Corals contain numerous substances that could potentially be used medicinally. One problem with research so far, however, has been that it was unclear how these substances are produced in the coral. Researchers have now found that. Contrary to what was previously assumed, symbiotic microorganisms are not responsible for the production. Instead, the blueprint is in the genome of the coral itself, as the researchers showed using a substance that is considered a potential anti-cancer drug. With this knowledge, it should be possible in the future to produce corresponding compounds in the laboratory and to further research their possible medical use.
Many corals produce toxins to protect themselves from predators. They rely in particular on so-called terpenoids – chemical compounds that are otherwise mainly found in plants. How these substances are produced in corals, which are animals, was previously unclear. One assumption was that microorganisms living in symbiosis with the corals are responsible for the production of the terpenoids. This question is relevant, among other things, because many of the terpenoids from coral are being discussed as a possible basis for new medicinal substances. However, in order to be able to reproduce them in sufficient quantities in the laboratory, it is important to research their natural origins.
Self-produced by corals
Two research teams have now independently addressed this question. A team led by Immo Burkhardt from the University of California in San Diego has examined various types of so-called octocorals, a class of corals that are widespread worldwide. Unlike stony corals, they do not have a solid exoskeleton but rely on inedible and toxic metabolites to protect themselves from predators . “In most sedentary marine animals, the antibodies are produced by symbiotic bacteria,” explain Burkhardt and his colleagues. “In contrast, we have shown that the octocorals produce terpenoids themselves, according to a blueprint that is laid down in their genome.”
A research team led by Paul Scesa from the University of Utah in Salt Lake City came to the same conclusion. Scesa and his colleagues focused on a substance called eleutherobin, which was detected in corals as early as the 1990s and, according to earlier laboratory studies, inhibits the growth of cancer cells. So far, however, there has not been enough of this substance available to research a medical use in more detail, and production in the laboratory was not possible without information on the natural origin of the substance.
Looking for the blueprint
While previous research groups assumed that bacteria produce the potential anti-cancer drug, Scesa and his team looked for the blueprint for eleutherobin in the genome of the coral species Erythropodium caribaeorum, which is widespread off the coast of Florida, among other places. With the help of modern methods of DNA sequencing, it was no problem for the researchers to read the genome of the coral. The challenge, however, was to identify the previously unknown blueprint of the substance being sought in the code. “It’s like looking for an answer in the dark if you don’t know the question,” says Scesa’s colleague Eric Schmidt.
To address this problem, the researchers searched the coral genome for areas that resemble the sequences of other blueprints of related substances and are found in bacteria, for example. Indeed, this is how they came across the region of coral DNA that encodes eleutherobin. To their surprise, they discovered that it was a gene cluster, i.e. a group of genes that provide the blueprint for proteins with similar functions. “This suggests that other defenses in animals may also originate from gene clusters,” they write. “This would greatly facilitate biotechnological access to the chemical diversity needed for the synthesis of potential drugs such as eleutherobin,” they write.
From seabed to sickbed?
Compared to other active substances from the animal kingdom, which also have a possible medicinal use, the coral substances offer a decisive advantage: While many other animals, including spiders and snakes, inject their venom into their prey, the compounds that the coral crafts, meant to cast when eaten. It would therefore be possible that therapeutics derived from this could also be swallowed and do not have to be administered by syringe. “These compounds are harder to find, but they’re easier to make in the lab and easier to take as medicine,” says Schmidt.
With their decoding of the genomic origin of eleutherobin, the researchers have laid the first foundation for establishing the connection in the laboratory and researching it on a larger scale in the future. “My hope is that one day doctors will be able to use the therapeutic agent,” says Scesa. “From the seabed to the laboratory bench and to the bedside.”
Sources: Immo Burkhardt (University of California San Diego) et al., Nature Chemical Biology, doi: 10.1038/s41589-022-01026-2; Paul Scesa (University of Utah, Salt Lake City) et al., Nature Chemical Biology, doi: 10.1038/s41589-022-01027-1