The medicines that lie beneath

We are taking a look back at stories from Cosmos Magazine in print. In June 2024, Drew Rooke looked into the groundbreaking research that is deriving medicines from the depths to transform our lives on land.

On 5 June 1981, the US Center for Disease Control published an article in its regular newsletter, Morbidity and Mortality Weekly, which described a strange cluster of sudden cases of pneumonia in Los Angeles. All of the patients were young gay men who did not know each other, had no known common contacts and no knowledge of sexual partners who had similar illnesses. Despite courses of treatment, two of the men had already died and the other three remained seriously ill and died shortly after the article was published.

“Pneumocystis pneumonia in the United States is almost exclusively limited to severely immunosuppressed patients,” the editorial note read. “The occurrence of pneumocystosis in these five previously healthy individuals without a clinically apparent underlying immunodeficiency is unusual.”

This article marked the first official reporting of the HIV/AIDS epidemic. By the end of the 1980s, more than 100,000 people in the United States alone had died from AIDS and it was the leading cause of death among young adults – especially men aged between 25 and 44 years old.

The severity of the situation triggered an intense effort to develop a medicine to treat HIV/AIDS. As part of this push, scientists investigated the potential of abandoned drugs that had been developed decades earlier for other illnesses but had been shelved because they were ultimately ineffective.

Azidothymidine was one such drug. Also known as AZT and belonging to a class of drugs called nucleoside reverse transcriptase inhibitors, it had first been developed in 1964 as a possible treatment for cancer. In 1985, scientists involved in a screening program run by the National Cancer Institute in Maryland, US, to identify possible medicines for the deadly new virus discovered that AZT suppressed HIV replication without damaging normal cells.

Shortly afterwards, a British pharmaceutical company called Burroughs Wellcome funded a clinical trial to evaluate the drug in people with AIDS. The results offered a twinkle of hope: although it had adverse side effects, including severe intestinal problems, damage to the immune system, nausea, vomiting and headaches, AZT did significantly decrease the fatality rate.

“A lot of chemicals that showed promising medicinal properties were coming from sponges”

In March 1987, AZT became the first drug to gain approval from the US Food and Drug Administration (FDA) for treating AIDS. Further clinical trials followed, testing different doses to attempt to reduce the side effects. One of these trials – known as ACTG 019 – proved particularly pivotal: it showed that AZT effectively delayed the onset of AIDS in asymptomatic people with HIV.

Since then, AZT has radically improved and prolonged the lives of countless people with HIV; decades later, the drug remains a common component of a HIV patient’s treatment plan. But what many people might not know is its oceanic, spongey origin – which is also the source of many other lifesaving drugs in use today.

For millennia, humans have explored the natural world and collected resources from it, including medicines. Most of these medicines have come from land-based organisms; perhaps the most famous examples are penicillin – first discovered from bread mould in 1928 – and aspirin, which was first isolated from the willow tree.

But recently, scientific attention in this field has also turned to the ocean and the creatures that reside in it.

In the last 40 years, more than 30,000 new chemicals have been discovered from marine-based species including microbes, algae, sponges and bryozoans. According to a 2016 study in the journal Biomolecules & Therapeutics, these chemicals “are often characterised by structural novelty, complexity, and diversity”.

Marine sponges in particular have proved to be an especially rich source of new biochemical compounds.

There are nearly 10,000 known species of sponges worldwide (for comparison around 6,400 extant species of mammals have been described). They’re among the oldest lineages of animals on the planet, with research published in Nature in 2021 indicating they first emerged on Earth nearly 900 million years ago – a time when the planet was populated by simple multicellular organisms like algae.

Found at all depths in the ocean, they can form vast gardens that can be several hundreds of years old, cycle huge amounts of carbon and store a record of Earth’s climatic history. In February 2024, for example, a study published in Nature Climate Change used 300 years of ocean temperature records contained in marine sponges to show that global warming has increased by 0.5°C more than previous estimates.

Being such ancient creatures, marine sponges lack complex organs and tissues. Most survive by filter feeding, actively pumping large quantities of water through their porous body tissue to capture microscopic, organic organisms – although some, such as the harp-like Chondrocladia lyra, are carnivorous and capture prey with barbed hooks that cover their ghostly, branching limbs.

But their survival is also aided by something else. Because sponges are immobile and cannot flee or attack predators, they have evolved to protect themselves by producing novel toxic chemical compounds, which also enable them to thrive in some of the most extreme and inhospitable places on Earth. In fact, every year, more than 200 new chemicals are discovered just from sea sponges.

One scientist who has discovered many of these new chemicals is Shirley Pomponi. A self-described “medical sponge hunter”, Pomponi is a research professor and the executive director of the Cooperative Institute for Ocean Exploration, Research, and Technology at Florida Atlantic University’s Harbor Branch Oceanographic Institute. She has spent nearly 40 years collecting sea sponges from around the world and analysing their chemistry in search of new medicines.

Pomponi says she “got hooked” on marine biology in college. In 1984, soon after she had completed her PhD in biological oceanography, she received a call from the Harbor Branch Oceanographic Institute, which had just founded a marine drug discovery program and needed someone to assist in collecting and identifying sponges and other marine organisms.

“A lot of chemicals that showed promising medicinal properties were coming from sponges, and they really wanted to get a feel for what these sponges were and refine the sample acquisition program,” she says.

With her previous experience studying sea sponge ecology, Pomponi was an ideal person for the job – and was soon leading the Institute’s acquisition program. Her work is global in scope and has taken her to some of the most biodiverse regions of the planet, including the Great Barrier Reef and Ningaloo Reef in the late 1980s. “That was a really successful trip,” she says. “We were looking at not only the tropical organisms, but more warm temperate ones as well.”

According to Pomponi, her work is underpinned by a simple concept: “find and grind”.

First, she searches for organisms that are in some way unusual – either because of their shape, colour or size – which can be an indication of a novel chemical composition. These organisms are not confined to one region of the ocean; rather, they are spread throughout it and at various depths, from the shallows to several kilometres underwater.

To collect those living in shallow waters, Pomponi and her colleagues will dive using SCUBA gear. For those residing in the dark depths, they now use remotely operated submersibles; however, up until 2011 they used human-operated ones.

Back in the lab, Pomponi will then make an extract of a sample by grinding it up and mixing it in with a solvent. “And then we test that extract, which might contain dozens or even hundreds of different chemicals to see if it’ll, say, kill cancer cells or inhibit microbial growth.”

If the extract achieves this, the next step involves isolating which particular molecules are the active ones, using a series of chemical procedures such as spectroscopy or chromatography.

“More than three quarters of the ocean has never been mapped, explored or observed”

“And gradually,” Pomponi explains, “you narrow it down to a single molecule. And ideally, at the end of the day, it’s a novel molecule that’s never been discovered before with a novel biological activity, or it’s a known molecule that has hasn’t previously been reported to have that particular type of activity.”

With the active molecule identified, the process of identifying its exact mechanism of action begins.

“You have to figure out: how does the chemical actually work – how does it kill cancer cells, for example? Because it’s not good enough just to say that it kills cells; you have to be way more specific than that.”

An oft-quoted fact about the ocean is that it covers more than 70% of Earth’s surface, or roughly 361 million square kilometres. But this only gives a superficial sense of the scale of what marine biologist Rachel Carson once called “that great mother of life”, for it explains very little of the vast world beneath the waterline.

That world is one which we are still – despite decades of research and huge leaps in technology – in the nascent stages of perceiving, let alone understanding. It harbours 99% of all living space on the planet, more than three quarters of which has never been mapped, explored or observed by humans.

What we do know is that the ocean is far from being physically featureless. It contains huge volcanoes, seamounts, canyons, trenches, abyssal plains and mountain ranges that dwarf many of those found above the waterline. In fact, it’s home to the biggest mountain range on Earth: the mid-ocean ridge, which stretches 65,000km. Its average depth is roughly 3,800m – four times deeper than the average land elevation is high – and its deepest point, the Mariana Trench, east of the Philippines, is nearly 11,000m deep, into which Mount Everest would fit with almost two kilometres to spare.

This space does not contain a monoculture, even though it might seem like it from our land-based vantage point. Within it are five distinct zones of life, which are defined by the amount of sunlight that reaches them. The most extreme – the Hadal zone, from 6,000m below – is characterised by complete darkness, freezing temperatures and crushing pressure more than 1,000 times higher than at the surface.

In all of these zones live an array of strange and wonderful species – 91% of which scientists estimate are yet to be classified.

And among the most strange and wonderful forms of life that exist down there are the sponges.

It was a German-American chemist from Yale University named Werner Bergmann who – quite accidentally – pioneered scientific interest into Earth’s underwater pharmacy nearly 80 years ago.

In the autumn of 1945, Bergmann – who had a stern, serious face punctuated by a toothbrush moustache that overshadowed his small, thin mouth – travelled to Florida Keys, where he found a previously undescribed sea sponge in shallow waters, which was eventually taxonomised as Tectitethya crypta.

Within a few hours of collecting samples, he preserved them in a solution of seawater and formalin, then dried them in a vacuum oven. Bergmann was looking for fat molecules called sterols which he knew play a key role in biological systems, but four years passed before he investigated his samples for them. When he did, he found something quite different – and very strange.

When he placed the samples in boiling acetone, a “rather copious amount of a nicely crystalline material” began to form in the flammable, pungent liquid. He later showed it to be a nucleoside, but, oddly, not one of the four types that were already known (and would later be found to form the structure of DNA): thymidine, cytidine, guanosine and adenosine. While it resembled thymidine in structure, this new compound, instead of being linked in a chain with other nucleosides, was all alone.

“These ‘unusual nucleosides’ ultimately paved the way for the release in 1969 of cytarabine”

As a testament to both the organisms from which it was derived and the nucleoside it resembled, Bergmann named this compound spongothymidine. He also isolated from this sponge two other previously unknown nucleosides: spongouridine and spongosine. Bergmann got to work synthesising these “unusual nucleosides”, which ultimately paved the way for the release in 1969 of cytarabine – a drug that blocks DNA replication in acute leukaemia and lymphoma tumours, effectively killing them. A synthetic nucleoside modelled after spongothymidine, cytarabine was the first-ever marine-derived medical drug. It is still used to treat leukaemia patients, though it does come with a number of side effects, including gastrointestinal disorders, pneumonia and confusion.

After the approval of cytarabine, research in the field of marine pharmacology “lapsed for a while”, according to Pomponi. But in the mid-1980s, “everything started up again” – with the benefit of increased funding from large pharmaceutical companies like Merck.

This led to the development of new drugs that were modelled after the strange nucleosides Bergmann found within Tectitethya crypta.

One of these drugs was the HIV/AIDs treatment, AZT. Another was aciclovir – the first antiviral medication. Discovered in 1984, it was approved for the treatment of herpes, chickenpox and shingles seven years later and is now considered by the World Health Organization to be an “essential medicine”.

In the years since, marine pharmacology research has continued. Trabectedin – which was isolated from Ecteinascidia turbinata, a sea squirt species that lives on corals in the Mediterranean – is a chemotherapy drug first approved for use by the European Union (EU) in 2007 and eight years later by the FDA. The FDA has also approved eribulin mesylate: a medication used in the treatment of patients with breast cancer. It’s a synthetic analogue of the molecule halichondrin B, which is produced by dinoflagellates that live symbiotically in marine sponges.

In October 2023, a team from the University of Mauritius, led by Rima Beesoo, published the results of their study into the sponge Neopetrosia exigua. Collected from coral reefs near Amber Island off the northeast shore of Mauritius, the sponge was transferred to the lab under seawater, cleaned of debris and frozen at minus 80°C, before being ground into a powder and soaked in solvent to obtain different chemical extracts. The extracts were then tested at the University of Edinburgh for their efficacy in fighting human cancer cells.

The results were enormously promising. One particular extract not only killed liver cancer cells at very low doses by activating various proteins that led to their breakdown, but it also displayed very low toxicity towards normal cells. Many more marine-derived drugs are currently in clinical trials.

In May 2023, a team of researchers led by Muriel Rabone, a deep-sea ecologist at the Natural History Museum in London, published a landmark paper in Current Biology: “How many metazoan species live in the world’s largest mineral exploration region?”

The region in question is the Clarion-Clipperton Zone (CCZ), which spans approximately six million sq. km – about twice the size of India. It lies in the Pacific between Hawai‘i, Kiribati and Mexico and is the focus of deep-sea mining explorations due to the abundance of potato-sized nodules – found in mud 4,000 to 6,000 metres below the surface – that are rich in minerals critical for the renewable energy transition, like nickel, cobalt and copper.

Rabone and her fellow authors said the paper represented the “first comprehensive synthesis” of biodiversity within “the largest ecosystem on our planet” on “the eve of possible large-scale mining operations” (currently, there are 17 contracts for mineral exploration covering more than one million sq. km).

They parsed through more than 100,000 records of creatures found in the CCZ gathered from numerous deep-sea research cruises, and found evidence for 5,578 different species, with as many as 92% being entirely new to science.

But, according to Rabone, the paper “barely scratches the surface” of the biodiversity found in the CCZ. Indeed, she believes there could be up to 8,000 more unknown species located there. And even of those species that have been identified, our knowledge of them is extremely limited.

“We don’t know about their ecology or their functional role,” she says, “and we certainly don’t know about their chemistry.”

Based on what is already known about marine organisms like sponges, however, there is good reason to believe that the chemistry of at least some of those found in the CCZ will be novel – and so, according to Rabone, could potentially be the foundation of “lifesaving, blockbuster drugs”. Deep-sea mining poses a serious threat to these potential discoveries. “If we don’t protect [the CCZ], what are we potentially losing? It’s a difficult question to answer, but one we will never answer if we aren’t looking at potential applications of the organisms found there.”

According to Pomponi, deep-sea mining and trawling are the “biggest threats to the biodiversity of the deep sea” – and by extension to the potential development of new, marine-based drugs that could help in the fight not just against cancer but also deadly diseases that, over time, become resistant to antibiotics. As Rabone points out: “There are predictions that in 20 to 40 years’ time, bacteria diseases are going to be number one killer because of antimicrobial resistance.” (See ‘Rebelling against resistance’, Issue 100.)

Deep-sea mining is just one of the challenges affecting the development of new marine-based drugs. Another is the sustainable supply of sponges and other oceanic organisms. Part of this problem is that, as Pomponi says, “deep-water sponges are very difficult to access”. But in addition to this, it’s often necessary to collect a huge amount of sponge samples to conduct useful experiments.

Indeed, scientists were only able to produce 300 milligrams of halichondrin B from the one tonne of a rare, deep-water sponge they collected. As the 2016 paper in Biomolecules & Therapeutics said: “This very low yield did not allow the sustainable isolation of halichondrin B.”

In the case of halichondrin, this problem was solved by chemical synthesis in 1992. For others, it has been solved with aquaculture. But Pomponi is working on another solution: in vitro cell development.

“How can we get cells from these sponges that produce chemicals that have human health applications and grow those cells in the laboratory, so we don’t have to keep going back and collecting from the natural environment?” she asks.

“We don’t know about their ecology … and we certainly don’t know about their chemistry.”

Her process is to take small fragments of cells from sponges and then cryopreserve them so they stay alive, before thawing and attempting to grow them in the lab – a process she says can be applied to other marine organisms as well.

Four years ago, she made a “big breakthrough” on this front when she and colleagues grew sponge cells in culture for the first time.

“It took me 30 years to successfully do it. And we just got a grant from the [EU] to scale up production for anti-cancer compounds.”

Our standard world maps centre the land. Looking at them, we have our land-bias reinforced; we see the continents fringed by segregated oceans, which exist almost in the background. But one map flips this representation.

Known as the Spilhaus projection, it was developed by South African-American geophysicist and oceanographer Athelstan F. Spilhaus more than 80 years ago. It shows Antarctica floating in the middle of one continuous body of blue water – around which lay the other land masses, like an audience.

This map provides an opportunity to reimagine the ocean and see it for what it is – namely, the protagonist who plays the starring role in the grand narrative of life on Earth.

The research by Pomponi, Rabone and others offers a similar kind of opportunity. It expands how we think of the ocean, transforming it from simply a flat expanse stretching to the horizon into a multi-dimensional, multi-zonal space.

It’s an opportunity to appreciate just how vast and complex the ocean really is. But it also helps us appreciate something else about it as well: the seemingly infinite discoveries to be made underwater, including those hidden in the porous tissue of ancient marine animals which, quite literally, can save our lives.