Mud and sponges probably aren’t high on most divers’ bucket lists. But scientist and explorer Professor Brian Murphy, based at the University of Illinois at Chicago, has his sights set on sediments lurking at the bottom of lakes and slimy animals clinging to submerged shipwrecks. And for good reason. When he brought back a drop of mud from Lake Michigan, he discovered that it contained bacteria that created two previously unknown molecules.
Laboratory tests have shown that this class of compounds is lethal to the bacteria responsible for tuberculosis, a disease against which existing drugs fight. “For millions of years, bacteria have fought each other,” Murphy says. “We’re just harnessing that power.”
All over 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, accelerated by the global overuse of these drugs.
“The way to fight drug resistance is to find new chemistry,” says Murphy. It is one of many modern-day prospectors searching for this new underwater chemistry.
From icy polar seas to searing hydrothermal vents, from coral reefs to inland lakes, the vast aquatic kingdoms covering seven-tenths of our planet are home to an immense diversity of life. They include many animals that have evolved complex chemical defenses, as well as a profusion of microbes; approximately 90% of ocean life is thought to be microscopic. Among these creatures, researchers are discovering molecules that could form the basis of new drugs.
Exploiting the natural world for pharmaceuticals is nothing new – take an aspirin and your headache will be soothed by a substance that has been discovered in willow bark. With the rising tide of drug resistance, the hope is that nature has much more in her medicine cabinet for us to tap into. The trick is to sift through all those potent chemicals to find the ones that might fight disease.
“It’s no secret that there is an incredibly high failure rate in drug development,” Murphy says. “It’s really difficult to find a set of molecules that can target a specific disease and do so in the incredibly complex environment of the human body.”
To help with that, Murphy is working to improve the sample collection process, as it’s one of the few stages of drug development that hasn’t seen a major revolution in recent decades. According to Murphy, finding molecules in original places is an important part of drug development, so he decided to use an entirely new resource: the general public.
Talking to recreational divers gave Murphy the idea to search shipwrecks for sponges. These unprepossessing animals spend most of their lives stuck in place, sifting through water for food and absorbing hordes of bacteria. “Bacteria can constitute up to 30 or 40 percent of sponge biomass,” says Murphy.
Freshwater sponges are common in the Great Lakes of the United States, but almost nothing is known about them. Rather than going out and collecting sponges himself – a time-consuming and expensive endeavor – Murphy piloted a citizen science project asking divers to collect tiny samples for him. while they are on the move. He sent out collection kits and got a great response, receiving over 40 pieces of sponge in the mail.
In 2016, he rolled out the project across the Great Lakes and hopes to sample as many sites as possible. Ultimately, Murphy wants to map the distribution of sponges and bacteria in the lakes so that future efforts can be more efficient and focus on fruitful locations, both in the Great Lakes and beyond.
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These creatures contain chemicals that could defeat cancer, MRSA, etc.
- Horseshoe Crabs: The blood of these arthropods is filled with amoebocyte cells that react to minute traces of bacteria. Their blood has been used for 50 years to test equipment and vaccines for contamination.
- Conical snails: The bites of these molluscs contain conotoxins. There is already a conotoxin painkiller that is more potent than morphine. There are also treatments for cancer and diabetes on the horizon.
- Spiny Starfish: The body of this starfish is covered in slime that is made up of 14% carbohydrates and 86% protein. The substance is being studied as a treatment for arthritis and asthma.
- Pufferfish: These fish contain tetrodotoxin (or TTX). This is what makes fugu (a puffer fish delicacy) a risky dinner. TTX is being developed as a treatment for pain experienced during chemotherapy.
- yellow microshell: This bacteria produces a pigment called sarcinaxanthin that can block long-wave UV rays. This could be used in the development of more effective sunscreens.
- Membranous dendrilla: This sea sponge contains a molecule called darwinolide. This substance has been shown to be effective against the drug-resistant superbug MRSA, 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 being studied as a potential antitumor agent.
Scientists explore 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, teeming with species, are a logical place to look and they have produced many natural products, including some that have reached the end of the drug development pipeline.
At first, the chemotherapy drug cytarabine, approved in the United States in 1969 and originally found in a sponge on a reef in the Florida Keys. Another anti-cancer agent called trabectedin, from a Caribbean sea squirt, has been used in Europe since 2007 and in the United States since 2015.
Elsewhere, other researchers are looking for new chemistry even further below the waves. An international team called PharmaSea, led by Professor 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 them as “negative islands” sunk into the seabed, instead of pointing up. “It’s possible that there were millions of years of separate evolution in each trench,” he says.
Jaspars and his collaborators send unmanned probes miles into the depths to bring back mud loaded with unique bacteria. Techniques for keeping these extreme creatures alive in the laboratory have advanced in recent years, so that experiments can be carried out. According to Jaspars, they performed around 100,000 tests, with targets including the so-called ESKAPE pathogens. This group of six bacterial strains shows increasing resistance to several existing antibiotics.
Ultimately, the PharmaSea team aims to refine two compounds that can be produced on a larger scale and offered for preclinical testing. Their most promising findings so far are compounds that may be effective against diseases of the nervous system, particularly epilepsy and Alzheimer’s disease.
Who will benefit?
But to whom belong these discoveries of the depths? The word “bioprospecting” generally has a negative connotation. At worst, it is reminiscent of indigenous peoples who give away their knowledge of traditional medicines and receive little reimbursement.
Fortunately, things have changed in recent years and benefit-sharing protocols are now commonplace. Before collecting anything, researchers usually enter into written agreements with the country of origin. In 2010, the Nagoya International Protocol entered into force, making these agreements a legal obligation. But not everyone is registered in Nagoya – the United States is notably absent.
The “high seas” start 200 nautical miles from shore and are technically not owned by anyone, making them difficult to control. Currently, the United Nations Convention on the Law of the Sea (UNCLOS) covers certain activities, including deep sea mining and cable laying, but it says nothing about biodiversity. Formal discussions began in 2020 to amend UNCLOS to encompass bioprospecting. Various points of view are on the negotiating table. “The G77 and China believe that this should be the common heritage of mankind, which would mean that everyone could benefit from it,” says Jaspars. The idea is that a single nation or company should not be allowed to benefit alone.
On the other hand, there is the concept of “freedom of the high seas”, supported by the United States and Norway, which would give any nation the freedom to carry out bioprospecting on the high seas, just like any who can fish there. They could search anywhere and keep the profits. Other groups, including the EU, are keen to find a solution. It will probably be several years before deep sea bioprospecting is regulated.
The next steps
Back in the lab, Murphy’s TB molecules enter the next round of testing to see if they could lead to new drugs. Even if they don’t, Murphy is confident they’ll still come in handy. “They showed very selective antibacterial activity against tuberculosis,” he says. Other bacteria were not affected. Finding out exactly how these molecules selectively kill TB bacteria could reveal vital information about the disease itself and perhaps pave the way for effective drugs.
But bioprospectors will have to hurry. In recent years, the ailing Great Barrier Reef has made headlines around the world, and human activities continue to threaten the health and biodiversity of Earth’s oceans, rivers and lakes. Hopefully, we can find the medicines and cures we need before our planet’s waters become irrevocably sick.
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