A LIVING LIBRARY
Rare collection at UF drives breakthroughs in biomedical discovery
Peek through the labyrinth of vials that make up the Natural Products Discovery Center, and you will see thousands of purified, freeze-dried microbes once assembled from across the planet’s most diverse ecologies. Some were gathered from the soil beds of rainforests. Others came from coastal marshes and estuaries, the deep waters of the ocean, the fallen leaves of withering plants, and even the decomposing dung of animals.
Compiled over the course of 80 years, some of the organisms in the collection’s glass vials are likely extinct in the natural world, offering an irreplaceable window into the past. For Ben Shen, PhD, a professor of chemistry and director of the Natural Products Discovery Center, and his research team at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology in Jupiter, Florida, these unexplored microbes — a treasure trove of biodiversity — hold untold promise for treating disease, providing a tantalizing glimpse into the future of drug discovery.
Nature’s Pharmacy
A natural product is a substance produced by a living organism that imparts an evolutionary or fitness advantage. Such materials can be found in soil, water, roots, algae, plants, animals, or microbes and in all types of ecologies. Because the microbial organisms that create these natural products evolve amid unique surroundings, they develop adaptations that are finely tailored to their environment and aid their survival. These advantages can range widely, from assisting in reproduction to poisoning adversaries or disarming predators.
Researchers have prized natural products, in all their astonishing diversity and unmatched structural complexity, for their pharmacological and medicinal potential.
“Natural products have made a profound impact on the history of drug development, leading to the creation of some of the world’s most important medicines,” Shen said.
Across the globe, more than 500,000 natural products have been characterized so far and approximately 50% of Food and Drug Administration-approved drugs are directly derived from or inspired by natural products. Many of these, such as penicillin, lovastatin, ivermectin, and streptomycin, earned their discoverers the Nobel Prize. Others have become essential in the treatment of infectious diseases and cancer.
Ben Shen, PhD, inspects shakers, incubators where small quantities of microbes are added to nutritional media, so there is enough to study in depth.
Photo by Stacey DeLoye
Unlocking potential treatments
Shen and his team of scientists are mining the collection of microbes, one of the world’s largest, believing it offers the best resource for expanding the frontiers of scientific knowledge and developing new treatments. Their hunch is supported by history: Of FDA-approved small-molecule therapeutics, 67% of anti-infective and 83% of anticancer drugs are derived from or inspired by natural products.
Shen’s lab has already demonstrated success in developing possible treatments by applying genomic sequencing and computational methods to mine the microbes and better understand their biochemistry. The lab recently discovered tiancimycins, members of the enediyne family of natural products that are among the most cytotoxic molecules known to date.
While tiancimycins are too toxic to be administered systemically on their own, Shen’s team connected them to monoclonal antibodies as antibody-drug conjugates that can target tumors with high precision. Antibody-drug conjugates are among the most promising drug classes and are being increasingly used in combination with other agents, including as first-line cancer therapies. Other natural products have been extensively investigated as potential antibiotics, with some able to bind well to their biological targets.
“We know this collection has incredible potential to develop the next class of antibiotics and anticancer drugs,” Shen said. “Nature is the best chemist, and through genomic technologies and advanced computational tools, we are making incredible progress.”
APPROXIMATELY 50% of Food and Drug Administration-approved drugs are directly derived from or inspired by natural products
Of FDA-approved small-molecule therapeutics, 67% OF ANTI-INFECTIVE and 83% OF ANTICANCER drugs are derived from or inspired by natural products.
‘An archive of biodiversity’
The microbial organisms that make up the Natural Products Discovery Center at The Wertheim UF Scripps Institute were originally amassed following the blockbuster discoveries of penicillin in the 1920s, streptomyces in the 1940s and the subsequent rush to find the next great antibiotic. Scientists across the globe combed through algae, soil, fungus, and any other living organisms that might hold the key to understanding the secrets of natural product biodiversity, forming the basis of drug discovery for decades.
Ben Shen, PhD, directs the Natural Products Discovery Center at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology. The center holds one of the world's largest collections of microbial natural chemicals.
Photo by Scott Wiseman
For years, the microbial strain collection was held by Pfizer Inc., which compiled it through commercial sources and acquisitions, successfully using the compounds to develop several historically significant drugs.
However, because much of the collection was left unexplored, Pfizer hosted a competition to find a new home for the biobank, so it could be further studied by academic researchers and made available to the wider scientific community. The collection was awarded to Shen and The Wertheim UF Scripps Institute because of their proven record of excellence in translational research, drug development, and scalable technologies. Shen was recognized as a global expert in a group of soil-based microbes — one of the richest sources of natural product-based pharmaceuticals — called actinobacteria. In spring 2018 the collection arrived in Jupiter, transported in 20 freezers and housed in a standalone cold room.
· Approximately 3.75 MILLION new natural products in the collection are awaiting discovery (GREEN).
· 15,000 GENOMES have been sequenced and assembled from the strains in the collection, which outnumber the collective total of sequenced genomes at the largest public depositories around the world by sixfold (RED).
· Globally, MORE THAN 500,000 natural products have been characterized so far (YELLOW).
The assemblage of ampules and vials that now call the Natural Products Discovery Center home is extraordinary in size and scale, including more than 125,000 bacterial strains. Approximately 15,000 of the biobank’s genomes have been sequenced so far, and Shen estimates more than 3.75 million new natural products are awaiting discovery.
Researchers inspect a natural product extract tray.
Photo by Scott Wiseman
Such a collection would be impossible to generate today due to global treaties that make it cost prohibitive to collect libraries of genetic biodiversity. The microbes in the collection come from more than 75 countries, including the United States, China, Indonesia, Fiji, Russia, and Togo. And while most of the specimens were acquired from 1940 to 2010, many are even older — with one dating to 1900. This makes the collection of microbes not only exceptionally unique from a biodiversity perspective but also one of the most promising sources for discovering natural products and devising drugs for the 21st century.
“We have specimens that highlight the biodiversity that people thought never existed,” Shen said. “It’s like an archive of biodiversity over centuries that allows you to look back and rediscover compounds that can be used to create the future of medicine.”
‘Tip of the iceberg’
In addition to his cancer research, Shen’s most ambitious goal as the center’s director is to digitally sequence the entire microbial collection and make it available to any researcher in the world. The number of actinobacteria housed at The Wertheim UF Scripps Institute outnumbers the collective total actinobacteria currently available at the largest public strain collections in the world by more than sixfold.
“The resources here are so huge that alone we can only reach the tip of the iceberg,” Shen said.
UF scientists prepare a natural product sample for sequencing. The Natural Products Genomics Resource Center provides a repository of genomic blueprints available to scientists worldwide.
Photo by Scott Wiseman
To share this massive repository and accelerate international drug discovery, Shen’s team created the Natural Products Genomics Resource Center, a searchable database where scientists can retrieve genomes and blueprints, access integrated bioinformatics analyses and request the physical materials to verify their findings.
He hopes the resource center will foster an interconnected web of global researchers united by their exploration of biodiversity and natural products to generate new life-altering medicines.
“You can’t compile anything like this collection anymore and it deserves to be shared with everyone,” he said. “When we are finished, this will probably be the largest depository available to scientists anywhere. This will be transformative. The research it produces can change the world.”
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