From afar, the multistory fermenters — towering metal cylinders encompassed by scaffolding, ladders, and pipes — look like rockets on a launch pad. Climbing to the top of the fermenter, visitors to the Mexico City manufacturing plant can peer down at a set of paddles churning 50,000 liters of frothy, golden broth. Within the mixture, genetically engineered yeast are synthesizing lactones — a family of molecules responsible for the aromas of fruits and flowers. MIT Department of Biology alumna Emily Havens Greenhagen ’05 has visited the plant over several weeks to monitor her company’s most promising project: a plan to make perfume from yeast cells.
Greenhagen is director of fermentation engineering at Ginkgo Bioworks, a Boston-based synthetic biology company seeking to turn microbes into customizable factories to produce products ranging from pesticides to perfumes. Scientists such as Greenhagen know that microbes can manufacture organic products more efficiently than any machine or production line. Instead of workers at an assembly line, yeast cells use enzymes — proteins that perform a specific task such as removing or adding a group of atoms to a molecule. Working together, teams of enzymes incrementally transform basic nutrients like sugar into other compounds such as alcohol and carbon dioxide. “By inserting DNA encoding for enzymes from different plants or animals into yeast cells,” Greenhagen says, “we can tailor microbes to produce different materials.”
Manipulating yeast cells is an old idea. For hundreds of years, people have been brewing beer through fermentation, a natural process where yeast consume sugar to create alcohol and different flavorings. In the 1930s, scientists began using microbes to create antibiotics and biofuels. “What makes Ginkgo cutting edge is the automation and scale,” Greenhagen explains of the company co-founded in 2008 by synthetic biologist Tom Knight ’69, SM ’79, PhD ’83. “Using robots, we can genetically modify hundreds of yeast strains and test how they perform in just one week.”
Ginkgo Bioworks’ automation played a critical role in creating the yeast strain that Greenhagen observed in the Mexico City manufacturing plant. These microbes, containing a set of enzymes needed to turn fatty acids into lactones, were engineered through thousands of trial-and-error experiments performed by robots. For each enzyme encoded in the final strain, a team of scientists and machines led by Greenhagen had tested hundreds of versions originating from diverse plant species and strategically mutated in different ways to work more efficiently in yeast cells.
During the testing process, researchers grew thousands of yeast strains, each genetically engineered for a single enzyme, in small tabletop fermenters before combining the most effective genetic modifications into a single cell to produce lactones. Ten years ago, when Greenhagen first started in industry, fermenting was a labor-intensive process done by hand, requiring a single researcher to manage four reactors at a time. In contrast, members of Greenhagen’s team — using robots to mix different concentrations of nutrients, add yeast extract, and monitor the output of desired molecules — routinely managed 24 experiments simultaneously. As a result of automation, the development process took six months instead of a year and half. After a purification process, the developed scent could then be delivered to Robertet, a French fragrance and flavor manufacturer and Ginkgo’s first commercial customer. “The robots don’t just speed up projects,” Greenhagen says, “they take care of the monotonous tasks so that we have more time to think about results and design new experiments — the fun stuff that scientists really want to do.”
Like Ginkgo Bioworks, Greenhagen embodies the convergence of biology and engineering. As a freshman at MIT, Greenhagen had decided to pursue chemical engineering but changed her plans when she learned about synthetic biology. “I couldn’t stop reading my textbook,” she recalls. “I was so excited by the idea that there are living organisms that we can modify to use as tools. That’s when I decided to become a scientist.”
Greenhagen credits one particular microbiology course, taught by Professor Graham Walker, for shaping her thinking as a biologist. While lecturing on organelles, Walker encouraged students to imagine the room as a cell and to point out where the nucleus or mitochondria might be located. “His teaching style inspired me to really visualize what’s going on in the fermentation vessel,” Greenhagen says. “Whereas fermentation engineers worry more about physical variables like oxygen transfer and think of organisms as black boxes, my training at MIT gave me an empathy for microbes. It’s an approach that a lot of chemical engineers don’t necessarily think about and has been key to my success.”
By harnessing biology and engineering, Greenhagen and others in the field of synthetic biology are beginning to transform manufacturing. Many consumer goods, from food to clothes to perfume, are produced using traditional ingredients and industrial processes that are increasingly unsustainable as planetary resources dwindle. By using microbes, companies can generate many of the raw resources they require with less energy and waste than factories.
In the case of flavors and fragrances, companies like Robertet had been extracting the majority of their starting compounds from plants and flowers, whose growth may vary dramatically from year to year. In contrast, Ginkgo Bioworks’s yeast feed on basic crops like corn and sugar cane, which are more economical to raise, and release their products in highly reliable reactions. Encouraged by its success with perfumes, Ginkgo Bioworks is using similar approaches to make organic pesticides, industrial enzymes, and products for human health.
For Greenhagen, scented yeast represent not only the potential of synthetic biology but also the culmination of years of work and education. Before joining Ginkgo Bioworks, Greenhagen had spent six years at another startup without seeing any of her projects commercialized. “When we were bought out by a larger company and taken off the commercialization path, I was told to sit back and relax but that’s not what I do,” she says.
Greenhagen traces her driving mentality back to MIT lab courses and an Undergraduate Research Opportunities Program (UROP) project in Professor Leona Samson’s laboratory. There, Greenhagen says, students were expected to read papers, design their own experiments, and place their findings in the context of published results. “This critical thinking and problem solving combined with real-life experience inspired me to think of my education as a gift that I should put to use,” she says. Years later, having traveled thousands of miles to see her first commercialized product, Greenhagen says she is still moved by MIT. “When I walk through campus, I get goosebumps from all the memories. It is such an amazing place.”