On Wednesday, a crew of technicians will hoist a remotely operated vehicle dubbed Hercules from its berth on an oceanographic research vessel down into a patch of ocean about 150 miles off the Southern California coast. After being released from the crane, the tethered craft will slowly sink to the seafloor between 2,000 and 5,000 feet below, and begin a treasure hunt for new kinds of compounds that could one day become medicines.
The VW Beetle-sized Hercules and 211-foot Nautilus will spend the next 10 days in a region called the Southern California Borderlands, which includes underwater seamounts, canyons, and ridges that are covered in layers of mineral-laden sediments and rocks. The expedition is led by Scripps and the Ocean Exploration Trust (which operates the Nautilus), and sponsored by the National Oceanic and Atmospheric Administration.
The geological features contain crusts of phosphorite and ferromanganese—minerals that have commercial value as sources of fertilizer and are mined from the seafloor off the coasts of Namibia and Mexico. But it’s the living creatures that populate this unexplored habitat that could hide a biological goldmine. That’s because the compounds produced by these seafloor animals may also have anti-cancer, antibacterial, or antiviral properties.
As of this month, 15 drugs derived from marine organisms have been approved by federal regulators, according to a database compiled by the Midwestern University Department of Marine Pharmacology, including treatments for various cancers and a cholesterol-lowering drug. Another 23 compounds derived from everything from marine sponges and worms to pufferfish are currently in Phase I, II, or III Food and Drug Administration clinical trials.
As just a few examples, in June, the FDA approved a new treatment for lung cancer called lurbinectedin that was originally synthesized from a toxin found in the sea squirt, or tunicate, a marine invertebrate that uses the poison to ward off enemies. A protein called griffithsin that was synthesized from a species of red algae from New Zealand a decade ago might also have use as an antiviral. In 2016, a group of US and French researchers published a study showing the chemical blocked infection of the virus that causes Middle East respiratory syndrome, or MERS. In December 2019, researchers at the University of Pittsburgh began a Phase I clinical trial with griffithsin to test its ability to block HIV infections as well. Now some researchers are investigating whether this same compound might help in the fight against the novel coronavirus.
To find new drug-producing animals, algae, and microbes, the oceanographers aboard the Nautilus first have to learn more about the animals that live there. The expedition’s chief scientist, Lisa Levin, a professor of integrative oceanography at the Scripps Institution of Oceanography, says the goal of the cruise is to understand the habitat and how animals interact with the mineral-laden rocks. “Most of the places we are going, nobody has been to,” Levin says. “But we do know the whole region has corals and sponges, anemones, and other invertebrates.”
Levin is studying the interaction between the animals and the rocky bottom they call home. “We don’t know very much about whether there are animals that prefer to be on those substrates, or avoid them,” Levin says.
Levin will help specially trained ROV pilots aboard the Nautilus hover the Hercules over the bottom habitats to observe the sea creatures using multiple cameras, including a high-definition video camera that sends images through a fiber-optic cable to the ship and then via satellite to scientists, students, and the public through a round-the-clock livestreaming system. The pilots operate the vehicle’s powerful robot arms to grab samples of rocks as well as to insert a coring device into seafloor sediments, where Levin hopes to find even smaller animals. “The rocks are full of animals, but most people aren’t looking for these little tiny things,” she says. “In the sediment, we take a core and slice it up into vertical fractions.”
Once the samples are collected and brought back to the surface, Paul Jensen will begin the task of identifying animals and microbes that might be good candidates for novel biopharmaceutical compounds. To do that, Jensen, a professor at the Center for Marine Biotechnology and Biomedicine, which is operated by the Scripps Institution of Oceanography at UC San Diego, will scrape bacterial slime from rocks, take razor-thin slices from sponges, and check for algae living on corals. He’s hoping to find chemical toxins that protect these animals from getting eaten by predators, but might also be harnessed to help humans fight cancer or infectious diseases.
“There are lots of sponges and soft corals that often have microbes with symbiotic associations with them,” says Jensen. “That often includes a chemical component they may produce that defends it from predation. Now we have deep sea communities that nobody has looked at.”
Jensen has been hunting for ocean treasures since he was a graduate student. In fact, a compound he and colleagues at Scripps found in sediments off the Bahamas back in 1990 is now undergoing Phase III clinical trials as a treatment for a type of brain cancer called glioblastoma. Back then, Jensen had to culture and grow the compound in a lab and see if it had any useful properties. Now researchers can skip the culturing step, collect DNA from the animal or microbe, and assess its potential to produce desirable molecules—looking for genetic sequences in the new creatures that they already know give rise to compounds that work against diseases. “If the compound is in the DNA from a sponge and looks promising,” Jensen says, “we don’t have to go out and collect kilos of the sponge to try to find the molecule. We can take the DNA and, using molecular approaches, we can clone that DNA in a microbe we can grow in the lab and make the molecule that way.”
These molecules are then tested against bacterial or cancer cell lines to see if they either kill them or stop them from growing. Additionally, by understanding the genes of the new organisms, researchers can decipher how the proteins are structured and then produce them synthetically.
“We now know a lot about the genes involved in making them,” Jensen says. “This is pretty fun and changed the face of how people do drug discovery.”
Jensen isn’t making any promises that the upcoming expedition will find any new blockbuster drugs. It takes years of basic science, lab testing, and then millions of dollars to run clinical trials to see if they are both safe and effective in fighting human disease.
The pipeline of drugs from the sea, or so-called “marine biopharmaceuticals,” has been growing, says Barry O’Keefe, a senior scientist at the National Cancer Institute who leads up drug development from natural products. O’Keefe says that so far 15 marine-related drugs have been approved for human use globally, while another 23 are being tested in FDA clinical trials. “Sometimes things take a while to mature,” O’Keefe says about the long time between discovery of a compound and development of a drug treatment. “There’s such a long time-frame to understand how things work.”
O’Keefe authored the research paper in 2009 about the properties that red algae from New Zealand has in blocking MERS infections. Jensen’s initial research found that griffithsin binds to the MERS virus’s spike glycoprotein and stops it from entering human cells, effectively stopping the infection. He says colleagues have been contacting him to see if it might work against the novel coronavirus, which is related to MERS.
He is excited that his paper is receiving new interest in the face of a novel health threat. “I’ve been getting a lot of calls about it,” O’Keefe says. “It’s not so usual that a 10 year-old paper gets that popular.”
For Jensen and the other scientists on board the Nautilus, they hope their search for nature’s medicines proves just as fruitful. “If we can find new classes of molecules, that’s a pretty big deal,” Jensen says. “Maybe they will be antiviral or antibacterial or anti-cancer. But finding them is the first part.”
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