From animals to plants, from the land to the sea, it has long been known that the natural world hides a potentially vast trove of medical breakthroughs. Naturally -derived biologic drugs drove a surge of pharmaceutical innovation in the 20th century, including revolutionary antibiotics that have transformed the treatment of infections.
After an initial outpouring of biopharmaceutical development in the decades after the Second World War, activity slowed down in the 90s as pharma companies and research organisations increasingly focussed on the chemical synthesis of more common small-molecule drugs.
Nevertheless, it is clear that the medical value that has been discovered and commercialised from nature represents only a small fraction of the biopharmaceutical potential that remains undiscovered in the unique compounds at work in the soil beneath our feet, under the ocean's waves or in the animal and plant kingdoms.
The needle in the haystack
According to studies less than 1% of bacterial species and 5% of fungal species are currently known, meaning that the secondary metabolites produced by micro-organisms as yet undiscovered could very well hold the key to solving many of the medical conundrums that persist in the 21st century.
"It's somewhere between 99.9% and maybe 99% [of microbes that are uncultured]," Dr Sean Brady of Rockefeller University's Laboratory of Genetically Encoded Small Molecules told Pharmaceutical Technology last year. "Even among the bacteria that we do grow, what we realise now is we were leaving behind most of the molecules they could make. We didn't know how to turn them on; we didn't know how to turn on the genes that make those molecules. So either we haven't brought the bugs in, or for the bugs we've already brought into the lab, we've missed most of the molecules that they make. That suggests that everything we've found is just the tip of the iceberg of what's possible out there."
Part of the immense challenge involved in creating new drugs based on natural processes is the scale of the search and screening work that is required to actually find the micro-organisms with properties that could prove beneficial to human health. Despite the medical potential that undoubtedly exists in the wild, finding it is a needle-in-haystack affair, as noted in a 2002 paper by the late Dr Richard Firn of York University's Department of Biology.
"There is no doubt that there are many exciting, very valuable chemicals awaiting discovery in organisms but they lie hidden among a much larger number of chemicals that are currently of little human value," Firn wrote.
The significant financial risks involved in searching for medical breakthroughs in the natural world, often referred to as 'bioprospecting', means that, for the most part, the undertaking of this work is today the preserve of university laboratories and academics hoping to make discoveries and then partner with or outlicence their findings to pharma and biotech companies to develop them into medical products. These scientists comb the countryside and the seabed, searching areas of high biodiversity for the naturally- produced chemicals that could eventually become new treatments.
From China to Kentucky: mining for medicines
Areas of high biodiversity are often targets for bioprospecting. China, for example, has become known for its many endemic plant and animal species, and its biodiversity has been harnessed for centuries for use in medicine. Today, new discoveries in naturally -derived treatments are still driving innovation - pharmaceutical chemist Tu Youyou became China's first recipient of the Nobel Prize in Physiology or Medicine in 2015 after her team discovered artemisinin, an antimalarial compound derived from the sweet wormwood plant native to temperate Asia, which has proved to reduce malaria mortality by an estimated 20% when used in combination therapy. This effectiveness is saving around 100,000 lives every year in Africa alone.
Like many regions in China, the Appalachian forests in the US state of Kentucky represent a global biodiversity hotspot, hosting thousands of species of wildlife and innumerable micro-organisms and fungi. A team led by Professor Jon Thorson, director of the University of Kentucky's Center for Pharmaceutical Research and Innovation, has been bioprospecting in the region since 2012, and has discovered around 200 molecules with pharmaceutical potential, including a class of enzymes that could make antibiotic daptomycin exponentially more effective, according to a Newsweek profile published in January 2016.
In order to narrow the search for 'extremophile' organisms that can survive in extreme conditions - and therefore may produce unique secondary metabolites that could prove useful in drug development - Thorson's team has teamed up with the university's geologists to explore many sites belonging to the state's large mining industry. The compounds produced by bacteria and other micro-organisms to survive harsh environments like coal fire sites and deep underground coal mines, from which samples have been taken, help even the odds for researchers looking for better treatments, with the project's initial focus areas being cancer, infectious disease and inflammation.
"As might be expected in a subsurface environment, the microbes are very different from those in a typical surface soil environment," said Kentucky Geological Survey research geologist and project partner Richard Bowersox in 2013. "These microbes have adapted to an environment of extremes in water chemistry, pressure and temperature."
The wider world of bioprospecting
Many other regions with high biodiversity - especially dense rainforests and underexplored marine environments - hold great clinical potential, and new compounds are being discovered every year.
Understandably given the natural roots of antibiotics, many of these discoveries are proving useful in the campaign to tackle the growing problem of antibiotic resistance. New antibiotics are being discovered that are active against drug-resistant pathogens, as well as novel mechanisms that attack resistance in other ways.
The University of Michigan's Life Sciences Institute has made several discoveries in the waters off Costa Rica that have shown significant potential in this area, the most recent being the identification of compounds derived from marine micro-organisms that prevent bacteria associated with hospital-acquired infections gathering into a biofilm, which cuts off one path by which antibiotic resistance can develop.
"This new class of biofilm inhibitors provides a foundation toward the development of safe and effective drugs to limit or prevent biofilm formation," said Professor David Sherman of the Life Sciences Institute in February 2016. "As antibiotic resistance becomes an increasingly important global health concern, marine microorganisms have a great - and largely untapped - potential to provide new classes of antibiotics and anti-biofilm compounds."
Scientific and economic hurdles
With the massive potential for pharmaceutically- active molecules undiscovered in nature clearly evident, why aren't we seeing more naturally- derived medications being developed and reaching the market?
As clear as the potential might be, bioprospecting is fraught with uncertainty, and as a result investment in collecting and screening samples is low. Even if a discovery is made, it may not be possible to gather enough material to synthesise the active molecule, and justified concerns about the biodiversity rights of countries in which these discoveries are made, there are complex legal and ethical considerations in play.
While the cheaper genome sequencing technologies that exist today are allowing faster screening of molecules, for some the money required to take these discoveries to the next level simply isn't coming through from big pharma.
"We've discovered six antibiotics in the recent past," said Professor William Fenical of the Scripps Institute of Oceanography in an interview with Motherboard in November 2015. "Of those, three to four have serious potential as far as we know, including anthracimycin. But we have no way to develop them. There are no companies in the United States that care. They're happy to sell existing antibiotics, but they're not interested in researching and developing new ones."
The economic and scientific complexities involved in bioprospecting are certainly speedbumps in the journey to introduce a new wave of biologic drugs, but they are not roadblocks. As the technology involved in the identification of medically- relevant molecules improves, hopefully so too will the investment proposition for pharma companies with the resources to accelerate the process. With antimicrobial resistance becoming an urgent global health concern, the risk of not fully pursuing an avenue for the development of new antibiotics is increasingly difficult to ignore.