Earlier this fall, Partners HealthCare spinoffs Editas Medicine and Spero received global recognition.

Earlier this fall, Partners HealthCare spinoffs Editas Medicine and Spero received global recognition when they were named to the prestigious Fierce Biotech's Fierce 15, an annual compilation of leading biotech upstarts. Researchers around the globe are pursuing various strategies for correcting defective genes in hopes of treating or reversing certain human diseases. But Editas' CRISPR technology stands out as among the most user-friendly. Short RNAs derived from a bacterial immune system called CRISPR direct a protein to home in on and edit virtually any site in an organism's genome. “These tools give you a very efficient and targeted way of editing or changing the DNA sequence in a human cell. They allow you to zero in on a specific location in the sea of 6 billion letters of DNA in human cells and exploit normal pathways that exist in most cells, including human cells, to make changes at that location,” says Keith Joung, MD, PhD, an associate professor of pathology at Harvard Medical School; and an associate pathologist, Associate Chief for Research, and the Jim and Ann Orr Research Scholar at the Massachusetts General Hospital. Each of Editas' five scientific founders—Keith Joung, George Church, PhD, Harvard Medical School, Jennifer Doudna, PhD, University of California, Berkeley, David Liu, PhD, Harvard Chemistry and Chemical Biology Department, and Feng Zhang, PhD, Broad Institute at MIT—are major innovators in the growing CRISPR community. “There are many, many diseases that are caused by genetic mutations, and the medical community has long-aspired to be able to repair these diseases at their root cause, the gene,” says Katrine Bosley, CEO of Editas. “In the laboratory, this technology has shown an unprecedented ability to achieve that, and Editas Medicine was founded to translate this science into new medicines. Keith's pioneering work in the field is fundamental to making this possible.” Spero's Fierce factor has to do with the startup's daring foray into antibiotic drug development, a field historically plagued by regulatory roadblocks that have discouraged industry R&D. But Spero's antibiotics are far from typical. The spinoff is taking a new tactic to fight drug-resistant bacteria, relying on so-called MvfR inhibitors – novel molecules that interfere with the bacterial communication system that normally drives many pathogenic functions – to disarm Pseudomonas aeruginosa from its ability to be infectious without killing it, a strategy that decreases selective pressure and sidesteps the evolution of multidrug resistance. “There are many multi-drug resistant P. aeruginosa strains that cannot be treated because they have resistance to every single antibiotic,” says innovator Laurence Rahme, PhD, Director of MGH Molecular Surgical Laboratory, associate professor of surgery, microbiology and immunobiology at Harvard Medical School. “This is a great tool because it gives us hope that when we don't have other options to treat drug-resistant infections, here is one that potentially can work in humans.” FierceBiotech also noted Spero's rapid ascent from a relatively modest pool of seed funding to a widely noted deal with Roche, which plans to acquire and develop Spero's lead program prior to clinical trials. “We were delighted to receive the Fierce 15 nomination,” says Ankit Mahadevia, MD, CEO of Spero. “Along with our scientific progress and the Roche collaboration, this was a nice validation of the team's efforts in creating a leading company in the anti-infectives space.” Discovering Editas Medicine In the field of genome editing, 2012 seems like a lifetime ago. But, in fact, not even 3 years have passed since Editas scientific co-founder Jennifer Doudna, PhD, and colleagues sparked worldwide interest in genome editing with a Science paper revealing that CRISPRs could act as “molecular scissors” to precisely alter the genomes of plants, animals, and bacteria. Joung's lab has a long history of innovation in genome editing. In 2008, the team released the world's first robust open-access platforms for programmable editing enzymes known as zinc finger nucleases. After years of working with earlier, labor-intensive tools for genome editing, Joung initially hesitated to believe that the CRISPR-based approach could be as easy as it was made out to be. “With the CRISPRs, we were very skeptical in the early days that something this easy to reprogram would actually work well, and work efficiently,” says Joung. In some early experiments, his group worked with collaborators Randall Peterson and Joanna Yeh at the MGH to test the CRISPR technology on 11 gene targets in the zebrafish; 10 failed. “I said, ‘See, I knew I was right. Nothing can be this easy in biology,'” Joung recalls. But the postdoc came back the next day and announced that an error had been made. When the team repeated the experiments, 9 of the 11 targets worked right out of the gate. Discovering Spero The pioneer behind Spero's pathogen-fighting molecules isn't one to say, “I told you so.” But if she did, few could disagree. In the early 90s, then-doctoral student Laurence Rahme, PhD made a discovery that went largely unnoticed – until now. Working in a plant pathogenesis lab at the University of California, Berkeley, Rahme was suddenly struck by the idea that Pseudomonas aeruginosa – a bacterial pathogen responsible for nearly 51,000 hospital-acquired infections, including 6,000 multidrug resistant ones, each year in the U.S. – might use similar strategies to infect both plants and people. “When I was talking about this so many years ago, people were looking at me and saying, ‘Are you crazy? This is a very risky project,'” says Dr. Rahme. As a postdoctoral researcher at Harvard and MGH in the lab of Dr. Fred Ausubel, Rahme performed high-throughput screens of P. aeruginosa clinical isolates and mutants in plants. She homed in on one virulence factor in particular: MvfR, or multiple virulence factor regulator. This regulator, she learned over the next decade, was the central command station of the pathogen's pathogenesis communication system – and its secret to evading killing by antibacterial drugs. Blocking it could hold the key to fighting acute, persistent, relapsing, and chronic multi-drug resistant infections in the clinic. Spero aims to do just that through the improvement of MvfR-inhibiting molecules. Rahme credits Partners Innovation for getting the project off the ground and Atlas Ventures for establishing the spinoff. Reza Halse, PhD, says, “We launched Spero at a time when policy makers, regulators and the drug industry were beginning to recognize the need for innovative approaches to address anti-bacterial drug resistance. Bringing a world class commercial team around Dr. Rahme's research has positioned Spero to have a great impact on this important, and growing, public health concern.” “It's quite interesting now that everyone is so excited about this approach. It's a great satisfaction,” Rahme says, recalling times of lean funding when a single postdoc in her lab worked part-time on the project just to push it through. In those moments of recollection, she says, it's clear that the years of labor and perseverance that gave way to Spero reflect the very essence of the name's Italian translation: Hope.