Mud and sponges probably don’t feature highly on most scuba divers’ bucket lists. But scientist and explorer Professor Brian Murphy, based at the University of Illinois at Chicago, has his sights set on the sediments lurking at the bottom of lakes and the gooey animals clinging to submerged shipwrecks. And for good reason. When he brought back a blob of mud from Lake Michigan, he found it contained bacteria that create two previously unknown molecules.
Lab tests showed that this class of compounds is lethal to the bacterium that causes tuberculosis, a disease that existing drugs are struggling with. “For millions of years bacteria have fought one another,” says Murphy. “We’re just harnessing that power.”
Around the world, superbugs are on the rise. There have been a number of patients in recent years who have strains of E. coli that are resistant to many antibiotics, including drugs that doctors only use as a last resort. It’s an alarming trend in which bacteria are gaining the upper hand in their battle against the antibiotics we use to kill them, hastened by the world’s overuse of these drugs.
“The way to combat drug resistance is to find new chemistry,” says Murphy. He’s one of many modern-day prospectors who are searching for that new chemistry underwater.
Medicine from the deep
From icy polar seas to scorching hydrothermal vents, and from coral reefs to inland lakes, the vast, aquatic realms covering seven-tenths of our planet are home to an immense diversity of life. They include many animals that evolved complex chemical defences, along with a profusion of microbes; it is thought that around 90 per cent of oceanic life is microscopic. From among these creatures, researchers are uncovering molecules that could form the basis for new medicines.
Tapping the natural world for pharmaceuticals is nothing new – pop an aspirin and your headache will be soothed by a substance that was discovered in willow tree bark. With the rising tide of drug resistance, the hope is that nature has plenty more in its medicine cabinet for us to dip into. The trick is sifting through all those potent chemicals to find the ones that could fight disease.
“It’s no secret that there’s an incredibly high failure rate in developing drugs,” says Murphy. “It’s really difficult to find a set of molecules that can target a specific disease and do it within the incredibly complex environment of the human body.”
To help with this, Murphy is working to smarten up the sample collection process, as it’s one of the few steps in drug development that hasn’t seen a major revolution in recent decades. According to Murphy, looking for molecules in original places is an important part of drug development, so he decided to use a new resource altogether: the general public.
Chatting with recreational scuba divers gave Murphy the idea of searching shipwrecks for sponges. These unprepossessing animals spend most of their lives stuck in place, sifting the water for food and taking on hordes of bacteria. “Bacteria can constitute up to 30 or 40 per cent of sponge biomass,” Murphy explains.
Freshwater sponges are a common sight across the USA’s Great Lakes but almost nothing is known about them. Rather than go out himself and gather sponges – a time-consuming and expensive business – Murphy piloted a citizen science project asking divers to collect tiny samples for him while they’re out and about. He sent out collecting kits and got a great response, receiving more than 40 nubbins of sponge in the mail.
In 2016 he rolled the project out across the Great Lakes and hopes to sample as many sites as possible. Ultimately, Murphy wants to map the distribution of sponges and bacteria across the lakes so that future efforts can be more effective and will zero in on fruitful spots, both in the Great Lakes and beyond.
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These creatures contain chemicals that could beat cancer, MRSA, and more
- Horseshoe crabs: The blood of these arthropods is packed with amoebocyte cells that react to tiny traces of bacteria. Their blood has been used for the last 50 years to test equipment and vaccines for contamination.
- Cone snails: The stings of these molluscs contain conotoxins. There is already a conotoxin-based painkiller that’s more potent than morphine. There are also cancer and diabetes treatments on the horizon.
- Spiny starfish: This starfish’s body is covered in slime consisting of 14 per cent carbohydrate and 86 per cent protein. The substance is being investigated as a treatment for arthritis and asthma.
- Pufferfish: These fish contain tetrodotoxin (or TTX). This is what makes fugu (a delicacy made from pufferfish) a risky dinner. TTX is being developed as a treatment for the pain suffered during chemotherapy.
- Micrococcus luteus: This bacterium produces a pigment called sarcinaxanthin that can block long-wavelength UV radiation. This could be used in the development of more effective sunscreens.
- Dendrilla membranosa: This sea sponge contains a molecule called darwinolide. This substance has been found to be effective against the drug-resistant MRSA superbug, which can often cause problems in hospitals.
- Elysia rufescens: This species of sea slug has a wide distribution. It contains a substance called kahalalide F, which is currently under investigation as a potential tumour-fighting agent.
Scientists are searching the deepest parts of the ocean
When bioprospectors first turned to the oceans in the 1950s, their initial targets were coral reefs. These bustling ecosystems, packed with species, are a logical place to look and they’ve yielded many natural products, including some that made it to the end of the drug development pipeline.
Early on was chemotherapy agent cytarabine, approved in the US in 1969 and originally found in a sponge on a Florida Keys reef. Another cancer-fighting agent called trabectedin, from a Caribbean sea squirt, has been used in Europe since 2007 and in the US since 2015.
Elsewhere, other researchers are hunting for novel chemistry even further beneath the waves. An international team called PharmaSea, led by Prof Marcel Jaspars, is searching for new antibiotics in the deep sea, including at the bottom of trenches – the deepest parts of the oceans. Jaspars describes these as ‘negative islands’ sticking down into the seabed, instead of pointing up. “It’s possible there have been millions of years of separate evolution in each trench,” he says.
Jaspars and his collaborators send unmanned probes miles down into the depths to bring back mud loaded with unique bacteria. Techniques for keeping these extreme creatures alive in the lab have advanced in recent years, so experiments can be carried out. According to Jaspars, they’ve done around 100,000 tests, with targets including the so-called ESKAPE pathogens. This group of six bacterial strains are showing growing resistance to multiple existing antibiotics.
Ultimately, the PharmaSea team aims to narrow down two compounds that can be produced at a larger scale and put forward for pre-clinical trials. So far, their most promising finds are compounds that could be effective against diseases of the nervous system, in particular epilepsy and Alzheimer’s disease.
Who will benefit?
But who owns these discoveries from the deep? The word ‘bioprospecting’ usually has a negative connotation. At worst, it brings to mind indigenous people giving away their knowledge of traditional medicines and receiving little reimbursement.
Thankfully, things have moved on in recent years, and protocols for sharing benefits are now commonplace. Prior to collecting anything, researchers will generally enter written agreements with the country of origin. In 2010, the international Nagoya Protocol came into effect, making such agreements a legal requirement. But not everyone is signed up to Nagoya – the US is notably absent.
The ‘high seas’ begin 200 nautical miles from shore and don’t technically belong to anyone, making them difficult to police. Currently, the UN Convention on the Law of the Sea (UNCLOS) covers certain activities including deep-sea mining and laying cables, but it says nothing about biodiversity. Formal discussions began in 2020 to amend UNCLOS to encompass bioprospecting. Various views are on the negotiating table. “The G77 and China believe that it should be the Common Heritage of Mankind, which would mean everybody could benefit,” explains Jaspars. The idea is that one single nation or company shouldn’t be allowed to solely benefit.
On the other hand is the concept of ‘Freedom of the High Seas’, backed by the US and Norway, which would give any nation the freedom to bioprospect in the high seas, just as anyone can fish there. They could research anywhere and hold on to the profits. Other groups, including the EU, are keen to find a solution. It’s likely to be several years until bioprospecting in the high seas becomes regulated.
The next steps
Back in the lab, Murphy’s tuberculosis-busting molecules are entering the next round of tests to see if they could lead to new medicines. Even if they don’t, Murphy is confident they will still be useful. “They showed very selective antibacterial activity towards tuberculosis,” he says. Other bacteria were left untouched. Finding out exactly how these molecules selectively kill the tuberculosis bacterium could reveal vital information about the disease itself and perhaps point the way toward effective medicines.
But bioprospectors will have to hurry. In recent years, the ailing Great Barrier Reef has made headline news around the world, and human activities continue to threaten the health and biodiversity of Earth’s oceans, rivers and lakes. Let’s hope we can find the drugs and cures we need before our planet’s waters become irrevocably sickened.
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