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Medicines from ocean depths
IF MORE than half the world’s drugs are inspired by nature and the ocean is the most chemically and biologically rich environment on the planet, then why are there no medicines from the sea? This is one question which used to bother me.
Over billions of years, life in the sea has evolved with a wealth of interesting and highly complex chemistry. Some of this has appeared in the strangest of places, produced by the weirdest of organisms — a chemistry that has exceptional potential for drugs. Sea sponges — metazoans of simple cellular structure with no sensory organs, no real tissues and no means to move — can provide defences against human pathogens such as viruses. However, harnessing these remarkable chemicals for human application has its challenges.
This article will chart a journey through this underwater chemical battlefield, then into the laboratory on the way to the clinic and the market. Along the way, we hope to reveal some of the reasons why a drug from the sea is an elusive entity.
Marine natural products
It has long been accepted that life evolved billions of years ago in the seas, and it is here that we find the greatest diversity of life. It is now believed that the chemical diversity found in marine organisms mirrors this biological diversity. However, there is little recorded usage of marine species to treat diseases, whereas there is a wealth of information about terrestrial species. Thousands of natural products have been described through academic and industrial screening efforts for pharmaceutical candidates.
The field of marine natural products is now almost 40 years old, and over 15,000 such compounds have been described in the literature. The field is international, and some key institutions in the field are Scripps Institutions of Oceanography, California; Harbor Branch Oceanographic Institution, Florida; Astra Zeneca at Griffith University, Brisbane, Australia, and the Marine Biotechnology Institute in Japan.
The search for bioactive marine natural products has been approached from unusual angles. An example is the study of toxins from venomous species. One study uses cone sail toxins to study ion channels in membranes, eventually leading to the development of novel analgesics.
With the supply problem resolved, marine natural products are set to take on a whole new life as therapeutics
Another approach to discover bioactive compounds involves collecting a range of taxonomically diverse species and screening their extracts. Using this method, it has been found that sponges (Porifera) and bryozoans (Bryozoa) are excellent producers of cytotoxic compounds with over 10 per cent of the specimens collected exhibiting bioactivity.
As a result, these phyla are now heavily investigated for anti-cancer potential. For example, we can plot the incidence of anti-tumour active extracts (from a broad collection and screening exercise) against the incidence of cytotoxic extracts organized by taxa, or growth form. If we do this for the sponges we find that those species that have heavy skeletal (spicular) armament, do not in general display interesting chemistry in a biomedicinal sense.
However, thickly and thinly encrusting fleshy species have comparatively high incidences of bioactive chemicals associated with them. Species that come from densely encrusting communities on the sea floor (as opposed to sponges not competing for space) have high incidence of bioactive metabolites with desirable qualities such as anti-tumour activity without gross cytotoxicity. Anti-tumour types of activity seem to be associated with those organisms that need to compete for space, hence keep neighbours at bay.
The aim is to find chemicals that are not just toxic, but those that have highly specific modes of activity. Understanding the roles of these compounds in nature can foster a more focused search and a smarter approach to coercing these organisms to produce compounds of specific medicinal use.
Sink or swim trends
The pharmaceutical industry has turned to technology-driven methods, such as combinatorial chemistry and rational drug-design to discover new leads. On the other hand, rational drug design, aimed at engineering a compound to block a target is an acknowledged route when the structure of the protein target has been defined. Either way, the dismal production rate of new chemical entities (drugs) in the last decade has been attributed to the loss of natural product discovery programmes from the pharmaceutical industry.
The strength of natural products compared to synthetic compound comes from the nature’s enormous chemical diversity. Put simply, nature is the better chemist. Its diversity increases the likelihood of finding treatments for diseases when the specific target or receptor involved in the disease is ill-defined.
With many of the technical difficulties connected with natural products now overcome and their intrinsic utility as ‘drug leads’ being recognized, the future looks good for a natural products of all types. This means that the old problems of hit reproducibility and the time taken from hit to structure, which could take months, have been circumvented, making the use of natural products much more tractable.
Bioprospecting vs biopiracy
There has been a perception that bio-prospecting is tantamount to biopiracy, that is, illegally obtaining biodiversity for screening with a view to commercializing successful finds and not providing due benefits to the country of origin. For natural product drug development to move forward there must be a watertight international policy on access and benefit-sharing that breaks down fear of unethical behaviour.
Agencies now prefer the term ‘biodiscovery’ to ‘bioprospecting’ as it is suggestive of the ethic now adopted. It is based on discovery without a view to ‘mining’ the resource later, with alternative methods to achieve sustainable supply. The taxonomy and sampling carried out for biodiscovery projects is often the first or only survey project in many habitats.
A major hurdle
There are several methods that can be applied to ensure an adequate supply of a biologically active compound from a marine source. These include collection, aquaculture, tissue culture, symbiont culture, chemical synthesis and molecular biological approaches.
The lack of a sustainable supply has blocked the development of many natural products, including terrestrial ones. An example is the anti-cancer drug TaxolTM from the bark of the Pacific yew tree (Taxus brevifolia), which was discovered in the late 1960s but did not make it to the clinic until the early 1990s. However, the route to produce the drug from a renewable supply, a compound obtained from the needles of the European yew tree (Taxus brevifolia) that could be modified to give TaxolTM, was not developed until 1989.
As an example of what may happen, a sponge (Lissodendoryx n.sp) collected from 100m depth on the lip of a marine canyon was found to contain the potent anti-tumour agent halichondrin B. There was a need for recollection of about 40kg wet weight of this material to enable enough halichondrin B to be re-isolated to facilitate the re-examination and follow up on its efficacy.
Drug candidates
While there are no marine medicines currently in the market place, there are numerous hot prospects. Many compounds are on the way to approval, and the next few years will see an increase in the number of marine compounds registered as pharmaceuticals. Two trends are apparent. One takes a global approach and looks at developing effective and inexpensive pharmaceuticals to treat millions affected by diseases such as malaria, tuberculosis and trypanosome diseases. Easily manufactured derivatives of artemisinin, originally isolated from the Chinese herb Artemisia anua, will be entering clinical trials for the treatment of malaria soon and should make a difference to millions of people worldwide.
The second trend offers the opportunity for personalized treatment with the advancement of pharmacogenomics (the science of understanding how genetic variations affect the way individuals responds to drugs). Moving away from ‘one size fits all’ pharmaceuticals allows the reduction of adverse events for genetic subgroups of the population for whom these drugs can be dangerous or even fatal. This is important as most marine natural products currently under development still base their clinical trials on their efficacy in the ‘average’ patient.
It is often easier to use a refined organism extract for cosmetic purposes than it is to have the pure active compound licensed as a pharmaceutical. This proved to be the case for the anti-inflammatory pseudopterosines, isolated from the Caribbean gorgonian (sea-whip) Pseudopterogorgia elisabethiae, which has been incorporated in the Estée Lauder anti-wrinkle cream ResilienceTM. The extract is currently obtained from environmentally managed sea-whip farms in the Caribbean.
A potent anti-inflammatory with potential for the treatment of asthma is a derivative of contignasterol, a steroid isolated from the sponge Petrosia contignata by Ray Andersen’s group at the University of British Columbia, Canada, and is currently in phase II clinical trials. It acts by inhibiting the release of histamines from mast cells.
Conus (cone snail) toxins have proved very effective in pain relief, and an example is the development of Ziconotide, a small cysteine-rich peptide isolated from Conus magus by Olivera’s group at the University of Utah, in the management of neuropathic pain. Ziconotide is an N-type calcium channel blocker and is 1,000 times more potent than morphine for the treatment of neuropathic pain.
There are many serious diseases such as malaria, tuberculosis, trypanosome diseases, Chagas disease and dengue fever that occur mainly in developing nations and cause millions of deaths and untold suffering worldwide. New tools for biomedical applications developed from marine sources have already made it to the market. Examples are the use of horseshoe crab (Limulus polyphemus) proteins in immunohisto-chemistry, jellyfish (Aequoria Victoria) green fluorescent protein in biosensors, and conotoxins in the study of ion channels.
The future
Will the oceans provide us with treatments for human diseases? With development gaining momentum, we believe that the hurdles will be overcome through innovation, imaginative thinking and groundbreaking research to give us an area of marine-derived compounds, and a major source of new pharmaceuticals and tools for biomedicine. Future developments will come from different arenas: ecology, the study of symbiosis, investigations of biosynthesis and molecular biology.
Biodiscovery in the past has been a haphazard process. Many marine species will only generate bioactive compounds when needed. They are metabolically expensive to make and, therefore, will not be made if not needed. It is possible to coerce many marine organisms to generate compounds on demand.
Molecular biology offers hope in the future for the large-scale production of bioactive metabolites isolated from marine invertebrates. The opportunities are to place these characterized gene clusters in alternative microbial hosts to achieve expression, or to clone large fragments of DNA from invertebrate and microbial symbiont into a host and screen for the presence of the relevant biosynthetic genes and or chemistry.
Further work in this field may enable expression of all natural products encoded in the genome of an invertebrate or its symbiont, not just those that are expressed under any particular set of circumstances (stress and infection, etc). With the supply problem resolved, marine natural products are set to take on a whole new life as therapeutics.
The writer arshad.saeed@iccs.edu is an HEC distinguished national professor who works for the Dr Panjwani Centre for Molecular Medicine and Drug Research, International Centre for Chemical Sciences, University of Karachi
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