When the earliest DNA synthesis tools were developed, the workflow was laborious, cumbersome, and extremely finicky. It often necessitated the use of hazardous chemicals that many laboratories were not equipped to handle. No wonder that scientists involved in drug discovery chose to outsource this work. So many decades later, most of them still do, even though gene synthesis is routinely used for target discovery and engineering, lead identification, biologic development, and a host of other applications across the discovery and development pipeline.
While outsourcing DNA synthesis overcame technical and staffing challenges in pharmaceutical companies, scientists had to give up control over their experimental timelines since delivery of their desired oligos or genes was dictated by a vendor’s often lengthy turnaround times. To place orders, they had to share valuable proprietary information outside the walls of their organization, sometimes with vendors that also performed their own drug discovery and development. It’s not unusual for scientists to split up their DNA orders across vendors, or even to order random sequences that aren’t needed, to avoid tipping their hand.
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Today, a new generation of automated benchtop systems for DNA synthesis has finally made it feasible to bring this capability back in-house. Unlike previous methods, these systems are designed to be user-friendly, requiring no specific technical expertise to operate. They typically produce a number of custom oligos in a single run that can be scheduled overnight to keep other scientific workflows on track during work hours.
With this development, the leaders in pharmaceutical and biotech companies finally have options to re-evaluate the business case for outsourcing DNA synthesis.
Key factors to consider
There are a number of elements to think about when deciding whether to bring DNA synthesis in-house. Given the easy-to-use tools now available for this, technical expertise is no longer a concern. But several other considerations remain.
Reducing cycle time. As a drug candidate is being designed and optimized, there are a lot of iterations —repeated cycles of building the candidate, testing in a certain situation, assessing results, tweaking the design, and starting again. Relying on a vendor for synthetic DNA can add weeks to each cycle, and several months to the overall process. It adds up to a significant and costly delay in drug development. When DNA synthesis can be performed in-house on an automated benchtop platform, though, oligos and genes can be made when they are needed. Slashing weeks from each iterative cycle helps companies get to their optimal candidate faster while reducing risk and preserving cash.
Better scientific control. Throughout the discovery and development pipeline, there are certain scientific processes that perform more reliably and effectively at very specific time points. For example, there’s a precise window during which transfection has to be done when mammalian cells are being grown. If researchers miss that window because an oligo shipment didn’t arrive when it was supposed to, they risk losing a high-value product that would take a fair amount of time and money to replace. The same is true for many other common processes, including CRISPR-based gene editing workflows. When DNA synthesis is outsourced, the lack of control over time can prove costly. Having in-house platforms to perform rapid gene synthesis ensures that scientists are better equipped to get their DNA at the right time and generate better results from their workflows.
Confidentiality. It’s no secret that pharmaceutical and biotech companies go to great lengths to keep information about their targets and drug candidates safely contained. That is essential for protecting intellectual property throughout the discovery and development process. Sharing DNA sequences with an external vendor has never sat well with these scientists, but until recently it was considered a necessary evil. Now that DNA synthesis can be performed internally with an easy-to-use system, that “evil” is no longer necessary. For most pharmaceutical and biotech leaders, keeping that proprietary information in-house is a safer bet than continuing to share it with external vendors.
New technologies
In the past decade, innovations in oligo and gene synthesis have led to the development of new benchtop technology platforms that perform these tasks in an automated fashion. At this point, the level of automation varies by platform, but across the board, developers are building toward a fully walkaway system that can start with the desired sequence and produce completely assembled genes.
Some of the platforms available today incorporate enzymatic DNA synthesis, an advanced technique that is safer, more accurate, and more environmentally friendly than conventional chemistries. Generally, these new tools prioritize ease of use with minimal hands-on time for setup, and they synthesize DNA in a matter of hours or, at most, a couple of days. Oligos are produced in parallel so users can submit dozens of sequences for synthesis at the same time.
Until gene assembly is fully integrated on these devices, scientists can incorporate basic liquid handling robots to assemble oligos into the genes of interest. This approach is straightforward and fairly inexpensive, and results in an automated workflow to generate the needed genetic material.
The upshot
In the days when DNA synthesis was too onerous to manage internally, it made sense for drug discovery and development organizations to outsource this process and live with the compromises that ensued. However, company leaders no longer have to accept losing control of their timelines, experiments, and proprietary information. With robust benchtop platforms for automated DNA synthesis, the capability can be brought back into pharma and biotech laboratories for better control of processes and results.
Sylvain Gariel is co-founder and chief operating officer of DNA Script.