Celebrating iGEM + Ginkgo History

We are so thrilled to be announcing a new partnership with iGEM (the International Genetically Engineered Machine competition). As sponsors, we’ll be supporting iGEM’s future growth and the growth of the community of synthetic biologists that they have built.

The connections between Ginkgo and iGEM go deep. Tom Knight was one of the original founders of iGEM when it was an intersession (IAP) class at MIT in 2003, along with Randy Rettberg, Drew Endy, and Gerry Sussman. Austin and Reshma took part in the first class, where they worked on designing oscillating logic devices.

Pathway design for the 2003 IAP iGEM class
Pathway design for the 2003 IAP iGEM class

The first summer program version of iGEM was in 2004, and I was on the MIT team along with Jason and Tom. The project was to build synchronized chemotactic oscillators (which may still be impossible—youthful optimism!), though one tiny part of that of that project eventually grew into the publication of the first datasheet for a standard biological part.

MIT iGEM 2004
The MIT iGEM team, summer 2004

In 2006 all the Ginkgo founders along with our Head of People, Samantha Sutton, were advisors to the MIT iGEM team. Our project was Eau d’e coli: E. coli engineered to smell like wintergreen and bananas. In many ways, Ginkgo’s eventual work in the fragrance industry traces back to this project!

The Ginkgo founders (minus Tom) at the 2006 iGEM competition

MIT iGEM 2006 Live Demo of Eau d’e coli

iGEM is one of the most important organizations in the field of synthetic biology, building a vast and open community of students and mentors that are committed to building synthetic biology according to their strong values in openness, responsibility, and fairness. iGEM is also a vital educator of synthetic biologists—10% of Ginkgo has participated in iGEM as a student participant, advisor, or judge (iGEM students and others, see open job postings here!). We’re so happy to be supporting iGEM and excited to be part of building the future of synthetic biology together.

Comments on DNA synthesis in light of our deal with Twist

Ginkgo has just announced a commitment to buy 100 million base pairs of DNA from Twist Bioscience in 2016. By volume, this equals 10% of the global volume for gene synthesis in 2015. Here, I provide some context for how we, the customer, view an agreement like this.

Engineering biology has become a big deal – booming investment in a range of markets, an academic ecosystem, and thriving educational initiatives. These activities are powered by a distributed, expensive, and largely manual effort to construct DNA. As the field develops, the role of DNA synthesis will become increasingly important. For example, at Ginkgo we make heavy use of sequences that must be synthesized because they don’t exist in any strain collection. Additionally, as our engineering becomes more sophisticated, each nucleotide becomes a target for design so writing the DNA from scratch is necessary. Ginkgo has always outsourced DNA synthesis and has ongoing relationships with synthesis companies including Genscript and Gen9. Our agreement with Twist is a logical extension of this approach.

We believe DNA synthesis belongs in specialized facilities serving many customers. In principle, outsourcing DNA synthesis should be easy; the customer provides sequence requests, the service provider returns sequence-perfect DNA. This is an attractively simple interface. However, large-scale adoption of synthesis services depends on cost, turn time, and what sequences can be synthesized. Let’s look at each in turn.

Cost: Synthesis costs are driven by labor, and materials. The leading synthesis firms drive down these costs using automation and miniaturized reactions that support substantial economies of scale. Their custom platforms incorporate glass or silicon chips, laser-printed reagents, multiplexed sequencing, and process control software. A researcher working in a conventional lab is simply not equipped to compete with these platforms on price, which are now crossing the $0.10/bp barrier. To appreciate the progress this represents, 2 years ago the market price was $0.30/bp for gene synthesis, 10 years ago it was $1.00/bp. We expect that synthesis platforms will become increasingly differentiated from the standard wet-lab in the future. Our partnership with Twist ensures we will be on the leading edge of the ensuing falling cost curve. Falling prices don’t mean a shrinking market since an ever larger fraction of the work done by researchers at the bench, such as PCR’ing from a template, can now be replaced by synthesis.

Turn time: The process time for DNA synthesis ranges from 8-20 business days and has stayed mostly constant in recent years. Those times are competitive with an expert researcher at the bench and should be sufficient to drive rapid growth of the synthesis market. However, errors in the synthesis process often extend turn time to a substantial and unpredictable degree. These uncertain delays impact the ability of a customer like Ginkgo to hit deadlines and meet our customer’s needs. Ginkgo has been tracking the difference between expected and actual turn times and some of our data is presented below. Interestingly, the delayed sequences tend to cluster around a delay of 20 business days, suggesting a second attempt was required to successfully build the sequence. While turn time will inevitably improve, we should seek ways to avoid long delays. For example, giving the provider and the customer a mechanism to cancel orders that prove hard to synthesize keeps everyone moving forward on a more predictable schedule. We have designed our agreement with Twist to provide such a mechanism that protects both side’s interests. At the same time, we must consider what makes certain DNA sequences hard to synthesize in the first place.

Sequence constraints: Repeat sequences, local regions of extreme GC percentage, and sequences constitutively expressing protein are often flagged as problematic by synthesis firms. These constraints are gradually being elucidated and loosened by ongoing process improvement. What we can do today is ensure that our designs avoid as many problematic sequences as possible. Some providers will endeavor to optimize the customer’s sequences to make them easier to synthesize but we believe that is not the right general solution. The customer needs to own the sequence design process in its entirety since they alone understand the design objective. This means integrating the synthesis constraints into the design process so all constraints can be considered together. Sharing of detailed synthesis constraints depends on trust and close relationships between customer and service provider. We think supply agreements like the one we have reached with Twist, and other companies previously, form the basis of that relationship.

Sequence length: Synthesizing long sequences (5-20kb) requires additional steps and effort and has consequently carried a price premium per base pair. This places customers in a bad spot. As sequence length (and design complexity) increases, our confidence in the design tends to go down, meaning we need to test more variants. But if the cost of each variant increases with length, the service becomes uneconomic as length increases. While falling prices in general help this problem, that is unlikely to be sufficient any time soon. A better solution is to rely on combinatorial assembly. This means synthesizing common sequences only once and then reusing that DNA in multiple longer constructs. Reusing DNA in this way spreads the synthesis cost across multiple constructs and leads to lower costs per base pair than shorter constructs. This works for the customer because sets of long sequences often involve considerable sequence reuse.  Note that the 100 Mbp we will be ordering from Twist does not include combinatorial assembly.

With continued progress on the parameters discussed above, it seems plausible that all in vitro DNA synthesis, assembly, and editing will happen at specialized firms and the role of the customer will be focused on the equally interesting challenge of introducing that DNA into their organisms. Lastly, we should remember that this is a young and rapidly learning field. Only through efforts at the scale of what we are doing with Twist will we learn the rules of fast and efficient DNA synthesis, and sophisticated design of organisms. We at the Ginkgo foundry, with our friends at Twist and elsewhere, are delighted to be leading the charge.

Some Synthetic Biologists aspire to live in a house grown from a reprogrammed tree. We’re not there yet but our ability to train trees to form useful structures certainly gives cause for optimism. Take for example the living root bridges of the War-Khasis tribe in Northeastern India. Strong, flexible roots are trained to grow across rivers and take root on the far side. While a bridge can take 10 years to grow some may be more than 500 years old and still getting stronger. Much like good whiskey, these root bridges take a long time to make, but once made, they get better and better.

Image source – Vanlal.

And the award for “best engineer” goes to…

On Oscar weekend, this story seemed appropriate. Ginkgo founder Tom Knight is nominated as one of the top 25 most influential engineers working today by Engineering and Technology Magazine, the trade publication of the Institute of Engineering and Technology. The list includes other engineering luminaries such as Vint Cerf, James Dyson, Julia King, and Ray Ozzie. We’ll be keeping an eye on how the voting turns out…

New events and new faces

We are looking forward to an exciting and busy year for Ginkgo and we wish you the same. The Ginkgo team is speaking at a number of events in the coming months – keep an eye on our news page for more details.

images.jpegWe are also delighted to announce the first annual recipient of the Ginkgo BioWorks undergraduate fellowship, Matt Gethers (MIT, ’09). Matt, a Biological Engineering major and accomplished fencer, will be interning with us for the next few months as we develop some new DNA assembly technologies. Matt is the recipient of numerous other less prestigious awards, including a 2009 Rhodes Scholarship. Great to have you around Matt!

Seed Magazine on DIYBio & iGEM

The always interesting Seed Magazine reports on the work of Mac Cowell and DIYBio to bring biology to the masses. In a long interview, Mac lays out his vision of how amateurs can contribute to biological research in a similar manner to how amateur computer scientists were, and continue to be, so influential in (silicon-based) computer programming.

As an added bonus, Seed also contains an article written by Ginkgo’s own Jason Kelly about the evolution of genetic engineering from the very first recombinant DNA experiments through to the iGEM competition today. He highlights the renewed sense of excitement and possibility about responsible and constructive engineering of biology. Much of this excitement stems from the enthusiasm, talent (and dance skills) of the iGEM teams.

Team Slovenia – iGEM grand prize winners again


Sorry to get this post up somewhat late, the afternoon has been somewhat hectic. Slovenia once again had an extremely strong project and in the opinion of the judges were deserving of the grand prize.

Slovenia developed some very nice vaccine technology to fight Helicobacter pylori. The first part of the project was to engineer a live Helicobacter strain that expresses an antigen to trigger both the innate and adaptive immune response. The second half of the project involved engineering a constitutively active variant of TLR (toll-like receptor) to remove the requirement for receptor agonists. The latter has the potential to be a novel general strategy for developing vaccines.

Congratulations also to Freiburg and Caltech who were first and second runner’s up respectively.

Thanks are due to the organizers and the judges for such a well-organized weekend.

(The image above shows some of the crowd during the award ceremony and Tom Richard, head judge, bathed in light).