AS CORAL BLEACHING IS OCCURING
Scientists find sea corals are source of sought-after “anti-cancer” compound
IMAGE: ERIC W. SCHMIDT, PH.D., PROFESSOR, MEDICINAL CHEMISTRY, UNIVERSITY OF UTAH view more
CREDIT: KRISTAN JACOBSEN FOR UNIVERSITY OF UTAH HEALTH
(Salt Lake City) - The bottom of the ocean is full of mysteries but scientists have recently uncovered one of its best-kept secrets. For 25 years, drug hunters have been searching for the source of a natural chemical that had shown promise in initial studies for treating cancer. Now, researchers at University of Utah Health report that easy-to-find soft corals—flexible corals that resemble underwater plants—make the elusive compound.
Identifying the source allowed the researchers to go a step further and find the animal’s DNA code for synthesizing the chemical. By following those instructions, they were able to carry out the first steps of re-creating the soft coral chemical in the laboratory.
“This is the first time we have been able to do this with any drug lead on Earth,” says 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.
The advance opens the possibility of producing the compound in the large amounts needed for rigorous testing and could one day result in a new tool to fight cancer.
A second research group led by Bradley Moore, Ph.D., from Scripps Institution of Oceanography at the University of California San Diego, independently showed that corals make related molecules. Both studies are published in the May 23 issue of Nature Chemical Biology.
A World of Possibilities
Soft corals have thousands of drug-like compounds that could work as anti-inflammatory agents, antibiotics, and more. But getting enough of these compounds has been a major barrier to developing them into drugs for clinical use. Schmidt says that these other compounds should also now be accessible using this new approach.
Corals aren’t the only animals that harbor potential therapeutics. Nature is crawling with snakes, spiders and other animals known to carry chemicals with healing properties. Yet that compounds from soft corals offer distinct advantages for drug development, Schmidt says.
Unlike venomous chemicals that are injected into prey, corals use their chemicals to ward off predators that try to eat them. Since they are made to be eaten, the soft coral chemicals are easily digestible. Similarly, drugs derived from these types of compounds should be able to be given as pills with a glass of water, rather than taken by injection or other more invasive means. “These compounds are harder to find but they’re easier to make in the lab and easier to take as medicine,” says Schmidt.
These possibilities had been just out of reach for decades. Getting to this point took the right know-how, and a little luck.
CAPTION
Soft corals make thousands of drug-like compounds that could work as anti-inflammatory agents, antibiotics, anti-cancer therapeutics, and more.
CREDIT
Bailey Miller
Hunting for the Source
Scesa found the long-sought-after compound in a common species of soft coral living off the Florida coast—just a mile from his brother’s apartment. In the 1990s, marine scientists reported that a rare coral near Australia carried a chemical, eleutherobin, with anti-cancer properties. The chemical disrupts the cytoskeleton, a key scaffold in cells, and soft corals use it as a defense against predators. But laboratory studies showed that the compound was also a potent inhibitor of cancer cell growth.
In the decades after, scientists searched but could not find the fabled “holy grail” chemical in the quantities needed for drug development and couldn’t remedy the problem without understanding how the chemical was made. Dogma had it that, similar to other kinds of marine life, the chemical was synthesized by symbiotic organisms that lived inside the animals.
“It didn’t make sense,” Scesa says. “We knew that corals must make eleutherobin.” After all, he and Schmidt reasoned, some soft coral species don’t have symbiotic organisms and yet their bodies contain the same class of chemicals.
Solving the mystery seemed a job made 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 penchant for organic chemistry and combined the two interests to better understand the chemical diversity of the seas.
Later, he joined the lab of natural products scientist Schmidt with a mission to track down the source of the drug lead. Scesa suspected coral species familiar to him might have the answer and brought small live samples from Florida to Utah, and the real hunt began.
CAPTION
Paul Scesa, Ph.D., dives for soft corals off the Florida coast. He studies the potential of soft coral chemicals as drug leads.
CREDIT
Paul Scesa
Decoding the Recipe
The next step was to find out whether the coral’s genetic code carried instructions for making the compound. Advances in DNA technology had recently made it possible to rapidly piece together the code of any species. The difficulty was, the scientists didn’t know what the instructions for making the chemical should look like. Imagine searching a cookbook for a certain recipe, only you don’t know what any of 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,” remarks Schmidt.
They addressed the problem by finding regions of coral DNA that resembled genetic instructions for similar types of compounds from other species. After programming bacteria grown in the lab to follow coral DNA instructions specific to the soft coral, the microorganisms were able to replicate the first steps of making the potential cancer therapeutic.
This proved that soft corals are the source of eleutherobin. It also demonstrated that it should be possible to manufacture the compound in the lab. Their work is now focusing on filling in the missing steps of the compound’s recipe and determining the best way to produce large amounts of the potential drug.
“My hope is to one day hand these to a doctor,” says Scesa. “I think of it as going from the bottom of the ocean to bench to bedside.”
# # #
The research was supported by the National Institutes of Health and the ALSAM Foundation and published in Nature Chemical Biology as “Ancient defensive terpene biosynthetic gene clusters in soft corals
CAPTION
Eric W. Schmidt, Ph.D., and Paul Scesa, Ph.D., of the University of Utah research marine natural products that could become drug leads.
CREDIT
Kristan Jacobsen for University of Utah Health
About University of Utah Health
University of Utah Health provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $428 million research enterprise and trains the majority of Utah’s physicians and health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.
JOURNAL
Nature Chemical Biology
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
Ancient defensive terpene biosynthetic gene clusters in soft corals.
ARTICLE PUBLICATION DATE
23-May-2022
COI STATEMENT
The authors declare no competing interests.
Microparticles with feeling
Watching corals breathe: Researchers develop a new method to simultaneously measure flow and oxygen.
Peer-Reviewed PublicationIMAGE: WATCHING CORALS BREATHE: A SPECIAL CAMERA RECORDS HOW OXYGEN SENSITIVE PARTICLES FLOW PAST THE CORAL SURFACE. THIS ALLOWS THE RESEARCHERS TO DIRECTLY SEE THE INTERACTION BETWEEN THE FLOW FIELD AND OXYGEN CONCENTRATION. view more
CREDIT: SOEREN AHMERKAMP/MAX PLANCK INSTITUTE FOR MARINE MICROBIOLOGY
The surface of a coral is rugged. Its hard skeleton is populated by polyps that stretch their tentacles into the surrounding water to filter out food. But how exactly does the water flow over the coral surface, what eddies and flows develop, and what does this mean for the oxygen supply around the coral and its associated algae? Until now, there was no answer to these questions. Now an international research team around Soeren Ahmerkamp from the Max Planck Institute for Marine Microbiology in Bremen, Klaus Koren from the Aarhus University in Denmark and Lars Behrendt from the Uppsala University and SciLifeLab in Sweden has developed a method that allows studying the flow and oxygen concentrations simultaneously at very small scales. Now it is possible to see how the corals generate a flow with their cilia, thus increasing oxygen transport.
Accurate and fast as never before
Oxygen and life are inextricably linked, from single cells to whole organisms. Across a few micrometers and within milliseconds, oxygen concentrations can change as a result of flow or organisms' activity. Existing methods typically measure oxygen concentrations and flows separately and, as a result, many correlations between these two parameters could not be detected. Ahmerkamp and his colleagues are now doing this in one fell swoop: They measure oxygen concentrations and flow simultaneously and with previously unattained accuracy and speed. The researchers named their newly developed method sensPIV. PIV is the abbreviation for "Particle Image Velocimetry", an established method for measuring flow with particles. Now the “sens” is added, the particles sense their chemical surroundings.
The work was a technical challenge. In fiddly detail, the team managed to produce tiny particles with a diameter of less than 1 micrometre, which are soaked in a luminescent dye (for comparison: A human hair has a diameter of about 100 micrometres). This dye glows brighter the less oxygen is present. “It was particularly important that the particles react very quickly to changes in oxygen concentrations. We also needed special cameras to accurately record the fluorescence,” explains co-author Farooq Moin Jalaluddin from the Max Planck Institute in Bremen. He adds, “With the sensPIV-method sensPIV we are able to resolve in rapid and small-scale fluid flows.”
Useful in medicine, biology, and much more
The possible applications of sensPIV are manifold. Many organisms interact with oxygen, and thus sensPIV can provide answers to open questions in life sciences. Ahmerkamp and his colleagues used it, for example, not only on corals, but also to take a detailed look at how oxygen flows through sand. Small-scale metabolic processes in microbes, animals and plants can also be studied in this way. Numerous other applications are arising in microfluidics, which examines how liquids behave in the smallest of spaces, and in medicine.
The first idea for this method came up already several years ago. "But it was only achievable through the great international team and our close cooperation that the idea has now turned into a functional and versatile application," says Ahmerkamp. Now the team is excited about the upcoming applications of the method. "The particles are not difficult to produce once you know how," says Klaus Koren. They are also thinking about further developing the method: "We would like to make sensPIV receptive to substances other than oxygen. Klaus is already working on it," adds Lars Behrendt.
CAPTION
The flow of newly developed particles across the coral surface is clearly visible.
CREDIT
Soeren Ahmerkamp/Max Planck Institute for Marine Microbiology
JOURNAL
Cell Reports Methods
METHOD OF RESEARCH
Experimental study
ARTICLE TITLE
Simultaneous visualization of flow fields and oxygen concentrations to unravel transport and metabolic processes in biological systems.
ARTICLE PUBLICATION DATE
23-May-2022
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