Synthetic DNA Manufacturer has the “Write Stuff”

In research, the demand for DNA strands often outpaces supply. To help supply keep up, researchers may set aside traditional molecular cloning techniques and embrace polymerase chain reaction select PCR)-based techniques. Alternatively, researchers may perform gene synthesis, or the de novo chemical synthesis of DNA. Besides accelerating the creation of genetic sequences, gene synthesis avoids the need for template strands and simplifies procedures such as codon optimization and the fabrication of mutant sequences.

Although gene synthesis can be performed in house, many laboratories prefer to focus on their core competencies and outsource their gene synthesis projects to service providers, especially if sequences of over 1,000 base pairs are desired. Outsourcing also allows laboratories to take advantage of service providers’ economies of scale and quick turnaround times. Finally, service providers offer ease of use. Clients can go online, upload the desired sequences, choose the vector, get the price, and place the order. The entire process takes only a few minutes, and the genes can be delivered a few days later.

Researchers needing a few genes have a choice of several providers. But what if researchers need 10,000 genes? “We’re probably the only game in town,” suggests Emily Leproust, PhD, co-founder and CEO of Twist Bioscience.

Twist has developed a synthetic DNA manufacturing process that emulates the miniaturization seen in the semiconductor industry. For example, reaction volumes for the stepwise addition of bases to a single strand of DNA have shrunk. “Our competition uses 50-µL reaction volumes—the equivalent of one tear when crying. We use 50-nL volumes,” she asserts. “That’s one-thousandth the volume.”

As a result, Twist can synthesize 9,600 genes on a single chip, compared to the single gene that traditional methods produce in the same footprint. As a result, more DNA can be synthesized on each chip, fewer quantities of reagents are used, and the per-gene cost is two to three times lower.

“This enables researchers to do more with less expense,” Leproust notes. “The synthetic DNA market is like the sequencing market. As we lower the price, we increase the market. The difference is that with sequencing, you send a gene and get back a file. With DNA synthesis, you send a file and get back genes cloned into a plasmid. Whether it’s 1 µg or 100 µg, you choose how much DNA you want.”

Prudence and disruption

New projects are developed frequently at Twist, but until they’re ready, they remain secret. Their commonality is innovation. “Everything we try to do must be disruptive and best in class,” insists Leproust. “I demand that it be disruptive.”

For example, about two years ago, Twist helped a customer contribute to a pandemic prevention program organized by the Defense Advanced Research Projects Agency. “The goal,” Leproust recalls, “was to respond with a pandemic therapy within 60 days of the onset of illness.” Twist made thousands of genes for the customer, Vanderbilt University Medical Center, which was focused on antibody discovery.

“We participated in two pandemic exercises. In January, we experienced a real-life pandemic,” she says. “All that well-oiled machinery was turned to action, and now AstraZeneca is pushing into the clinic with a number of antibodies discovered through this program at Vanderbilt.”

Leproust views Twist as an enabler that works upstream of its customers, creating products that empower customers to pursue their goals. “They are so creative and have so many research questions,” Leproust emphasizes. “With Twist, they get to explore more ideas.”

Twist doesn’t fulfill all requests for DNA synthesis, however. “We care about biosecurity,” Leproust declares. “Sometimes, we get requests for things that are too dangerous to make, such as smallpox.”

Although biosecurity represents a hard limit, Twist is interested in seeing other limits dissolve. “Some sequences of DNA are extremely difficult to make,” Leproust points out. “A homopolymer, for instance, could be 50 consecutive ‘Gs.’ That’s very hard to make and hard to read.” Secondary structures with odd folds are another challenge. Even the ratio of the letters affects manufacturability.

A dedicated team, a winning formula

Leproust remembers that when Twist was formed in 2013, “Bill Banyai [senior vice president of advanced development and general manager of data storage] and Bill Peck [co-founder and chief technology officer] took care of the technology and the operations, and I raised the money. We were three people with an idea and 20 pages of PowerPoint slides, asking for millions of dollars. It wasn’t an easy sell.

“After 50 ‘No’s,’ we got a ‘Yes,’ and then we had to attract people to join us. That was hard. Then we had to do the science, and that was hard. People said that to me. I responded, ‘Yes, it’s good that it’s hard. Otherwise, everyone would be doing it. You have to pick your challenges.’”

Leproust remarks that the first year Twist made $1 million in revenue stands out. But she also notes that even more impressive gains followed: “Then we had a million-dollar quarter, and then a million-dollar month. Now if we have a million-dollar week, it’s a bad week. Our goal is to reach $1 million per day.”

This year, Twist achieved a $3 billion valuation, and its European division will be as large this year as the entire company was in 2018. “That shows the speed of growth,” she maintains, “and that you constantly must reinvent yourself to adapt to changing circumstances.”

Adaptability and staying power

When COVID-19 hit, Twist moved quickly to cope with new challenges. The company, Leproust points out, decided that it needed to continue manufacturing its products, which are essential for pharmaceutical development. She and the office staff worked from home, but the company’s laboratories never closed. Twist gave laboratory workers “shelter in place” benefits, ensured air in the labs was 100% fresh, and began testing laboratory personnel regularly for COVID-19. “When the governor’s stay-at-home mandate came,” she says, “there were no changes for us, because we already were doing it.”

“We do the impossible and make things happen,” she proclaims. But she also admits that the company’s hard-charging attitude can be too much of a good thing. She recognizes that for her, personally, Twist is all-consuming, but that employees have lives outside of work: “We have a lot of dedication, but we need to know our limits and not cross them.”

That Twist can withstand the COVID-19 pandemic restrictions is due, partially, to its structure. Under Leproust’s leadership, Twist has adopted a diversified business model. The company has also enhanced its synthetic DNA manufacturing platform, adding next-generation sequencing, antibody development, and DNA data storage functions. The company is positioning itself to serve multiple market segments.

“Our next milestones aren’t big flashy things,” Leproust relates, “but the small impacts Twist has on customers every day.” That means the day-to-day work of launching new products and converting new customers. “We’re at the end of the beginning,” she observes. “We have a long way to go.”