Sea Cure : Scientists Enthusiastic About Potential Medical Compounds From Deep
The ancient Hawaiians called it “the deadly seaweed of Hana,” and declared it “kapu, “ taboo.
Today the rare and extremely poisonous soft coral, known as Palythoa toxica, has become one of a growing number of sea creatures that may be a new source of modern medicine.
The research with palytoxin, while at an early stage, is indicative of renewed scientific enthusiasm in finding potential cures from the oceans.
“We see the sea as (containing) many interesting and exotic compounds, some of which have exciting possibilities as drugs,” said Steve Brauer of the Hawaii Biotechnology Group, which is working with palytoxin as part of a $990,000 federal small-business innovative research grant. “The process of culling them out is a massive task and one which is just beginning.”
One extract at an advanced stage of research is manoalide, named after the University of Hawaii at Manoa and derived from a sponge found at the Pacific island of Palau.
Discovered in 1977 by Paul Scheuer of the University of Hawaii, it was demonstrated by a group of University of California scientists to have potent pain-killing and inflammation-fighting properties. Allergan Pharmaceuticals of Irvine now has an option to license the product commercially and has begun testing it for toxic side effects.
The UC program is a collaboration between organic chemists John Faulkner and William Fenical at Scripps Institution of Oceanography in La Jolla, Phillip Crews of UC Santa Cruz and pharmacologist Robert Jacobs at UC Santa Barbara.
“My feeling is, manoalide or one of its relatives or descendants will eventually be available for treatment of certain forms of inflammatory disease,” such as arthritis, said Jacobs.
Other promising compounds:
* Didemnin B--Isolated from tiny Caribbean sea squirts called tunicates, Didemnin B is the first wholly natural marine product to enter clinical trials with cancer patients as a potential anti-tumor drug. Pioneered by Kenneth Rinehart at the University of Illinois at Urbana, Didemnins A and B also have shown promise as inhibitors of oral and genital herpes, flu and fever viruses.
* Pseudopterosins--This class of anti-inflammatory compounds, developed by Fenical and colleagues at Scripps, comes from fernlike soft corals known as sea whips. Both manoalide and pseudopterosins offer unique metabolic approaches to controlling inflammation, said Fenical. Pseudopterosins chemicals also have proved effective as painkillers in animals tests.
* Dolastatin 10-G--Robert Pettit and colleagues at Arizona State University painstakingly extracted this compound from an Indian Ocean sea hare, a mollusk not known to develop cancer. Supply problems have hampered research with dolastatins and another group of compounds called bryostatins, which were discovered by Pettit in a barnacle-like “false” coral that attaches to ships and piers. Bryostatins have shown promise against leukemia in mice and human ovarian cancer.
* Punaglandins--These natural extracts from a soft coral found in Hawaii and Eniwetok in the Marshall Islands were found to be too toxic, but a similar synthetic version is currently under clinical trials as an anti-tumor drug in Japan.
Often compounds that prove too poisonous in their natural states for humans still can lead to new and promising chemical models.
“In many cases the natural product provides a good template, and then if undesirable side effects show, they can manipulate things pretty well and try to eliminate them,” said Scheuer, emeritus professor of chemistry, who helped identify punaglandins in 1982.
One anti-cancer drug, Ara-C, was modeled chemically after a substance isolated from a Caribbean sponge in the 1960s.
Until World War II, land plants provided the raw material for nearly all pharmaceutical research. Some of the more effective drugs have properties well known to ancient peoples. For example, the key ingredients in aspirin and quinine came from tree barks while painkillers such as morphine and codeine came from opium poppies.
With the discovery of penicillin in 1928 from mold, lower forms of plants became a source of new medicines. Thanks to easy access of land plants and the process of fermentation, which allows large-scale production, research and development of land-based drugs moved rapidly.
But the terrestrial medicine cabinet now looks about as full as it’s going to get, scientists believe. Hence the renewed interest in the seas--home to an estimated 80% of all life forms.
Some of the more interesting discoveries have come from the so-called “sessile” sea creatures that cling to rocks, hulls, piers or the seabed. These often have developed chemicals as a defense against predators.
Research into organic marine chemicals has been slow for a couple of reasons. First, only a small fraction of the ocean has been explored; second, even after being identified as “biologically active” in humans, many compounds cannot be easily produced in quantities necessary for testing, much less wholesale marketing. Interest in marine pharmaceuticals ebbed in the late 1970s, but has revived in the last five years or so, much of it building on university research funded by the Commerce Department’s Sea Grant Program.
In 1986, the National Cancer Institute launched a large-scale program to collect new specimens of marine life for screening for anti-tumor agents. The institute awarded contracts worth $3.6 million to SeaPharm Inc., a private research company based in Princeton, N.J., for the collection of 10,000 deep- and shallow-water specimens.
SeaPharm works with the Harbor Branch Oceanographic Institution in Ft. Pierce, Fla., to collect organisms using the Johnson-Sea-Link manned mini-sub and other underwater technologies. Since it began operating five years ago, the company has screened some 11,000 compounds for signs of activity against tumors, viruses and fungi and for effects on the immune system.
The company has applied for more than 30 patents and hopes to begin clinical testing of an anti-cancer compound from a South Pacific sponge by mid-1989.
At the University of Hawaii, researchers led by chemist Richard Moore have been studying hundreds of varieties of blue-green algae for drug potential. In 1986, under a five-year grant from the National Cancer Institute, Moore and colleagues began to grow another 1,000 strains of blue-green algae for tests against the AIDS virus and 100 types of cancer.
Palythoa toxica, found only in a small tidepool on the eastern coast of Maui, has had a dark history in Hawaii.
In December, 1960, on the day that specimens were first collected, despite warnings by native Hawaiians that the tidepool was taboo, a mysterious fire gutted the university’s marine biological laboratory.
Three years later, pure palytoxin was isolated, but its chemical description, ultimately by University of Hawaii chemist Moore in 1981, required technologies that did not become available until the mid-1970s.
Today, researchers at Hawaii Biotech hope to attach the palytoxin molecule to a lab-grown monoclonal antibody that will attack specific cancer cells while leaving healthy tissue alone. But developing such an “immunotoxin” has proven difficult.
No marine pharmaceuticals are expected to make it through the regulatory process and onto the market until at least the early 1990s. But that prospect has not dampened the enthusiasm of many in the field.
“I believe that there is a very large untapped resource of chemical entities from the ocean,” said Thomas Matthews, a microbiologist at Syntex Corp. in Palo Alto. “I also believe that they are going to play a major role in the drugs of the future.”
