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November 01, 2017 (Vol. 37, No. 19)

Scanning Fungal Warscapes for Drug Candidates

To Sharpen Its Drug-Development Strategies, Hexagon Bio Studies the Fungal Art of War

  • Hexagon Bio leverages expertise in genomics, synthetic biology, chemistry, and computation to identify small molecules produced by fungi. These molecules, which are of intense interest to drug developers, might otherwise remain hidden.
  • Hexagon Bio was formed in 2016 to gather military intelligence on warring fungi. By tapping fungal communications and observing how fungi mount defensive and offensive operations, Hexagon Bio hopes to learn about wartime practices worth emulating. The company is especially interested in biochemical weaponry. For example, small molecules that act as toxins or devious forms of signaling could inspire the development of new classes of drugs that could address unmet medical need.

    Fungal espionage, like military espionage, involves maps and statistics. The fungal maps that are most relevant to Hexagon Bio are genomic. When studying these maps, the company relies on advanced data science algorithms to identify genes that likely produce novel small molecules. Then the company determines which small molecules qualify as the most clinically relevant drug candidates.

    “Three-quarters of all antibacterial drugs and half of all cancer drugs came from living organisms,” points out Maureen Hillenmeyer, Ph.D., Hexagon Bio’s CEO. Dr. Hillenmeyer’s appreciation of the natural origins of many drugs, combined with her expertise in data science, catalyzed the founding of Hexagon Bio. The nascent company, which recently set up a 2,500-square-foot lab and office in Menlo Park, CA, uses its advanced algorithms in combination with a synthetic biology platform to sift through fungal genomes and identify genes that encode unusual small molecules.

    Dr. Hillenmeyer and colleagues developed the company’s original algorithm and platform under grants from the National Institutes of Health (NIH) and the Burroughs Wellcome Fund. At the time, she was director of the Genomes to Natural Products program and group leader at the Stanford Technology Genome Center. Since Hexagon Bio was formed, additional algorithms have been developed to tease out clinically valuable molecules from datasets.

  • The Genesis of an Idea

     “This is the beginning of a wave,” asserts Dr. Hillenmeyer. There are an estimated 1.5 to 5 million species of fungi, but only about 135,000 have been described, and only about 1,000 have been sequenced. And, she adds, “The number of species sequenced is doubling every two years.” Drug developers, consequently, are beginning to look more closely at fungi as a source for novel drugs.

    Historically, small molecules from fungi and other natural sources were major sources of drugs, but over time, researchers focused on fungi were unable to identify new blockbusters. Some researchers thought the field was “tapped out.” Other researchers, such as the bioinformatics-savvy scientists at Hexagon Bio, remained optimistic. “We realized that data science can revolutionize this field,” Dr. Hillenmeyer recalls.

    “Fungi evolved potent small molecules, usually as a form of warfare between species or as a form of chemical signaling. They evolved for millions of years to bind to their protein targets,” she says. “We don’t have that kind of time. Therefore, we’re identifying small molecules from these organisms and, more specifically, their DNA sequence.”

    “Fungi, like humans, are eukaryotes. Many people don’t realize that, thinking they’re bacteria, but actually, we’re very closely related,” Dr. Hillenmeyer says. That similarity is very helpful, revealing clues in the fungal genomes that help her team prioritize genes that could be developed into potential blockbusters.

  • A Bioinformatics Approach

    Hexagon Bio’s greatest contribution may be the example the company sets: Fungi-focused drug discovery may incorporate bioinformatics approaches. When Dr. Hillenmeyer entered the field of natural products biosynthesis, it was populated largely by chemists and, therefore, limited to certain approaches.

    The bioinformatics specialists that joined Hexagon Bio created new data algorithms, expanding the company’s capabilities. “We gained the ability to predict from DNA sequences which genes would make small molecules,” recalls Dr. Hillenmeyer. “Work under my grants prioritized those genes using data science. The second half of that program involved using synthetic biology to produce those small molecules.”

    That program focused on bakers’ yeast, a powerful host system. The same yeast used for beer and bread also can make statins, penicillin, and new chemicals never seen before. Typically, fungi make polyketides, terpenes, and peptides.

    “It took several years to coax yeast to make new compounds,” Dr. Hillenmeyer continues. “It was hard work.” Details on exactly how that was accomplished are being prepared for journal publication. In general terms, however, the innovations involved genetic modifications to improve the profile of the types of compounds the yeast can make.

    The company’s key challenge has been the unpredictability of the science. “There were parts of the data platform and the scientific approach that required a lot of creativity,” notes Dr. Hillenmeyer. The solution required bringing together expertise from different disciplines to determine why some aspect of the program didn’t work, and then either making it work or finding another way to accomplish the objective.

    That, in fact, is what Dr. Hillenmeyer considers one of Hexagon Bio’s greatest triumphs: bringing together people from the very different disciplines of information technology and synthetic biology. “That’s been groundbreaking,” she insists. “It really helps us progress.”

  • Access to Expertise

    One of the reasons for the company’s interdisciplinary approach, she says, is the guidance of seasoned advisors: “We’ve had a lot of help from the community. Pharmaceutical industry veterans’ help and enthusiasm for the idea of data science entering drug discovery was pleasantly surprising. People have been very generous with their insights and expertise, talking in great detail about the types of drugs that are needed and the gaps in certain human protein targets.”

    Pharmaceutical expertise, whether originating from outside the company or from within the company, has been particularly helpful to the data scientists among Hexagon Bio founders. “Having a team that is similarly good at data science and wet lab work is unusual,” Dr. Hillenmeyer points out, but “we focused on getting people who could speak to both worlds.”

    Hexagon Bio’s interdisciplinary expertise is evident from this partial list of cofounders:

    • Brian Naughton, a “world-class expert in data science and bioinformatics,” in Dr. Hillenmeyer’s estimation. Naughton was the founding scientist at 23andMe. He met Dr. Hillenmeyer when the scientists were in graduate school together.
    • Colin Harvey, Ph.D., another graduate school colleague and a scientist who brings “deep biology and chemistry expertise.” He headed synthetic biology work in natural product discovery for the Stanford Genome Technology Center. “[Dr. Harvey is} excited about bringing synthetic biology to fungal genomics as a new, next-generation tool,” attests Dr. Hillenmeyer.
    • Professor Yi Tang, Ph.D., a global expert on fungal enzymes and natural products. His UCLA lab worked with Dr. Hillenmeyer’s Stanford laboratory as part of Stanford Genome Technology Center’s Genomes to Natural Products Network.

    Like many biotech startups, Hexagon Bio is skewed toward scientists who have had little hands-on experience running a company. This science-over-business bias does not seem to have diminished the company’s ability to raise capital, however. Incorporated in November 2016, Hexagon Bio closed its first seed round of financing in June for $8.3 million. It plans to use those funds to develop additional algorithms to identify novel drug candidates.

  • Small-Molecule Drugs

    Hexagon aims to develop small-molecule drugs in house by applying its novel data algorithms to fungal genome analysis. The resulting platform already produces small molecules in the company’s laboratory. “In house, our focus is on oncology and infectious disease, but our platform is much broader and could target many applications,” states Dr. Hillenmeyer. We’re open to all options, including partnerships with pharma.”

    The small-molecule aspect of the program is important because unlike biologics, which are limited to extracellular targets, small molecules can cross cell membranes to work inside cells. Because of this capability, and the novelty of the molecules being discovered, Hexagon Bio’s fungi-derived drug candidates may be able to address a broader range of need than could conventional drug candidates.

  • Hexagon Bio

    Location: 1505 Adams Drive, Suite A, Menlo Park, CA 94025

    Phone: (650) 485-2359

    Website: www.hexagonbio.com

    Principal: Maureen Hillenmeyer, Ph.D., Cofounder and CEO

    Number of Employees: 8

    Focus: Hexagon Bio is a startup company developing advanced data algorithms to screen fungi genomes for novel, clinically relevant drug-development candidates.

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