The captain of the research vessel Hyas leans out over the stern. Controlling a winch with one hand, he watches as a cable winds slowly up from the depths, trailing a triangular green net about the size of a wheelbarrow.
Marine biologist Richard Ingebrigtsen kneels to tip and then shake the heavy net, sending an avalanche of scallops, seaweed, algae, sea cucumbers, sponges, starfish, tiny shrimp, and shell fragments tumbling into a black plastic tub. There is even a spider crab, called hyas in Norwegian.
We are off the coast of Northern Norway, far above the Arctic Circle, and although it is early summer, the high peaks in the distance are blanketed with fresh snow. Little wonder Ingebrigtsen is decked out in winter gear. He examines today’s catch as if every object contains a secret treasure and two red urchins catch his eye. Because these organisms are harder to come by, Ingebrigtsen places them in a separate bucket. Later, he will deliver them to a colleague who specialises in urchins and molecules derived from them. “He’s going to be happy,” says Ingebrigtsen. “Maybe I can get one or two beers as payment.”
Scientists are on the hunt for a different sort of bounty: chemistry that might just save your life
Despite the leisurely feel of this cruise, it has a serious mission. For centuries, people in this part of the world subsisted on protein-packed resources from the sea – salmon, cod, halibut, whale. Fisheries (and oil) continue to provide the country with riches. But now scientists like Ingebrigtsen are on the hunt for a different sort of bounty: chemistry that might just save your life.
Humanity is facing an all-out emergency when it comes to the absence of new drugs. Antimicrobial resistance is fast becoming a scourge of our time, while the fight against unremitting killers like cancer and heart disease can always benefit from novel molecular weaponry. And that’s just the start. Alzheimer’s, diabetes, pain medications and anti-viral medication — we need it all, and more, not to mention new chemical tools for applications as varied as cosmetics and dairy products. All of which is to say that excursions like this one are about far more than the romance of cataloguing the natural world.
As a PhD candidate at the University of Tromso and a member of the Polar Research Centre’s biodiscovery program, Ingebrigtsen has been at the heart of this mission. “Valuable stuff is out there,” he says. “But you have to look for it.” As we talk, he picks up a scallop shell, attached to which is a bryozoan, that looks like a leafy crimson-coloured tree half an inch tall. Next he inspects something called a colonial sea squirt, an organism that is as charismatic as the contents of a used tissue.
Despite their unassuming appearance, creatures like these squirts, bryozoan, sponges, and microalgae show great promise for new drug development, because the molecules that evolution has equipped them with can be downright radical. How else are these stationary and otherwise defenseless creatures going to survive the dark, corrosive, turbulent conditions of the sea and incessant threats from predators? “They’ve been floating around or stuck down there on the bottom for millions and millions of years,” says Ingebrigtsen, marveling at another bryozoan as if it were a diamond. The solutions they have evolved to survive are wild, weird, mysterious and potentially quite useful.
And there is one other adaptation that squirts, sponges, microalgae and other creatures in the waters around Norway possess that is of particular interest to Ingebrigtsen and his colleagues, one that has made the waters of the far north a hotspot in the search for novel chemistry: they can handle the cold.
There’s nothing new about looking to nature for useful goodies. Indeed, the story of human history could well be written by ticking through the various ways our ancestors and contemporaries figured out how to exploit natural resources to better our chances of survival, be it stone tools, firewood, fish, cows, or copper.
At every step in that journey, our ancestors have also turned to Mother Nature to heal the body; herbal medicine was a thing long before “herbal medicine” was ever a thing. More recently, biodiscovery programs in terrestrial environments have yielded or inspired many important medicines in use today. A common example: the chemotherapies docetaxel and paclitaxel, both derived from yew trees. Organisms from forests to deserts have revealed all kinds of secret chemistry, some of which have led to therapeutics, others of which have proven useful for everyday products like laundry detergent.
But in the latter half of the 20th Century, lab technology for synthesising chemistry became so powerful that most pharmaceutical companies turned their attention away from the natural world as a source for the next generation of great remedies. The thinking was that rapid and high-volume synthesis and screening of molecules would deliver a greater rate of successful “hits,” as compared with expensive expeditions out into nature to uncover new molecules cooked up by evolution.
That thinking was wrong. Despite all the investment in lab-based shotgun approaches, the majority of new drugs to enter the market over the last 40 years have their origins in the natural world. As former chief of the natural products branch at the National Cancer Institute in the US, David Newman, recently told Pharmaceutical Journal, “Making something from nothing has failed miserably.” For now, not even supercomputers can beat 3 billion years of evolution. Compounds gleaned from nature “are so different from what a chemist can think of, it’s incalculable.”
People often think that we’re the best at making things chemically and then we discover that nature has been there before
“People often think that we’re the best at making things chemically and then we discover that nature has been there before,” agrees Marcel Jaspars, professor of chemistry at the University of Aberdeen and Director Marine Biodiscovery Centre at Aberdeen and an advisor to the program in Tromso. “You ask, ‘Why wouldn’t nature do this?’ And the answer is, it already did. We only just found it.”
Even so, only a small part of bioprospecting takes place in the field, and the bulk of the hunt continues in the lab, where scientists screen and test the chemicals for so-called bioactivity. When you combine compounds derived from whatever species with cells associated with Alzheimer’s disease or cancer, say, do reactions happen? If so, what kind? Are they big, small, temperature-dependent? And what is the underlying chemical structure behind it all? Oftentimes, such reactions, and indeed the molecules that catalysed them, are already known to science. To date, there are an estimated 24,000 catalogued marine-derived molecules, give or take a few hundred. But sometimes molecules prove to be new and show enough promise that they are pushed forward into the drug development pipeline.
The sea is a particularly rich resource. Up until about 20 years ago, people studied marine organisms mainly just to know which creatures not to step on swim alongside: the stinging jellyfish, shocking eel, deadly stonefish. Yet it’s precisely those kinds of defenses that may be of use to science. And evolution has been at work in the sea much longer than it has on land, which means life in the oceans has had more time to evolve more diverse chemistry.
In the 1990s, scientists began searching for new molecules in the oceans, mainly in more hospitable latitudes, where the oceans are more diverse and – let’s be honest – more pleasant to explore, at least by the metric of swimsuit weather. Results from this work have been impressive. According to the National Cancer Institute in the US, anywhere from 15,000 to 20,000 compounds, irrespective of where they come from, need to be evaluated in order to find just one that eventually leads to a medicine. Of the roughly 24,000 known marine natural compounds, 13 different chemical agents that have their origins in marine environments are in clinical trials, 11 of which show cancer-fighting properties. “Marine natural product drug discovery is maybe seven- or eight-fold more effective than other methods,” says William Gerwick, professor of oceanography and pharmacology at the University of California at San Diego.
And there have been many rewards besides these medicinal trophies. For one thing, bioprospecting and new species discovery go hand in hand, which influences what we know about various ecosystems and may well contribute to conservation efforts. In other cases, novel chemistry that doesn’t eventually lead to a drug does become an essential pharmacological tool – toxins or other agents used in the various processes to form, sculpt, bake, or refine molecules. To date, at least 121 such products have been gleaned from marine sponges, algae, bacteria, and other organisms.
Not that we have even really begun mining this resource. By current estimates only 1% of the bacteria present in seawater has been examined for potentially beneficial chemistry. But the value of bioprospecting is now more widely understood, and research initiatives are underway from Florida to the Arabian Peninsula.
In recent years, marine biodiscovery researchers are pushing into more hostile and largely unexplored territory. What makes it possible for certain bacteria to live alongside a hydrothermal vent? Because fish can’t regulate their body temperature, what metabolic machinery has evolution equipped them with so that they can tolerate the cold? And in lieu of defenses like claws, camouflage, or the ability to swim away, how do tiny creatures like sponges and bryozoan defend themselves?
One drop of palmyrolide would kill a swimming pool full of target cells
“There are some fabulously bioactive compounds coming from cold waters,” says Gerwick. One, from Antarctica, is called palmyrolide. “It’s an exquisitely active toxin to cancer cells,” says Gerwick. A generation ago, Gerwick says, investigators would have been excited if just one drop of a novel molecule would kill enough nasty cells to fill a bathtub. “Now one drop of it would kill a swimming pool full of target cells.” The toxins these organisms deploy have to be this potent to cope with diffusion in the water; otherwise they would become too diluted too quickly to be of much use against a predator.
What makes the marine environment near Norway an especially exciting site for biodiscovery is that here, the icy waters of the arctic collide with warmer waters carried north by the Gulf Stream. Here, organisms must tolerate not only freezing or near-freezing temperatures, but also incessant turbulence caused by this clash of currents. At the same time, those currents are what make this corner of the Atlantic so high in nutrients, which makes it biodiversity rich and, by extension, full of undiscovered chemistry.
What was missing was a way to go after it.
Not a lot of people can say they rescued an industry, but Trond Jorgensen is one of them. Trained in mammalian immunology, Jorgensen was working at the University of Tromso in the 1980s when whispers began to circulate about a disease that was hitting stocks of farmed Atlantic salmon.
The disease, cold-water vibriosis, is caused by a bacterial infection, and in the early 1980s it was on course to devastate the fish population, and with it a large part of Norway’s economy. Jorgensen led the team that successfully developed a vaccine, resulting in a 95% drop in the rate of new outbreaks. It was a huge leap for marine biotech in Norway. Afterward, Jorgensen could write his own ticket. He chose to stay in Tromso to continue basic research in fish immunology, although he is quick to point out the blurry distinction between basic and applied research. After all, the human immune system evolved from that of fish.
Then one afternoon in the spring of 1999, he found himself talking with the head of the Norwegian Research Council in Oslo about a famously missed opportunity. In 1969, a Swiss biologist exploring an alpine plateau in southern Norway brought home a soil sample that included material from the fungus tolypocladium inflatum. A compound derived from the fungus, ciclosporin, proved to be an effective immunosuppressant for transplant patients. In order to help the body accept a new kidney or liver, the immune system needs to be tricked into not rejecting the newcomer. That is ciclosporin’s job, and it has since earned the pharmaceutical company Sandoz (now owned by Novartis) billions of dollars.
Norway earnt nothing from the discovery of ciclosporin. “We were jealous of the Swiss,” recalls Jorgensen. “They picked up the molecule in Norway – it’s almost a kind of piracy.” He is kidding about piracy; the discovery, development and use of ciclosporin is perfectly legal. (And Norwegians know better than to complain about other countries’ good fortune. In fact, exploitation and development of Norway’s vast oil reserves was beginning at about the same time the Swiss scientist was wandering around collecting fungus.)
The NRC man asked Jorgensen if ciclosporin could have been detected or exploited by Norwegian scientists. Jorgensen explained that it was certainly possible to find such things, but Norway lacked the necessary infrastructure to carry discoveries like that any further – collections programme, access to natural compounds databases, a dedicated repository, tools for screening, isolation, structure analysis and so forth. “It was then that I decided to change my life,” Jorgensen says. “Instead of just exporting these resources, we should develop them ourselves.”
Among the latest discoveries are molecules that inhibit plaque buildup in blood vessels
Capitalising on his connections in marine science, his reputation for saving the salmon industry, financial resources available in such a wealthy country, and support from both academia and the private sector, Jorgensen raised some $20 million to launch a biodiscovery program at the University of Tromso. (It was called MabCent-SFI, but was recently reorganised as part of an expanded program called the Artic Biodiscovery Centre.) “He knew nothing,” says Jaspars. “But he saw that this was a good idea and convinced others that that was the case.”
The program is structured so that natural compounds screening is done “on behalf” of industry partners that contributed on the front end, hoping to cash in on intellectual property gleaned from whatever novel chemistry Jorgensen and his colleagues discovered. (If no commercial partner wants rights to a molecule, the rights revert back to the University.) Between 2007 and 2014, the program conducted sampling during hundreds of days at sea, at more than 1,100 locations up and down the Norwegian coast and around the Spitsbergen Islands. Jorgensen says that 80% of the time the molecules in question have been seen before. “But in 20% of the cases, they are new – and the bioactivity is new!” To date, MabCent has characteried some 150 novel bioactive compounds and produced 50 drug development leads, the majority of which are active against cancer or influence immune response.
Among the latest discoveries are molecules that inhibit plaque buildup in blood vessels. Jorgensen says he’s not permitted to say more at this point, but confirms that the find came from a sea sponge. His favorite lead, though, is something called breitfussin; he even has a picture of its chemical structure taped to his office wall. The hydrozoan-derived molecule has at least 10 different variants, and has shown promise as an anti-microbial agent. Jorgensen loves this one in part because it was found at 74.5 degrees north, near Bear Island, and also the challenge of understanding its precise structure, which required an assist from imaging wizards at IBM.
And while the ideal outcome of bioprospecting is to find molecules that by themselves, or after some tweaking, work as effective medicines, other findings can still be of enormous utility for molecular biology and/or diagnostics applications generally. Enzymes, for instance, are essential for studying, synthesising and refining different biochemical structures. But while enzymes adapted to warmer temperatures are better known to science, cold-adapted enzymes are not – and they might hold their own, hidden properties.
Earlier this year, Jorgensen and his team formalised an agreement with the Max Planck Lead Discovery Center in Dortmund, Germany. Tromso has a burgeoning biotech cluster, and a handful of local startups are partners in the Arctic Biodiscovery Centre project. But they can only carry molecules so far before handing them off to an institution better equipped to refine the chemistry and liaison with industry. “It’s better to use their pipeline,” Jorgensen says. “Big Pharma is knocking on their door every week asking: ‘What do you have?’”
Back on the Hyas, Ingebrigtsen is nearly finished combing through another haul of material from the seafloor. He starts explaining how he first became interested in marine science, which sounds similar to how every one of his colleagues became interested in marine science: as a kid, he spent part of every summer at his grandparents’ cabin, which was right near the seashore. All day long and well into the night, he would hike around and explore, searching for nothing in particular yet curious about everything.
Ingebrigtsen gets a little giddy when talking about his research with microalgae because of all the bioactivity potential and because this niche of bioscience is so new. And from a chemistry standpoint, it is. Yet marine bioprospecting in the arctic is really just the latest version of the same story for Norway, a country where the area of water within its borders is about six times that of the landmass. It is the story of riches from the sea – fisheries, oil and gas and now, quite possibly, novel chemistry.
Before turning the Hyas around to head back to the dock in Tromso, the captain asks Ingebrigtsen if he would like to fish for a few minutes. Ingebrigtsen says sure and picks up a hand line. In no time at all he lands a nice haddock for dinner.
David Wolman tweets at @davidwolman
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