The ocean floor is full of mysteries, but scientists have recently uncovered one of its best kept secrets. For 25 years, drug hunters have searched for the source of a natural chemical that has shown promise in early cancer treatment studies. Now, researchers at the University of Utah Health report that easy-to-find soft corals – flexible corals that look like underwater plants – are the elusive compound.
Identifying the source allowed the researchers to dig deeper and find the animal’s DNA code to synthesize the chemical. By following these instructions, they were able to take the first steps to recreate the soft coral chemical in the laboratory.
“This is the first time we’ve been able to do this with a drug in mind on Earth,” said Eric Schmidt, Ph.D., professor of medicinal chemistry at U of U Health. He led the study with Paul Scesa, Ph.D., postdoctoral scientist and first author, and Zhenjian Lin, Ph.D., assistant research professor.
This breakthrough opens up the possibility of producing the compound in the large quantities needed for rigorous testing and could one day lead to a new tool in the fight against cancer.
A second research team led by Bradley Moore, Ph.D., of the Scripps Institution of Oceanography at the University of California, San Diego, has independently shown that corals produce related molecules. Both studies are published in the May 23 issue of Biology of the chemistry of nature.
A world of possibilities
Soft corals contain thousands of drug-like compounds that could act as anti-inflammatory agents, antibiotics, etc. But obtaining sufficient quantities of these compounds has been a major obstacle to their development into drugs for clinical use. Schmidt says these other compounds should now also be accessible using this new approach.
Corals aren’t the only animals harboring potential therapies. Nature is teeming with snakes, spiders, and other animals known to carry chemicals with healing properties. However, these soft coral compounds offer distinct advantages for drug development, says Schmidt.
Unlike the poisonous chemicals that are injected into prey, corals use their chemicals to ward off predators trying to eat them. Since they are made to be eaten, the chemicals in soft coral are easily digested. Likewise, drugs derived from these types of compounds should be able to be administered as pills with a glass of water, rather than by injection or other more invasive means. “These compounds are harder to find, but they are easier to produce in the laboratory and easier to take as a medicine,” says Schmidt.
These possibilities were simply out of reach for decades. Getting to this point required the right skill and a bit of luck.
Hunt for the source
Scesa found the long-sought compound in a common species of soft coral that lives off the coast of Florida, just a mile from his brother’s apartment. In the 1990s, marine scientists reported that a rare coral near Australia carried a chemical, eleuterobin, with anticancer properties. The chemical destroys the cytoskeleton, a key scaffold in cells, and soft corals use it as a defense against predators. But laboratory studies have shown that the compound is also a potent inhibitor of cancer cell growth.
In the decades that followed, scientists searched but failed to find the legendary “Holy Grail” chemical in the quantities needed for drug development and failed to solve the problem without understanding how the chemical was produced. The dogma said that, like other types of marine life, the chemical was synthesized by symbiotic organisms that lived inside animals.
“It didn’t make any sense,” said Scesa. “We knew that the corals had to produce eleuterobine. After all, he and Schmidt reasoned, some soft coral species have no symbiotic organisms and yet their bodies contain the same class of chemicals.
Solving the mystery seemed like a job done for Scesa. As a boy growing up in Florida, the ocean was his playground and he spent countless hours exploring its depths and wildlife. In graduate school, he developed a passion for organic chemistry and combined the two interests to better understand the chemical diversity of the seas.
Later, he joined the laboratory of natural products scientist Schmidt on a mission to trace the source of the main drug. Descended suspected that familiar coral species might have the answer and brought small live specimens from Florida to Utah, and the real hunt began.
Decryption of the recipe
The next step was to find out if the coral’s genetic code contained the instructions for making the compound. Advances in DNA technology have recently made it possible to quickly piece together the code of any species. The difficulty was that the scientists didn’t know what the instructions for making the chemical had to look like. Imagine you are looking for a certain recipe in a cookbook, but you don’t know what the words inside the book mean.
“It’s like going into the dark and looking for an answer where you don’t know the question,” observes Schmidt.
They solved the problem by finding regions of coral DNA that looked like genetic instructions for similar types of compounds from other species. After programming the lab-grown bacteria to follow specific soft coral DNA instructions, the microorganisms were able to replicate the first steps in creating the potential therapeutic cancer.
This proved that soft corals are the source of eleuterobin. It also showed that it should be possible to produce the compound in the laboratory. Their work now focuses on filling in the missing steps in the recipe of the compound and on how best to produce large quantities of the potential drug.
“My hope is to deliver them to a doctor someday,” says Scesa. “I think it goes from the bottom of the ocean to the bench to the bedside. “
The research was supported by the National Institutes of Health and the ALSAM Foundation and published in Biology of the chemistry of nature as “Ancient defensive terpene biosynthetic gene clusters in soft corals