Raising glasses of genetically modified beer, the synthetic biologists at Ginkgo Bioworks celebrated the launch of a new automated lab last month. By applying engineering principles to biology, and with the help of some nifty robotic equipment, Ginkgo has created a factory for churning out exotic lifeforms, the likes of which have never before been seen on this planet.
The home brew was an example of the potential applications of synthetic biology, a new field that builds on recent progress in genetic assembly methods. Scientists can now manufacture snippets of synthetic DNA and slip them into organisms, giving those critters strange new capabilities.
For example, the brewer’s yeast used to make beer for the launch party had genes from an orange tree added to its own DNA. During the fermentation stage of the brewing process, those genes caused the yeast to produce valencene, an organic compound with a citrusy flavor. Speaking scientifically, it was delicious.
Ginkgo Bioworks, a hip young company based in South Boston, recently raised $100 million on the promise of finding many such useful applications for synthetic biology. And it used some of that cash to build Bioworks2, the company’s vast new lab that uses robotic systems to make an assembly line for organisms.
Ginkgo needs to make microbes on a grand scale in order to find those that can function as tiny biological factories. When a client comes in with a request for a custom-made organism, Gingko begins its bulk experimentation. Many of the altered organisms will be duds, but through cycles of iteration the bioengineers eventually devise a microbe that turns out the desirable product. The company is messing around with organisms that produce chemical ingredients for perfumes, beverages, pesticides, and laundry detergent.
Ginkgo Bioworks’ business model centers on the microbes themselves, not the end products. “We’re not in the business of manufacturing chemicals, flavors, or fragrances,” explains Ginkgo creative director Christina Agapakis. “We specialize in the organsims, and we partner with our customers who will make the product.” Ginkgo licenses organisms to its customers, she says, and gets royalties if they’re used.
But building an organism to spec is no easy task. Genetics still isn’t well understood; there’s no universal catalog listing of genes that details what they all do. And biology is messy. Even if researchers know what a particular gene does in an orange tree, for example, when they add it to a yeast cell, it might interact with the native DNA in unexpected ways. If they’re adding several genes from different species to that yeast cell, things get even more complicated.
That’s why Ginkgo takes an engineering approach to biology, hewing to a rigorous design-build-test cycle. In this case, they’re designing, building, and testing living organisms.
The new lab’s extreme automation is critical to this approach, says Patrick Boyle, Ginkgo’s head of organism design. “In grad school, I might have taken my five best ideas and tried them out,” Boyle says. “Here we take our 1000 best ideas, try them all out, and see which works best.”
So how does that design, build, and test cycle work in practice? Take Ginkgo’s first efforts in the perfume business as an example. Ginkgo is working with the French perfumier Robertet on a yeast that spits out rose oil. There’s a business case for making this microbe: Extracting traditional rose oil from rose petals is expensive, and high-end perfumiers look down on chemical substitutes. But adding the right genes from a rose plant to a yeast cell could make it produce the real oil, just in an untraditional way.
Design: A yeast serves as the biological “chassis,” the base for the customized creature. Ginkgo designers then search the scientific literature, looking for genes that would cause a cell to produce useful enzymes. They’re looking for enzymes that can work within the yeast cell’s metabolic process; when they feed sugar to the yeast it should carry out chemical reactions that ultimately result in rose oil.
They hunt for genes all across the biological kingdoms: “We ask, ‘How have different biological niches solved this biochemistry problem, and how can we adapt them to our purposes?’” says Boyle. They can combine genes from different organisms into metabolic pathways, but this requires scaled-up science. “If you have 100 possible enzymes that can serve as a step in a four-step pathway, that’s a lot of design space to explore,” Boyle says.
Build: Ginkgo outsources the actual manufacturing of synthetic DNA, ordering up batches from companies like Twist Bioscience and Gen9. Boyle says the company will receive 700 million base-pairs of synthetic DNA in the next year and a half, which represents half the world’s current market for synthetic DNA. A company like Ginkgo can only exist because the cost of manufacturing DNA has recently come down dramatically.
When a batch of manufactured DNA arrives at Ginkgo, liquid-handling robots add the various snippets to yeast cells and let the cells grow and multiply. Creative director Agapakis says these robots are getting better and better. “During my PhD, I spent a lot of time moving tiny amounts of fluid around,” she says. “When we started Ginkgo, a lot of the robots looked like eight-armed grad students—there were a lot of pipettes.”
Now Ginkgo has liquid-handling robots like the Echo 525, which moves nanoliters of liquid using targeted pulses of sound. The machine sends ultrasonic waves upward at a sample plate, focusing on just one of the plate’s 1536 tiny wells, and propels the droplet of liquid upward to a new vessel. It can move the contents of a plate in about 20 minutes.
Test: Once Ginkgo has 1000 yeast variants containing different mashups of genes, it’s time to see if the cells are making their product: for example, rose oil. The researchers use mass spectrometry machines to break apart the cells and examine all the molecules inside. They check whether the yeast is producing the oil, of course, but also whether the yeast is healthy. Using some of the cell’s metabolic energy to produce rose oil could interfere with other processes and “change the total picture,” says Agapakis.
Even when they’ve found a few yeast variants that seem to do a good job of cranking out oil, Ginkgo’s job isn’t done. The bioengineers still need to see whether the organism can make a product that’s truly useful to the customer.
Boyle says that in the case of rose oil, they study each yeast to determine its overall “fragrance profile.” While a cell may be making certain useful fragrance molecules, it may be making other molecules that are distinctly not useful. “I like the fresh-baked bread smell, but it’s not great when you’re trying to sell a perfume,” Boyle says. “So how do we cut down on background fragrances?” The perfume, which could currently be calledeau de baguette, is still a work in progress.
Perfume is just the beginning for this ambitious company. Agapakis sees biological manufacturing as the way of the future, and she doesn’t mind sounding like “a college student in a dorm room” when she talks about it. “Biology makes things that grow themselves,” she says. “A tree grows itself from sunlight and water, that’s amazing.” At Bioworks2, she hopes to create experimental lifeforms that will really blow college students’ minds.