Three years ago, Brady got a cold call from the Bill and Melinda Gates Foundation. On the line was Trevor Mundel, a former pharmaceutical executive who’s now the organization’s president of global health. The foundation wants to find drugs that treat TB, a disease that kills two million people a year, rivaling AIDS as the leading cause of death worldwide. TB used to be treatable with a triple-antibiotic cocktail that included rifampicin. Rif, as it’s known, was discovered almost 50 years ago, and over time the bacterium causing TB has developed a resistance. Intrigued by Brady’s “science fiction approach,” Mundel asked Brady if he could come up with a couple of new molecules that would be effective against TB.
Brady is focused on finding analogs, which are slight tweaks or modifications to the chemical structure of drugs that already exist. (Think of it as a variation on a familiar theme—a riff on rif.) Searching through metagenomic libraries Brady created from soils, he could see the different ways nature evolved to make rif. He looked for a familiar pattern: the gene clusters that created something similar to the original rif molecule, only with a chemical bond in a slightly different place, or an additional atom.
Find these analogs, and we’d once again be able to outwit Mycobacterium tuberculosis and effectively treat TB. Within six months, Brady convincingly demonstrated that he could find rif analogs as well as variants of the antibiotics vancomycin and daptomycin, which have also become increasingly ineffective because of bacterial resistance. The foundation set up a lunch meeting for him with Bill Gates, and the following January, with $17 million in venture capital from the Gates Foundation and Seattle life sciences investment outfit Accelerator, Brady founded his company.
On a bright clear day in September, Brady brings me up to Lodo’s office on the eighth floor of a glass-fronted tower at the Alexandria Center for Life Science. We pass a small room with a freezer and two shaker incubators the size of pizza ovens that warm flasks filled with bacteria, and he leads me into a pristine lab overlooking Bellevue Hospital. Ten people work at Lodo. Eleven if you count the robot. The automated Perkin-Elmer workstation, large enough to crawl inside, speeds up the discovery process by searching metagenomic libraries and plucking out the clones containing a target sequence, almost like a precision mechanical claw. Work that once took technicians and post-docs six months to a year to complete can now be accomplished in a week. That speed is already paying off. A chart on the wall lists at least 30 potential antibiotics Lodo is in the process of generating and characterizing this week alone. Brady recently identified one that cured MRSA in mice.
Brady circles the robot, hands in his pockets. The machine has been acting up. Its arms stand motionless. The process begins with soil, which arrives from donors and volunteers. Brady’s team then reduces dirt to its constituent DNA and clones the gene fragments from unculturable organisms into bacteria, which are stored in rectangular well plates the size of a brick—the so-called libraries. The challenging part is searching for a target, since all the genetic fragments are jumbled up, almost as if someone’s haphazardly tossed thousands of jigsaw pieces into a box. “So we have this very big mixture,” Brady says, “and it starts with 10 million clones and we divide it into a subset of pools.”
Lodo’s bioinformatics team uses algorithms to predict which fragments in which libraries are likely to synthesize which molecules, so that, in the end, the robot recovers the ones with the gene clusters needed to create antibiotic molecules. A smile forms at the corners of Brady’s mouth. “There are many other steps downstream for engineering those things,” he says, “but that’s the real novelty of what we do here.”
Brady sometimes describes this search as a kind of archeological dig: He is examining the remnants of a microbial civilization, poring over their genetic instruction manual to figure out how to build a specific aspect of the society. “If you’re doing drug discovery,” he says, “you don’t have to know what’s going on in the rest of society—how they built their huts or their canoes—if we’re going to say that antibiotics are weapons, you just need to figure out that information, which ones encode antibiotics, and then you have to go one step further and build that antibiotic.”
To do so, Lodo’s team of molecular biologists manipulate DNA and grow the clones in heated Erlenmeyer flasks. The bacteria proliferate in a liquid broth that often resembles the color of Yoo-hoo and gives off an earthy smell, like a freshly dug hole in the ground. In an adjacent room, chemists extract and purify the resulting organic molecules, looking for new chemical structures and, perhaps, that one perfect molecule which could save millions of lives.
In recent years, researchers have been trying to reinvigorate antibiotic discovery in several ways. A team from Northeastern University developed a specialized plastic chip that allowed them to culture a broader diversity of bacteria in the field, which led to the discovery of teixobactin from a meadow in Maine. Nearly everyone acknowledges that the promise of metagenomic mining has yet to materialize. As Jill Banfield, a biochemist at UC Berkeley, explains, the applications thus far have been “fairly limited.”
Warp Drive Bio, in Cambridge, Massachusetts, is one of the few companies that employs similar techniques; Brady once sat on its scientific advisory board. Greg Verdine, a company cofounder and chemist at Harvard, is confident that a DNA-directed “genomic search engine” will turn up antibiotics. “If you brought me the flower pot,” he says, “I guarantee that I could find novel antibiotics there.” Verdine has focused more narrowly on existing culturable bacteria. He argues that, by cloning DNA out of uncultured bacteria, Brady may be making an already difficult task “unnecessarily complicated.”
Several of the biotech firms that first attempted to use metagenomics to discover new drugs failed. “The big idea was in the air,” says Jon Clardy, who served as Brady’s doctoral advisor and is now at Harvard. “But I think that Sean was first person to reduce it into practice in a useful, robust way.” Clardy says one remaining challenge is to systematically predict what genes encode for molecules with a particular function. Put another way, no one knows exactly where to find nature’s instruction manual for disarming deadly infectious organisms. “That is a huge bottleneck,” he says. “Sean has ideas about how to do that, but that’s very different than the problems he solved.”
Brady takes a seat in a conference room overlooking the East River. He admits that he never imagined setting up a company on prime real estate in Manhattan. The Alexandria Center, a “big fancy building,” has a beer bar and a restaurant run by a celebrity chef. Brady sees himself as a do-gooder, an obsessively humble guy whose pipe dream involves setting up drug discovery pipelines in every country. He wonders about a time when resistant strains escape hospitals and start disrupting public transit—a scenario that is already playing out with TB. Lodo was founded on the idea that another future is possible, and that means bringing life-saving medications to patients in the next 10 or 20 years. Brady recently made his feelings clear at a company-wide meeting: “The purpose of being here is not anything besides saving people’s lives.”
An email blast went out from Lodo in September. “We need your dirt,” it said. Brady keeps an entire room filled with the rainbow of bags that resulted—dull gray, reddish, dark brown. A few summers ago, he hired a rock climber to ship him bags of dirt. Hundreds of additional volunteers have since scooped up a gallon Ziplock’s worth of soil. “We’re not panning for gold in the stream in your backyard,” Brady says. “We’re taking out a little bit of soil that otherwise you’re never going to use.” In other words, humanity’s next best hope could come from a pinch of something that turns out to be priceless—and as common as dirt.
Source : https://www.wired.com/story/how-dirt-could-save-humanity-from-an-infectious-apocalypse/