The skinny on the benefits of brown fat
As a young man, Olivier Boss’s idea of a good time was to spend a summer day cycling a few hundred miles through the mountains of Switzerland or France. La Marmotte, he says, was an especially fun day: a 108-mile road race with nearly 17,000 feet of climbing. “It’s comparable to one of the bigger stages of the Tour de France,” Boss says. “One year it was held on the Fourth of July, and it snowed on top of each mountain.”
Boss stopped cycling competitively almost 20 years ago, though he still can hop on a bike and easily bang out 150 miles on a Sunday. (At age 49, his body fat percentage is 9.) On weekdays, though, you can find him in a Kendall Square lab, participating in a different kind of endurance sport: trying to turn a scientific breakthrough into a company that might one day be worth something. Boss left GlaxoSmithKline in 2010 to start Energesis Pharmaceuticals, but the venture is still small: four people and space in a shared laboratory.
Energesis is trying to develop drugs that might help those of us who don’t bike the Alps stay thin, and to stave off or better manage type 2 diabetes. The foundation of the company’s work is new insights into a substance called brown fat — a much better form of fat than the flabby old white stuff.
In babies, brown fat in the neck and shoulders burns calories to help them stay warm because they haven’t yet developed the ability to shiver. Scientists had long assumed that most of our brown fat vanished as we aged. But starting around 2008 and 2009, papers started showing up in prestigious journals to report that adults do, in fact, have stores of brown fat; that it can be kicked into gear by cold temperatures; and that we also have stem cells that might be able to create more of it. That’d be a good thing, Boss points out: “The more brown fat you have, the leaner you are.”
Boss joined up with Brian Freeman, who’d been a founder of another local startup working on treatments for obesity, Zafgen. Both felt like the moment was right to try to start down the path of finding a drug that might activate the brown fat we have, or produce more of it. Their notion was that they could learn more, faster, than the bigger (and more conservative) pharmaceutical companies.
“I had no financing aside from my savings,” Boss says. Freeman had been working at a Cambridge venture capital firm called GreatPoint Ventures, so he was well connected to the world of investors. But when he and Boss pitched, most venture capital firms felt that “it was too early,” he says. “We started with an adult stem cell that can become a brown fat cell.” Their pitch was that this cell could serve as a kind of test-bed for new drugs. But they were far from using it to actually test stuff that might work.
So instead of banking a few million bucks from a venture capital firm, Boss and Freeman began to hunt for government grants from the National Institutes of Health, and money from individual angel investors. Funding came in dribs and drabs — $50,000 from angels, $90,000 from the NIH, and $50,000 for being a winner of MassChallenge, a startup competition in Boston. A partnership with Johnson & Johnson brought in a bit more money, a way for the company to gain some knowledge about brown fat without necessarily dedicating a team of its own scientists to the topic.
Boss was always paranoid about spending too fast and running out of cash. “For the first two years, I went without a salary,” he says. “We don’t fly. We don’t go to conferences. It’s not essential to what we’re doing. We don’t have a luxury lab space.”
In December 2011, a Boston venture capital firm suddenly got interested in brown fat — in a big way. Third Rock Ventures put out a press release to say it was forming a new company, led by one of its investment partners, Lou Tartaglia, and bankrolling it with $34 million. The new company, Ember Therapeutics, had as cofounders three prominent academic researchers from the Joslin Diabetes Center, the Dana-Farber Cancer Institute, and the Scripps Research Institute.
The company set up shop in Watertown, eventually hiring about 30 employees. Boss says he was “assuming they could do a good job with all that money.” (By contrast, Energesis has raised about $5 million since it was founded.)
Ember moved fast to try to show that a drug it was developing would work in monkeys, in part to try to persuade a pharmaceutical company to supply additional funding. But the drug caused side effects that forced that trial to be halted before the company could determine whether it was having an effect on brown fat. “What was underestimated was how challenging it was going to be to show effects in animals larger than mice,” says Ronald Kahn, a founder of Ember and a researcher at the Joslin Diabetes Center. “We sort of ran out of time,” says Bruce Spiegelman, another Ember founder. “The VC world is not especially patient.” And, he adds, big pharmaceutical companies were losing interest in new treatments for metabolic diseases like diabetes.
Ember laid off its employees in early 2015. One of the molecules that the company was developing reverted to Spiegelman’s lab at Dana-Farber. “We continue to work on it and make good progress with it,” he says. Energesis hired one of Ember’s former scientists.
The smaller company is still “trucking along, trying to be careful,” says Brian Freeman, studying ways to activate and create more brown fat in mice. Boss says he is “building something I believe in, and I’m in control.” Both say their goal is to bring to patients a drug that can help those with type 2 diabetes or obesity. A 2016 grant from the National Institutes of Health will give the company about $1.8 million over the next two years to see whether already approved drugs can affect brown fat production.
Some companies, Freeman says, get so much funding all at once that they’re like spaceships. “It may explode, or it may reach the moon.” Ember fit that mold.
Energesis is more like a long-distance cyclist — just keep pedaling, and don’t think too much about how many miles might be ahead.