Antibiotic abyss: The extreme quest for new medicines
- 27 January 2014 by Jon White
As antibiotic resistance increases, audacious expeditions are taking the quest for new medicines to the ocean depths, and not a moment too soon
THE 150-kilometre trip out from Chile won't be comfortable. It will be hot, choppy and take all night. Travelling across this patch of the Pacific Ocean, you run afoul of both El Niño and La Niña, whose perpetual tug of war with the weather can make even the most stoic seafarers lose their lunch.
Luckily, once the crew – an eclectic mix of hardened South American mariners and British salvage engineers – reach their destination, they should find placid waters. That will make it a lot easier for the engines to steady the ship's position. They certainly can't use an anchor: out here, the ocean floor is 8 kilometres down, a treacherous abyss known as the Peru-Chile trench. But what the team haul out of these depths could save your life.
The Peru-Chile trench is only the first stop. This year, Marcel Jaspars, a chemist at the University of Aberdeen in the UK, is leading an international raid on the unexplored recesses of the oceans. The exotic organisms that thrive there could be pressed into service against some of our worst enemies, from cancer to drug-resistant bacteria. There's not much time to lose. Without them, some say we may be heading for an antibiotics apocalypse.
We have always relied on nature to fill our medicine cabinets. Over half of all drugs on the market are either derived from or inspired by plants, animals or bacteria – aspirin is extracted from the bark of the willow tree, penicillin comes from a fungus, and we have soil bacteria to thank for many antibiotics.
Some of these discoveries were happy accidents, but traditionally pharmaceutical companies went foraging for medicinal treasures in remote locations – a practice known as bioprospecting. Such expeditions have struck gold in the past: vinblastine, a chemotherapy drug used to treat Hodgkin's lymphoma, is derived from the rosy periwinkle, a plant native to Madagascar.
Out of time
But over the past 20 years, conventional bioprospecting has seen diminishing returns, particularly among microorganisms. The same thing keeps happening; bioprospectors find a promising candidate, companies spend small fortunes on development – only to find that everyone has wasted their time. This is happening even as our need for new antibiotics grows steadily more urgent, says Laura Piddock, a microbiologist at the University of Birmingham, UK, who directs a global initiative to develop new antibiotics.
Antibiotic-resistant strains of gonorrhea, tuberculosis and MRSA are on the rise. Such bacteria have evolved resistance mechanisms even against the antibiotics of last resort. Within a decade or two, they will have become resistant to all major antibiotics, and simple infections will become fatal. But no new organisms have been found on which to base better drugs. "The pipeline is pretty empty," Piddock says (see diagram).
Desperate for new compounds, pharmaceutical firms turned to synthetic analogues. But these have not equalled the natural diversity that has evolved over billions of years. The effect has been fewer products, not more, says Guy Carter, an industry consultant in New York.
But Jaspars is convinced nature still has a few tricks up her sleeve. The organisms that flourish in the comfort zone of Earth's biosphere make up only a fraction of life on our planet. Outside what we consider the habitable regions – in the desiccated soils of deserts or buried beneath thick ice or rock – creatures not only survive, but thrive, at extremes of temperature, salinity and darkness.
The world's most hostile environments house more life than anyone suspected (Image: Frans Lanting/NGS)
We first realised that their unusual adaptive chemistry could be used to our advantage about 40 years ago. Thomas Brock – at the time a microbiologist at the University of Washington – was driving through Yellowstone National Park on his way back to the lab. The hot pools and geysers proved too tempting; he stopped to admire them and returned to the lab with a water sample. He was stunned to discover life thriving in the near-boiling liquid. So began a decade of study of thermally resistant microbes. One species, Thermus aquaticus, turned out to make an enzyme, taq polymerase, that was key to automating methods used to amplify small amounts of DNA. It turned a tricky, labour-intensive process into one doable on any lab bench, effectively ushering in the genomics revolution.
It wasn't until a few years ago that we began to realise that these adaptations could also be turned against some of our nastiest medical foes. Fungi discovered in the acidic lakes of Lechuguilla Cave in Carlsbad, California – whose metal-infused waters should have stymied all life – tipped us off (see diagram). One hardy strain of Penicillium produces a compound that inhibits the growth of lung cancer cells. Another compound, berkelic acid, isolated from fungus and bacteria found living in the toxic water of an open pit mine, slowed ovarian cancer cell growth by 50 per cent (Journal of Organic Chemistry, vol 71, p 5357). The hunt was on to unearth more of nature's extreme medicines.
But if we thought life would be rare in such spots, we were in for a surprise. Microbiologist Alan Bull of the University of Kent, UK, has scoured the driest and highest desert on Earth: the Atacama, which straddles northern Chile. Microbes there face dessication and intense bombardment by ultraviolet light; the environment is so punishing that NASA has used it as an analogue for Mars. Here, Bull hoped to find his favourite microbial group: actinobacteria, rich in the molecules that are essentially ready-made medicines, small enough to slip through the body's defences.
He expected to find a few hardy species barely eking out a grim living. But at last count, Bull's group has collected 1000 cultures. Some pump out compounds with antibiotic, anti-cancer and anti-inflammatory properties. Some are familiar. Many are not. "The majority are likely to be new species whose medical potential is virtually untouched," Bull says.
The desert isn't the only place revealing an unexpected cornucopia. Antarctica, another vast, underexplored region, has been opening up for bioprospectors, aided by an unexpected ally – climate change. David Pearce at the University of Northumbria, UK, has been analysing samples taken from sediment beneath the subglacial waters of Hodgson Lake. The lake is emerging from under what was a very thick ice cap thanks to deglaciation, allowing the first recovery of 100,000-year-old Antarctic subglacial sediment. What they found echoed Bull's findings: the biomass was higher than he expected. "Perhaps the selective pressures aren't as severe as we once thought," he says. "It looks as if it might be quite conducive to life."
More importantly, these weren't just many members of a few species. Genomics revealed that the lake site was teeming with diversity. "We might have expected there to be highly specialised organisms," Pearce says. "But we found a very diverse range; some freshwater, some marine, some extremophilic, some more cosmopolitan – that was quite a surprise."
That diversity was also represented in the biochemical makeup of the organisms. DNA analysis showed that about a quarter of the biological material present at Hodgson Lake couldn't be matched to any known sequences. The group is still awaiting final results, but it seems that these are brand new species.
If life at extreme temperatures was thought to struggle, it was believed to be entirely nonexistent in the rocks deep beneath our feet. But in the past few years, we have been proven wrong yet again. The rocky depths harbour yet another other vast microbial ecosystem that is as untapped as Antarctica and spans pretty much the entire globe.
Into the deep
Everywhere we have looked, microbial life has surprised us with its tenacity, versatility and abundance. But perhaps no extreme environment is more unexplored – or more promising – than the ocean trenches. While we have made large leaps in understanding deep-sea life, the trenches are the last unknown, says Tim Shank, a deep-sea biologist at Woods Hole Oceanographic Institution in Massachusetts. "It's the largest unexplored biome on Earth," he says.
"Ocean trenches are pretty unique places," says Jaspars. Here, the so-called hadal zone combines several extremes at once: immense pressure, total darkness and temperatures down to 2 °C – a temperature that, while not obviously extreme, stifles most bacterial growth. Punishing environment aside, the trenches' isolated nature and unique ecology make them underwater versions of the Galapagos Islands. Each should hold a rainbow of unique life that has had to adapt to its unusual home.
Last year, Jaspar's hunch that deep trenches hold rich life was verified: microbial ecologist Ronnie Glud and his team at the University of Southern Denmark in Odense revealed the results of an analysis of samples collected from Challenger Deep at the bottom of the Mariana trench, nearly 11 kilometres below the surface of the western Pacific. Every cubic centimetre of mud brought back contained, on average, 10 million microbes – about 10 times more than in mud collected from a plateau at the top of the trench. How could these light-deprived organisms be so prolific? Glud says that the trenches are particularly good at capturing life-supporting nutrients. Their broad, steep slopes act as a funnel to channel organic matter down to the bottom, where it feeds the waiting bacteria.
But would trench organisms also contain possible new medicines? Early hints came when Jaspars collaborated with Bull on chemicals isolated from a different cluster of Mariana trench microbes. Dermacoccus abyssi, an actinobacterium hauled from the seabed by a Japanese remotely operated submarine, produces dermacozines, a never-before-seen family of biochemicals that are showing promise against the parasite that causes sleeping sickness (International Journal of Systematic and Evolutionary Microbiology, vol 56, p 1233).
The Peru-Chile trench, says Jaspars, should hold a similar population of novel bacteria – and no one has ever looked for them. "Only two or three samples have ever been taken there," he says. But bacteria weren't on the shopping list of those collectors: that project was after worms and other small organisms. "What they found was pretty unusual and different," Jaspars says. "So we have good evidence that that will be the case for us."
Jaspars had his work cut out for him. After all, these trenches have remained unexplored for good reason – it's been all but impossible to reach them. So with £9.5 million in funding from the European Union to begin his bold project – dubbed PharmaSea – Jaspars got to work. He assembled his partners carefully: spanning 13 countries and comprising 25 institutions and commercial groups, they would be an all-star team. Chile was chosen for its access to the trench; other partners for their expertise. British salvage firm Deep Tek have created a novel combination of rope and winch that, its designers hope, will eliminate the need for specialist scientific ships and thereby cut sampling costs by a factor of 10.
But there's one final obstacle that won't be so easily negotiated. For the creatures that call this hostile terrain home, our temperate environment is every bit as deadly as their home is to us. Tracy Mincer, also at Woods Hole, points out that many are likely to be piezophiles – pressure-sensitive organisms that need a crushing environment to thrive. These deep-water bacteria may not survive their journey to the surface.
A handful of sophisticated high-pressure chambers allow researchers to grow small quantities of these extremophiles, but such equipment is rare and tricky to use. Luckily, Jaspars has got his hands on a chamber that can simulate a depth of 4000 metres, which should help keep some of the less hardy bacteria on life support. But he plans to sample from a range of depths, and he thinks some of these bugs can adapt to sea-level pressures.
Only when the samples have been safely retrieved and placed into cold storage can the long road from deep-ocean gloop to new drug begin. The PharmaSea team hopes to get several drug candidates into animal testing by the time the project finishes in 2016.
First they will isolate the bacteria and coax them into larger colonies. Then they will make an extract of the bacteria and pit the hundreds of compounds they produce against cells infected with various diseases. "If something is a match, you purify until you have the active chemical and test that further," Jaspars says.
Some cutting-edge screening methods will help speed up the process. To find activity against diseases of the nervous system, for example, Jaspars recruited researchers at the Catholic University of Leuven (KUL) in Belgium, who have developed novel zebrafish assays. Zebrafish are unexpectedly good animals on which to test new medicines as they have genetic, physiological and pharmacological similarities with humans. Most importantly, using the fish means screening is fast and can be done with small samples.
The final stop will be large-scale development by a pharmaceutical company. While big pharma may have largely stepped back from antibiotics, smaller firms are venturing into that territory. Ronald Farquhar, who leads drug discovery efforts at Cubist Pharmaceuticals of Lexington, Massachusetts, is enthusiastic about PharmaSea's prospects. "Diverse and exotic environments are vital to finding new classes of antibiotics," he says.
Jaspars aims to follow up his visit to the Pacific depths with similar trips to other ocean trenches; the Kermadec off New Zealand, the Mariana in the western Pacific and the Izu-Bonin off Japan.
But first, the Peru-Chile trench beckons. The ship will depart within a few weeks. Once in place, Deep Tek engineers will drop a metre-long coring device over the side. It will take 4 to 6 hours for the apparatus to sink down to the seabed and dig itself into the sediment. The journey up, powered by motors, will be faster. During their 10 days sampling the trench, the engineers will work round-the-clock shifts to collect the cores.