Thomas Ybert, PhD
Thomas Ybert, PhD

As we near the end of year two of the COVID-19 pandemic, it’s easy to understand a feeling of pessimism when confronting the state of the world. Although scientists have been able to develop near-miraculous vaccines in record time, vaccine resistance and emerging variants have allowed the virus to continue to burn through communities at an alarming rate.

Remote or low-resource countries have had little access to these life-saving vaccines, with only about 15% of people worldwide being fully vaccinated at the time I’m writing this.1

It’s not just the pandemic that is concerning. Fires have ripped through Mediterranean countries and the American West with worrisome intensity, fueled by climate change–induced drought. Floods in Europe and China have been responsible for nearly 500 deaths. Four hundred thousand people face famine in war-torn Ethiopia.

While I acknowledge the bigness of the challenges we face, I am optimistic about the potential for “smallness” to deliver critical breakthroughs that will help us navigate the pressures and demands of the 21st century. By smallness, I’m talking, of course, about the building blocks of life, especially nucleic acids and proteins that can be engineered to be powerful agents to do and make things that would be otherwise unimaginable. Microbes that make fuel. On-demand vaccines that fight emerging pathogens. Organisms that can clean up waste and manufacture products sustainably. Engineered crops that resist pests and require less water.

These advances and ones like them have long sounded like science fiction, but with $4.6 billion invested in synthetic biology in Q1 2021 alone, companies such as Ginkgo Bioworks, Novozymes, Gevo, and others are poised to bring these technologies into reality.2

While the progress we’ve seen in synthetic biology is exciting, we are not yet seeing the free-flowing innovation of a truly transformative wave, such as the one unleashed by information technology at the end of the 20th century. I agree with Craig Venter and others who have called the 21st century the “century of biology,”3 but we are going to need to accelerate our progress if we are to remain optimistic in the face of mounting challenges.

Research and development in synthetic biology still faces some key bottlenecks, and the most important of these is the lack of access to high-quality, affordable, on-demand synthetic DNA—the material backbone of all of synthetic biology.

The outsourcing problem

One of the most significant bottlenecks for bioengineers is that the bulk of synthetic DNA is available only through third parties. While these vendors generally do a good job with quality and have found ways to lower the overall cost, ordering DNA and waiting days or weeks for it to get made and shipped to you hinders the design-build-test-learn cycle. Imagine if, in the early days of desktop publishing, printers had been too cumbersome to house in an office, and every time you wanted to proof a document, you had to wait a week for a printing company to send printed copies. And changes would have meant another wait for new proofs. The value of being able to make quick design changes on a computer would have been severely diminished.

This has been exactly the conundrum slowing down bioengineers. Fast sequencing has provided bioengineers with ideas for designs that can be made relatively easily on a computer—Moderna famously designed its COVID-19 vaccine over a weekend4—but then they have to wait days or weeks to test the actual synthesized DNA. Fortunately, a new process for synthesizing DNA can now provide synthetic biology researchers and organizations the ability to print the DNA they need within their own labs within a day. And then they can turn around and print new DNA if the initial designs are unsuccessful.

DNA synthesis has traditionally been accomplished through the phosphoramidite process, a technology developed in the early 1980s, where chemical bases are added one at a time. This process requires a lot of space, proper ventilation, complex hardware, and harsh chemicals, and it produces harsh waste. It’s impractical for every bioengineer, or even every synthetic biology organization, to have on-site access to these tools.

DNA Script and other companies have recently made strides developing an enzymatic-driven process for synthesizing DNA. Enzymatic synthesis coaxes enzymes into building strands of DNA the way that nature does. Typically, this process does not require harsh chemicals, and it does not create waste beyond water. This means that the process can take up much less space and be done practically anywhere.

Bioengineers now can program in the sequences they need on a benchtop DNA printer before they leave at night and come back the next day to test what they made. This is a significant step in speeding up the innovation cycle in synthetic biology.

The capacity issue

What if you tried to render an edit of a 4K film on a 1992 Mac? Or what if you needed to code a website but had to send the code to a service bureau to see it come to life? This is essentially what synthetic biology researchers must contend with in the current system. But if researchers and developers could access large amounts or pools of DNA oligos, it would be possible to run screens and identify the best sequence of DNA for a particular purpose, whether it be an antibody that binds most closely to a pathogen, or a sequence that can program a protein to do something novel, like make fuel.

In the computing analogy, it was massively parallel data processing and then massively parallel processing arrays (MPPAs) that made our digital infrastructure so capable. “Massively parallel” processing means the coordination of large numbers of computer processors working in parallel. This kind of processing enables data to quickly move across computer networks and become usable by many people. Within an individual computer, an MPAA can enable data-intensive applications like video streaming.

Biology is no stranger to massively parallel processing. “Next-generation sequencing” is distinguished by the fact that it employs technology to conduct massively parallel sequencing. This technology is responsible for a “mini” revolution in biology, where the price of sequencing has dropped exponentially, even while sequencing has become much faster and more accurate. Massively parallel synthesis provides the much-needed mate to massively parallel sequencing that has the potential to unleash synthetic biology research, allowing it to develop in ways that we can imagine—and even in ways that we can’t yet fathom.

What synthetic biology really needs to move forward is plentiful, cheap large pools of DNA. Think of this as the processing power of synthetic biology. As microchips gained exponential amounts of computing power in ever smaller footprints—for computers, data servers, and mobile phones—information technology was able to transform our lives. I believe the same will be true for synthetic biology.

While current DNA vendors have successfully engineered a process capable of synthesizing large numbers of high-quality oligos in parallel, there are several significant limitations. These include the complex reaction cycle and purification requirements, the high cost and large footprint of custom instrumentation, and expensive substrates—as well as the need to dispose of harsh waste.

While these DNA pools can be made, the wait time and cost involved of paying a middleman means that bioengineers can’t do something that is critical for innovation: play! They can’t take as many risks or make as many mistakes, all essential for the level of innovation synthetic biology will need to achieve to pay serious dividends in reshaping our world for the better.

These limitations could all be overcome by a high-density enzymatic DNA synthesis process and benchtop instrument, something DNA Script is developing. In terms of instrumentation, the footprint and environmental control requirements will be much reduced. Manufacturing costs will be lower. Other key advantages are the aqueous chemistry, the ability to print on microscope slides, and the ability to use modified nucleotides and synthesize protein-DNA hybrids.

Putting the tools in the hands of entrepreneurial researchers and developers is what is going to move synthetic biology forward. Information technology has made it possible for a small developer to create the next killer app, or for an artist to create a feature film with an iPhone. The rewards of a thriving, entrepreneurial synthetic biology are much greater, while the cost of failing to innovate ourselves out of the looming health, food, water, and climate crises could be devastating.

References
1. Our World in Data. Statistics and Research. Coronavirus (COVID-19) Vaccinations.
2. Philippidis A. Top 10 Synthetic Biology Companies. GEN. Posted July 2, 2021.
3. Venter C, Cohen D. The Century of Biology. New Perspect. Q. 2004; 21: 73–77.
4. Neilson S, Dunn A, Bendix A. Moderna’s groundbreaking coronavirus vaccine was designed in just 2 days. Business Insider.

 

Thomas Ybert ,PhD (ty@dnascript.co), is co-founder and CEO of DNA Script.