A facility at the Broad Institute of MIT and Harvard and MIT that aims to achieve the full potential of engineering biology has received a five-year, $32 million contract from the Defense Advanced Research Projects Agency (DARPA).
The Foundry, started by MIT biological engineering professor Christopher Voigt and Broad Technology Labs (BTL) director Robert Nicol, is the result of a partnership between BTL and the Synthetic Biology Center of MIT, of which Voigt is co-director. The Foundry enables the rapid design, testing, and fabrication of large sequences of genetic information so they can be assembled like building blocks for myriad medical, industrial, and agricultural applications.
"Society relies on many products from the natural world that have intricate material and chemical structures, from chemicals such as antibiotics to materials like wood," says Voigt. "We've been limited in our ability to program living cells to redesign these products -- for example, to program living cells to create materials as intricate as wood or seashells -- but with new properties. Rather, products from synthetic biology have been limited to small, simple organic molecules. I want to change the scale of genetic engineering to access anything biology can do."
BTL's Nicol pioneered the application of manufacturing principles to DNA sequencing. This technology quickly scaled from deciphering a single human genome to examining thousands of organisms, including everything from soil bacteria to elephants. The Foundry is working to realize an analogous revolution in designing and writing DNA, in which instructions for useful biological functions are converted into physical DNA that can be put into living cells. This effort will be supported by DARPA funding derived from the agency's "Living Foundries: 1000 Molecules" program, which seeks to establish facilities that can rapidly engineer cells to make chemicals and materials not found in nature.
To create the efficient and innovative pipeline needed to meet its goal, the Foundry collaborates with academic and industry partners. Academic partners include Michael Fischbach, an associate professor at the University of California, San Francisco, who has pioneered methods to find combinations of genes that encode desired functions from vast databases of sequence information. "The Foundry has made it possible to do something that used to be a figment of my imagination," said Fischbach. Because combining these genes into a new design requires specifying a precise sequence of millions of DNA nucleotides (specified by the letters A, T, G, and C), a daunting task for an engineer to do by hand, the Foundry works with Douglas Densmore, a computer aided design expert in the Department of Electrical and Computer Engineering at Boston University. After a design is built, determining whether it works is slow due to the time required for DNA to be put into cells and for them to grow. Technology from Northwestern University allows newly built designs to be rapidly prototyped in advance in emulsions that mimic the interior of cells, cutting the time it would otherwise take for the new DNA to be put into cells that must then grow.
The Foundry also interacts with industrial partners through a consortium that seeks to disseminate advances in the foundational tools to design and build DNA. Member companies span industries including chemicals, pharmaceuticals, food, energy, agriculture, and biotechnology. They represent a diversity of interests: some hope to generate functionalized textiles with integrated biological properties, while others are in search of faster ways to manufacture biofuels and versatile plastics made from green sources rather than fossil-based ingredients.
Two years ago, with an infusion of $7 million in seed money from DARPA's "Living Foundries" program, Voigt and his colleagues laid the groundwork for the Foundry, creating a pipeline for swiftly assembling massive genetic systems involving many genes. They have now successfully demonstrated the viability of this platform, churning out hundreds of megabases of DNA in a fraction of the time it would have taken with conventional techniques. This work has already led to some significant advances.
Early collaborations with consortium member DSM, a Dutch biotech and materials multinational company, led to the design and delivery of 6 million nucleotides of synthetic DNA -- roughly equivalent to two bacterial genomes. "The Foundry is at the forefront of synthetic biology developments," said Hans Roubos, principal scientist of bioinformatics at DSM. "This collaboration gives us a way to see what's possible and what's not, to learn what is state of the art in our industry, and to inspire our scientists."
One agricultural challenge is the delivery of nitrogenous fertilizer to cereal crops. Currently, fertilizer is chemically produced using natural gas, consuming 2% of the global energy supply. In their first major paper, published November 24, 2014, in Nature Biotechnology, Voigt and research partners described how they applied the Foundry pipeline to redesign the genetics underlying the bacterial processes that convert the nitrogen in air to ammonia. Since then, the Foundry has partnered with global leaders in nitrogen research to provide megabases of DNA to facilitate attempts to find a solution to this problem.
Foundry capabilities are also enabling research in other fields, including medicine. Tapping the Foundry's resources, Voigt has begun research on how bacteria that naturally reside in humans make compounds that could be potent new drugs for infectious, autoimmune, and neurological diseases. Prior to this work, researchers could identify the genes that are likely encoding pathways to new pharmaceuticals, but had no way to make use of them for therapeutics.
"The Foundry vision is to apply the pipeline to scientific challenges that are too large for industry or academia," said Ben Gordon, the Foundry's director. Voigt explained that in the coming decades, this approach will offer critical new products in human health, agriculture, and chemistry, and serve as a mechanism for tackling some of the big problems of the world.
The website for the Foundry is: http://web.
About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to broadinstitute.org.