor than ever before. Unmanned submersible robots are capable of diving to depths of several 1000 metres to take samples.
In spite of these advances and the enormous biodiversity in the oceans (Chapter 5), few marine substances have so far been officially approved for clinical use. A new substance must not only attack the molecules that are key to the disease process, but it must also not interact negatively with food or other medication taken at the same time. It must also be capable of manufacture on a large scale.
Active agents from the sea – perfect for peopleThe appeal of most of the marine substances already approved lies in their potency. They are valued because they are produced from different source materials and compounds than their land-dwelling counterparts. The special structure of the molecules and components such as bromine and chlorine apparently help to make them so effective. The substances are not normally used in their pure form. First the molecules must be chemically modified and tailored to the human metabolism. The following marine substances are either already in clinical use or show promise for the future:
- 9.2 > Europe did not rediscover the benefits of the sea until the late 19th century. People living inland began to travel to the coast for rest and recuperation – as here on the East Frisian island of Norderney, off the North Sea coast of Germany.
NucleosidesSome of the best-known natural marine products are the unusual nucleosides spongouridine and spongothymidine derived from the Caribbean sponge Cryptothetya crypta. These have been in clinical use for more than 50 years. Nucleosides are components of DNA. For a cell to divide it must first replicate the DNA in its genetic material, incorporating the nucleosides precisely into the new DNA. Nucleosides contain a sugar component, usually ribose. Spongouridine and spongothymidine, however, are arabinose-containing nucleosides. When these exogenous nucleosides are incorporated in the DNA, they inhibit the replication of genetic material, which is known as nucleic acid synthesis.
It was not long before this principle was being used to treat cancer and viruses because tumour cells divide extremely quickly, and even viruses need an active DNA synthesis in the cell to proliferate. Administering substances that interrupt the nucleic acid synthesis can greatly inhibit tumour growth. Thus the sponge nucleosides were developed into a substance for this particular purpose, a cytostatic drug. They were the basis for the synthesis of Ara-C (Cytarabine®), the first marine-derived drug approved by the U.S. Food and Drug Administration (FDA), in 1969. The virostatic agent Ara-A (Vidarabin®), which inhibits the proliferation of viruses, was approved in 1976, and is still used today to treat serious herpes simplex infections.
9.3 > Many effective agents are derived from marine sponges. Substances from the Elephant Ear Sponge Lanthella basta inhibit tumour growth. This sponge is abundant in the waters off the coast of Australia or Indonesia..
9.4 > Scientists first isolated prostaglandins from the coral Plexaura homomalla in the 1960s. This coral is found in the Caribbean and the western Atlantic Ocean at depths of up to 60 metres.
ProstaglandinsIn 1969 it was established that Plexaura homomalla, a common coral found in the Caribbean and the western Atlantic, is a rich natural source of prostaglandins. Prostaglandins are important hormones produced from tissues that control essential body functions such as blood clotting and extremely complex inflammatory responses. The coral prostaglandins from Plexaura homomalla and other species have been researched exhaustively and have provided vital knowledge on the prostaglandin metabolism of humans. No drugs have yet resulted from this research.
9.5 > Cone snails such as Conus textile mainly inhabit tropical marine areas. They inject venom into their prey with a harpoon-like tooth. Scientists have succeeded in deriving a very effective painkiller from this venom.
9.6 > Moss animals are tiny animals that live in branch and leaf-like colonies. Bryostatin – an inhibitor of tumour cell growth – is extracted from the bryozoan Bugula neritina. It is probably produced by bacteria on the surface of the colony.
PeptidesIt took nearly 30 years after the development of Ara-C for the next marine-derived substance to be approved for the treatment of human medical conditions. This was the peptide Ziconotide (Prialt®), which is derived from the venom of various species of marine cone snail. Peptides are large protein components. Accordingly, the cone snail toxin consists of a highly complex mix of different protein components called conotoxins. These conotoxins attack the metabolism of animals and humans at different points. In their natural environment the toxins paralyse their prey by blocking ion channels in the cell membrane – small apertures that are important to the transmission of nerve impulses. Instead of the pure snail venom, a modified version of the venom cocktail is used to treat severe chronic pain. The drug Ziconotide prevents ions from entering pain-sensing nerve cells. By doing so it blocks the nerves in the spinal cord that send pain signals to the brain. This drug is used for patients whose pain is so severe that it cannot be controlled by morphine medication. It is also used in cases of morphine-intolerance.
AlkaloidsEcteinascidin 743 (also known as trabectidin) is an alkaloid, or nitrogen-containing organic compound marketed under the brand name of Yondelis®. It is the latest marine-derived compound and was originally extracted from the tunicate Ecteinascidia turbinata, a simple filter feeder living on the sea floor. The substance was only approved as a drug in 2008. Ecteinascidin 743 interferes with a complex metabolic mechanism that confers drug resistance on cancer cells. It binds in the minor groove of DNA, slightly distorting the shape of the DNA, which obstructs the metabolism of the cancer cell. In greater detail, ecteinascidin 743 unites with the DNA repair protein TC-ER, then links with the DNA, thus preventing the MDR1 gene (MDR = multi drug resistance) – vital to the cancer cell – from being selected. This gene contains the blueprint for the MDR1 protein, the function of which is to discharge toxins and exogenous substances from cells. In cancer therapy, therefore, its effect is counterproductive because it also discharges medication from the tumour cells. This can ultimately lead to resistance and failure of the therapy. Ecteinascidin 743 blocks the production of MDR1 and thus prevents it from discharging the drug. Scientists hope that ecteinascidin 743 will reinforce the potency of other chemotherapy drugs by preventing resistance. Yondelis® has so far been approved for the treatment of soft tissue sarcomas – rare, malignant connective-tissue tumours.
Other cancer drugs from the deepA number of other marine anti-tumour agents are currently under study in clinical trials. They include bryostatin extracted from the bryozoan Bugula neritina, squalamine lactate from the spiny dogfish Squalus acanthias and sorbicillactone which comes from bacteria present in sponges.
Substances such as dolastatin 10 and dolastatin 15 isolated from the Dolabella auricularia snail and their progeny appear less promising. Clinical studies show that these anti-cancer agents alone are not capable of healing breast cancer or pancreatic cancer. They could conceivably be effective, however, when combined with other preparations.
- 9.7 > Scientists have successfully extracted many active agents from organisms that live in the sea or fresh water. Some substances have already been developed into drugs.
- 9.8 > Countless bacteria live in the outer cell layer, the ectoderm, of the cnidarian Hydra. Staining them shows how closely they are interwoven. Under the microscope the cell nuclei of Hydra appear blue and the bacteria red.
What is the true potential of marine substances?Many substances derived from the sea are already in commercial use as pharmaceutical drugs. Others have future potential. The following are some interesting theories and questions on the future of research into marine substances:
1. The sea provides prime candidates for new medications. But locating them and then producing them on a large scale is not easy. This, on the one hand, is because the living organisms are difficult to find in the endless expanses of the ocean, and they often occur in very limited quantities. On the other, it is impossible to keep many of these organisms under laboratory conditions for long periods, or to cultivate them. For many years the pharmaceutical industry has had automated procedures in place for analysing variations of known substances and testing their suitability as drugs. This high-output screening allows researchers to test entire catalogues of related substances very rapidly. However, the molecular structure of marine substances is often so complicated that, even after being proved effective, they cannot easily be replicated or modified. This is what makes them so difficult to locate and develop. Finding them is also an extremely time-consuming process that requires expensive equipment. The time and effort involved are usually considered too great by the industrial sector. For this reason, most marine substances have thus far been discovered, isolated and analysed by researchers at scientific institutes. Moving the substance from the laboratory to the marketplace can also prove difficult – partly because patent law can create a barrier between universities and industry. The researcher would like to publish his findings. But the industrial sector wants to keep the agent and the drug formula secret, for fear of competition. Professional articles published too soon can also obstruct patent approval. This is why the pharmaceutical industry has long overlooked the ocean as a major and important source of new drugs. But industry and academia are now collaborating in promising new ways, such as the creation of start-up ventures. During the past few years these kinds of young businesses have sparked important new initiatives in this field. A vital question will be how to fund these risky schemes, and how appealing such individual paths out of academic research are likely to be considering the overall economic situation.
- 2. Which organism is the actual source of the marine substance is not always clear-cut. Many substances have been isolated from invertebrates in the past. In many cases, however, these did not originate from the animal itself but from the bacteria or fungi living in or on it. Microorganisms can make up as much as 40 per cent of the biomass of sponges, many of which are also colonized by microalgae. It is crucial to know when microorganisms are the actual producers of the agent, because it is hoped that they are more easily cultivated under laboratory conditions than the sea-dwellers upon which they colonize. It was initially believed that harvesting sponges and other animals on a grand scale was possible, but it soon became clear that the species could easily be completely wiped out. The focus then shifted to breeding bacteria in the laboratory, a process which is seldom successful. In some cases researchers have achieved results, however. For instance, large quantities of sorbicillactone, a substance mentioned above, were extracted within a short time from fungal cultures derived from sponges. Nevertheless, the difficulty remains that cultivating unknown bacteria can be a time-consuming process.
- 9.10 > Biomolecules of water organisms such as hydramacin isolated from the Hydra polyp are often complex. This makes them difficult to reproduce in the laboratory.
- 3. Today the search for new substances is facilitated by culture-independent methods of genetic analysis. This does away with the painstaking and complicated laboratory culture of bacteria and other organisms. For many decades expensive chemical and biochemical analyses alone were used to verify the presence of effective substances. Today, thanks to modern genetic analysis, this can be done much more quickly and easily. The latest procedures search the genetic material of marine organisms for conspicuous gene segments that contain the blueprint for promising enzymes. Such enzymes are the tradesmen of the metabolism, building different substances. The development of such DNA-sequencing techniques is definitely the greatest advance in substance research of recent years. Large-scale sequencing projects can now trawl through the genetic material of thousands of marine organisms within a short time, searching for promising gene segments. One example is the Global Ocean Sampling expedition by the J. Craig Venter Institute in the USA, which played a significant part in decoding the human genome a few years ago. The focus of this institute is now turning increasingly to the sea. Its objective is to search the genetic material of marine organisms for economically significant metabolic pathways. Entire habitats can be subjected to sequence analysis. Such major projects process both the organisms and the microbes growing on them at the same time. Therefore the findings can no longer be attributed to individual species, but the researchers anyway are mainly preoccupied with learning about the genetic make-up of an entire habitat within a short time, and finding out whether that location harbours any interesting substances at all.