NATURAL PRODUCTS
Hexagon Bio
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Launched: 2017 Headquarters: Menlo Park, Calif. Focus: Data-driven natural product drug discovery Technology: Genome mining Founders: Maureen Hillenmeyer, Brian Naughton, Colin Harvey, Yi Tang Funding or notable partners: $20 million from investors, including 8VC
C&EN | CEN.ACS.ORG | NOVEMBER 5, 2018
Hexagon Bio’s founders, from left: Maureen Hillenmeyer, Colin Harvey, Brian Naughton, and Yi Tang
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ot so long ago, scientists sought new drugs by gathering plants, dirt, or sea creatures, pulverizing them, testing the resulting broth in biological assays, and then figuring out which molecules in the mélange might be drug candidates. This “grind and bind” method of natural product discovery brought the world many blockbuster drugs, but it’s a slow process that’s fallen out of
fashion. The founders of Hexagon Bio think natural product drug discovery is due for a comeback. But they’re not searching for drugs in remote locations; instead, they’re mining the genomes of hard-to-culture microorganisms, particularly fungi. As many as 5 million species of fungi grow on Earth, each of which may encode biosynthetic pathways for up to 80 different natural products. Growing fungi in the lab tends to take a long time, and fungi don’t express all their biosynthetic gene clusters actively. So eking out enough of those natural products to study—let alone commercialize—has been nearly impossible. The scientists at Hexagon use a computer program to sift through genomic data from fungi and pluck out the genes that code for small-molecule biosynthetic pathways. They then insert those genes into a platform they developed—dubbed HEx, for heterologous expression—that coaxes engineered
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Using data science to drive gene mining
yeast to churn out proteins that biosynthesize natural products with possible therapeutic value. “Instead of brewing alcohol, which a lot of people use yeast to do, we’re brewing medicines,” explains Maureen E. Hillenmeyer, Hexagon’s CEO and cofounder. “We’ve become experts at using yeast as a platform for producing chemicals that otherwise would be difficult or impossible to access.”
gon joins a cluster of biotechs examining fungi. What’s unique to Hexagon, Hillenmeyer notes, is its data-driven approach. To figure out which stretches of DNA make small molecules that could have potential as medicines, Hexagon invested significant time developing an algorithm that prioritizes, among the millions of possible gene clusters out there, which ones encode small molecules that specifically target human disease proteins.
“Instead of brewing alcohol, which a lot of people use yeast to do, we’re brewing medicines.” —Maureen Hillenmeyer, CEO and cofounder, Hexagon Bio Hillenmeyer was working at the Stanford Genome Technology Center, part of Stanford University School of Medicine, when she and her colleagues invented the HEx platform. She was so enthusiastic about the technology that she decided to leave her position at Stanford to lead Hexagon Bio. It was clear to the company’s founders, she says, that they had discovered a way to capitalize on the past decade’s advances in DNA sequencing and synthesis. “For the whole natural products field in general, DNA sequencing is a big driver of change right now,” Hillenmeyer says. “Getting DNA is easy. Getting small molecules is hard.” The first wave of genome-mining companies, with Warp Drive Bio the most prominent among them, sifted through bacterial genomes. Hexa-
“We, at the heart, are a data science company,” Hillenmeyer says. Hexagon’s location suggests that’s true: Its offices in Menlo Park, Calif., are a stone’s throw away from Facebook’s headquarters. Half the staff does computational work, while the other half focuses on experimental research. With its computer algorithm and HEx platform in hand, Hexagon has the opportunity to access millions of compounds that have never been studied before. “These are compounds that have already gone through a form of combinatorial chemistry,” Hillenmeyer says. “Nature has already done the testing of millions of compounds and is serving us on a platter the ones that are exquisitely evolved to target proteins.”—BETHANY HALFORD
Mining fungi
C R E D I T: C& E N /S H UT TE RSTO CK
Scientists at Hexagon Bio mine fungal genomes using algorithms to find genes encoding biosynthetic pathways for natural products. They express these genes in yeast and test the natural products as drug candidates.
ACGTCTAGCTACGTTGCAGTCGG CTGCAGCTAACGTCTAGCTACGT TGCAGTCGGCTGCAGCTATCTAG CTACGTTGCAGTCGGCTGCAGCT AACGCTACGTTGCAGTCGGCTGC AGCTAACATCTAGCTACGTTGCA GTCGGCTGCAGCTATCTAGCTAG CAGCTAACGTCTAGCTACGTTGC
Fungal sequence
Genome mining and gene cluster selection
ACATCTAG ACATCTAG ACATCTAG ACATCTAG ACATCTAG ACATCTAG ACATCTAG ACATCTAG
Gene cluster expressed in yeast to generate natural product
Evaluation of natural product as a drug candidate
NOVEMBER 5, 2018 | CEN.ACS.ORG | C&EN
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