Cambridge-based startup Ensemble Discovery uses DNA to control chemical reactions and search for new drug compounds.

Neil Savage

The traditional image of a chemist is of someone mixing together solutions at the lab bench, but nature performs its own chemical reactions on vastly smaller scales, without the lab coats and beakers, inside living cells. Ensemble Discovery, a two-year-old startup company in Cambridge, MA, is trying to mimic nature’s process to develop a more efficient way of synthesizing novel pharmaceuticals and other interesting compounds.

“We use DNA as nanobots to make chemicals,” says Richard Begley, CEO of Ensemble.

The process of using DNA to control chemical reactions on a tiny scale was developed by David Liu, a professor of chemistry and chemical biology at Harvard and a founder of Ensemble. Liu takes advantage of the specific way that two single, complementary strands of DNA bind to each other.

First, he attaches a molecule of interest to a short strand of DNA. Then he binds another molecule to the complementary strand. When the two strands come together, so do the molecules bound to them, enabling a chemical reaction.

This technique gives chemists greater control over chemical reactions when making new compounds, which could reduce the amount of unwanted byproducts produced. It also requires far smaller amounts of chemicals, which are sometimes expensive. Chemists can identify the new chemical compounds by distinguishing the piece of DNA attached to them.

“The DNA serves essentially like a bar code,” Begley says. It’s possible, he says, to end up with a test tube containing five milliliters of a buffer solution and 15,000 pure, identified chemical compounds. “It’s the equivalent of making tens of thousands to hundreds of thousands of nanoreactors in the same pot,” he says.

One application for this technology is drug discovery, which is a primary aim for Ensemble. When a drug company finds a promising compound, it has to optimize it to turn it into an effective drug. It might be, for instance, that modifying the promising molecule to give it a slightly different shape allows it to fit better with the target protein on the surface of a cell.

Ensemble’s process creates what Begley calls a library in a flask: a large set of similar compounds with slight variations in shape and maybe a few extra chemical entities stuck to them. This library could make it much easier to find the perfect version of the compound.

Jonathan Witonsky, an industry analyst with the consultancy Frost and Sullivan, says this sort of technique has already proven itself as a tool for studying gene expression, but that using it to identify new drug candidates is unique. “It has the potential to give drug discovery workflow a new angle, a new approach,” he says. It can take many years and hundreds of millions of dollars to develop a new drug, and anything that makes the process more efficient, as Ensemble’s technology hopes to, has a lot of potential, Witonsky says.

The company is starting with pharmaceuticals to demonstrate that the technology works, but the process could be used to produce all sorts of desired synthetic chemicals, such as polymers, says Begley. He envisions teaming up with a company like 3M to look for, for example, new types of adhesives.

Ensemble completed a first round of fundraising earlier this year, netting $17 million from three major venture capital firms. It employs 22 scientists. In addition to this chemical synthesis technology, licensed from Harvard, Ensemble researchers have developed a specialized informatics system to catalog all the compounds they come up with. Begley hopes they’ll have identified enough promising compounds by next year to start signing collaboration deals with larger companies.