Scientists throughout history, from the ancient Amazonian shaman to the modern day laboratory technician, have searched to leverage nature to help mankind achieve prolonged life and better health. Earth’s plants and animals have provided the active ingredients in the development of most medicines designed to achieve this end; however, while the resources that land-based life has to offer have been examined extensively, the surface of the ocean has only recently been broken. The potential held by marine life to develop natural therapeutics and gain a better understanding of the human body is just now being realized. By identifying and harvesting aquatic organisms with unique chemical and physiological traits, scientists can begin to transform and adapt these natural abilities to a diverse range of human medicinal achievements. From muscular enhancement and neural regeneration to blood purification and anti-cancer therapies, marine life holds the potential to create a novel, potent breed of oceanic medicine.
Muscular Enhancement
The toadfish and the skate are not especially beautiful or exciting creatures, yet the former possesses the fastest twitching muscles in the vertebrate world and the latter has a visual capacity far exceeding that of a human. Toadfish can vibrate their swim bladder muscle up to 200 times per second, more than twice the speed of a rattlesnake tail and at least 40 times faster than the strides of the fastest human runner, as shown in Fig. 1. Their evolutionary advantage has attracted the recent attention of scientists looking for clues on how to help all kinds of failing human muscles; as muscle physiologist Iain Young noted, “When you want to develop a new system for a Ford Escort, you use the Formula One model to see the extreme version of motor performance” (1).
Larry Rome, who studies toadfish both at the University of Pennsylvania and at the Marine Biological Lab in Woods Hole, Massachusetts, attributes the toadfish’s ability to a protein called parvalbumin. Parvalbumin, aside from its presence in toadfish swim bladders, is present in human skeletal muscles. Researchers are beginning to examine potential parvalbumin usage with regard to cardiomyopathy, a muscular disease where the heart loses the ability to relax normally and cannot properly pump blood (2). The possibility of parvalbumin insertion into a human heart afflicted with such a disease could prove to benefit the thousands of people diagnosed with cardiomyopathy every year.
Researchers studying blindness and retinal infections hope that skates’ eyes can help them in the same way that toadfish muscles are aiding the study of cardiomyopathy. Unlike human eyes, which contain two kinds of light sensitive cells (rods and cones), skate eyes only use rods to detect light in both the lightest and darkest conditions (1). By examining skates, researchers can begin to understand what goes wrong in rod cells that cause retina-damaging infections, such as retinitis pigmentosa, a disease that can lead to total blindness and affects about 100,000 Americans (3). Research into marine-based muscle therapy could hold the key to solving prominent degenerative diseases.
Neural Response
Ziconotide, commonly known in the United States as the pharmaceutical, Prialt, is a marine-derived drug that has been tested for the treatment of chronic pain. The drug’s active ingredient consists of a peptide found in the venom of fish-eating marine snail, Conus magus (see Fig. 2). This species, one of a variety of Pacific cone snails, possesses poisonous stingers that can paralyze or kill fish and humans alike; over 30 people have died from cone snail attacks. The drug was developed by biochemist Baldomero Olivera, whose boyhood hobby of collecting cone snail shells motivated the pursuit of a career investigating these creatures, in the hopes that, “if these snails were so powerful that they could paralyze the nervous system, smaller doses of the compounds from the venoms might have beneficial effects” (4).
Olivera assumed correctly—today, Prialt serves as one of very few chronic pain drugs. The drug works by targeting and blocking calcium channels in the spinal cord, which control neurotransmission at many synapses. Pain inhibition had never previously been investigated through this pathway, which proves to be 1,000 times more potent and efficient than morphine. Yet, this drug is even more powerful in that it lacks morphine’s addictive potential and exhibits a reduced risk of mind-altering side effects (5, 6). A 30-year-old man who had suffered from chronic pain from and early age—associated with a rare soft-tissue cancer—reported to scientists that his pain had abated within days of taking Prialt (4). Thousands of others have received experimental treatment with overwhelmingly positive results.
While many simple marine animals defend themselves by inhibiting or paralyzing neural receptors, only a specialized few have the capacity to spontaneously regenerate their central nervous system. One such organism gifted with this evolutionary advantage is the toadfish, the same animal privileged to have the fastest muscle response in the vertebrate world (1). Along with a plethora of unanswered evolutionary and biological questions, the toadfish has introduced the possibility of copying and adapting this trait into human beings. While a human cannot recover from a cut spinal cord, the toadfish can grow back its nerves completely.
Recent research on the toadfish has involved studying toadfish behavior in its natural habit and monitoring neural activity leading to its brain. Scientists have observed tissue regeneration in toadfish by implanting electrodes into their nervous systems, and subsequently watching in awe as nerves grew through the holes in the implants and fixed the entire neural system (1). While human self-regeneration is a long way into the future, the hope is to leverage these observations in the advancement of prosthetic devices for people with central nervous damage or other crippling diseases.
Blood Purification
While much research on marine organisms is still very much a work in progress, the most commercially successful marine model for biomedical research has been spawning on beaches around the world for more than 250 million years: the horseshoe crab (see Fig. 3). A wide variety of bacteria populate the ocean, many of which are not favorable to the health of animals such as the horseshoe crab. While many organisms perish by these bacteria, the crab has a remarkable ability to protect itself; it is able to clot its blood as an immediate response to bacterial infection.
When this ability was discovered 25 years ago, it was immediately identified for its beneficial potential. By using horseshoe crab blood, unwanted bacteria in vaccines and other pharmaceuticals injected into humans could be identified. And thus, the Limulus test, also known as the Limulus Amoebocyte Lysate Test, was born (7).
Prior to this discovery, rabbits had been used to test for bacterial contamination. Although the test in rabbits was generally accurate, it was slow and expensive to perform. Additionally, the test was harmful to the rabbits and on many occasions resulted in death. The Limulus test, in comparison, uses blood that can be extracted from the crab without killing the animal and yields test results within 45 minutes.
The horseshoe crab’s highly developed sensitivity has been utilized by more than just the pharmaceutical industry. NASA’s Planetary Protection Program has adopted the Limulus test in maintaining a sterile environment for its Mars missions (1). International law requires that all spacecraft leaving the planet must be cleaned of all Earth microbes. Thus, the Limulus test is used as a precautionary measure. In addition, the Limulus test is also used on the surface of the returning spacecraft to prevent foreign microbes from returning to earth. Similarly, the horseshoe crab blood could also be used to discover a new microbe never before detected (8). The horseshoe crab and the Limulus test thus provide the means to both discover new organisms and prolong human life.
Anti-Cancer Drugs
To say that those marine organisms that spend their lives attached to docks, rocks, and the undersides of boats would possess the chemical means to develop a potent anti-cancer drug would have been considered near blasphemy just a few decades ago. However, these organisms, known as tunicates or sea squirts, have recently been identified as evolutionarily closer to vertebrates than most other invertebrate animals, and as such have been examined for their human-applicable chemical make-up.
One compound derived from tunicates is trabectedin, which has been isolated from Ecteinascidia turbinate, a Mediterranean and Caribbean native whose colonies look like transparent orange grapes, as shown in Fig. 4. PharmaMar, a pharmaceutical company based in Spain, has harvested this species in the creation of its anti-cancer drug, Yondelis. Laboratory tests to date indicate that Yondelis can kill cancer cells, and the first set of clinical studies has shown that the drug is safe for use in humans (4, 5). Further phases of clinical testing are currently underway in order to determine the effects of prolonged use of Yondelis and determine the types of cancers against which it is most effective.
Multiple other groups of compounds have also been identified for their anti-cancer properties. Dolastatins, isolated from the toxins of the sea hare Dolabella auricularia, have been used throughout history as a common food-laced poison and have recently been implicated for their cancer-targeting potential. Even more toxic compounds such as palytoxin, from the soft coral Palythoa toxica which was used on the tips of the spears of Hawaiian warriors to kill enemies in the past, have been identified and are currently undergoing extensive research to test their capabilities (4). A major concern in the development of these drugs is finding a concentration and dosage that is enough to kill only cancerous cells and not attack healthy tissue or, possibly, lead to death of the host (9).
Prolonged life and increased health are no longer unattainable goals. Mankind can leverage the diversity and potency of marine-derived medicines to achieve both of these ends and more. Along with therapies to combat muscle atrophy, other organisms have been identified and adapted to suit human needs. Anti-cancer and blood screening drugs can be created in the same way that blue mussels and hot vent microbes are utilized to make automobile paint glue and increase oil yields, or the way that fatty acid-producing microalgae are integrated into the production of breast milk formula (4). The potential is there and the research is progressing – only time will tell what a newly discovered sea creature will help mankind do.
References
1. S. Kay, Scientists Seek New Medicines from the Ocean (2001). Available at http://news.nationalgeographic.com/news/2001/08/0807_wireseamed1.html (November 2011).
2. Cardiomyopathy Information (2011). http://www.cardiomyopathy.org/Cardiomyopathy_Information.html (November 2011).
3. A. Meindl et al., Nat. Genet. 13, 35-42 (1996).
4. K. Krajick, Medicine from the Sea (2004). Available at http://www.smithsonianmag.com/specialsections/ecocenter/oceans/medicine.html?c=y&page=5 (November 2011).
5. Medicine by Design: Drugs from Nature, Then and Now (2011). Available at http://publications.nigms.nih.gov/medbydesign/chapter3.html (November 2011).
6. J. McGivern, Zicontoide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr. Dis. Treat. 3, 69-85 (2007).
7. U.S. Food and Drug Administration, Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices (Center for Drug Evaluation and Research, Rockville, Maryland, 1987).
8. National Aeronautics and Space Administration, Planetary Protection Methods (2011). Available at http://planetaryprotection.nasa.gov/methods (November 2011).
9. R. Tohme, N. Darwiche, H. Gali-Muhtasib, Molecules 16, 9665-9696 (2011).