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On the future of gene synthesis: an interview with Cedric Wu from GenScript

PLOS Blogs Interview

 

Synthetic biology relies on our ability to read and write DNA. GenScript is one of the companies active in the field of gene synthesis, and its senior vice president Dr. Cedric Wu was kind enough to answer my questions on the future of the technology.

 

Kostas Vavitsas: The development of synthetic biology has definitely benefited gene synthesis. What do you think is the biggest recent technological advance, and what should we expect from the future?

Cedric Wu: There are two emerging DNA synthesis technologies that could possibly dictate the future of the DNA synthesis industry. One is enzyme-based synthesis and the other is semiconductor-based DNA synthesis technology. Enzymatic DNA synthesis has come to the spotlight recently. Similar to the next-generation sequencer, scientists are working on finding an efficient way to stop and reinitiate DNA polymerization in a template-independent polymerase reaction, which was discovered in 1980s. This old but re-polished technology is attracting a lot of attention lately because of the success of 2nd generation and 3rd generation sequencing technologies. However, unlike sequencers that aim to read the sequence and can sequence millions of reads in parallel, spatially synthesizing “custom” DNA independently is challenging. In addition, this method has much lower coupling efficiency than conventional phosphoramidite chemistry.

On the other hand, scientists have combined conventional phosphoramidite chemistry with advanced semiconductor technology to create a reliable and expandable technology for DNA synthesis.  Fidelity and synthesis efficiency increase drastically with this method of DNA synthesis. DNA is synthesized on a tightly controlled integrated circuit to develop higher quality synthetic DNA consistently. This technology is evolving with the silicon industry and we expect there will be an ultra high-density DNA microarray coming in near future that could lower the cost of DNA synthesis by orders of magnitude. We believe the state-of-art semiconductor DNA synthesis technology could help to move the research focused synthetic biology community to industrial era by providing reliable and low cost synthetic DNA.

 

Kostas: There is a lot of hype about enzymatic DNA synthesis methods. Is Genscript planning to incorporate the technology?

Cedric: GenScript has evaluated multiple enzymatic DNA synthesis methods and conducted research projects early on. However, due to the throughput and low efficiency of the technology itself, we deprioritized these development projects. The enzymatic synthesis technology requires a reliable DNA polymerase and four reversible terminators on the nucleotides to be incorporated. The DNA polymerase activity has to be slowed down to accept one nucleotide in one cycle and fully stopped by a terminator. The terminator is usually attached to its substrate – nucleotides and needs to be reversed by chemical methods completely, which is usually challenging. Due to its unnatural bulky structure on the substrates, the terminal transferase has to be engineered to accommodate for synthesis. As a consequence, the reaction inevitably compromises coupling efficiency and fidelity and therefore cannot go as long as a “natural reason.”

In contrast, we focus on the development of semiconductor technology. Our coupling efficiency of a single unit could be as high as 99.5%, which is much higher than any enzymatic DNA synthesis methods (i.e., 98% to 99%). One percent efficiency difference may not sound like much, but it makes a lot of difference in a product. For example, making a single stranded DNA for 200nt long, the yield could be go from 37% (99.5% coupling efficiency) down to 5% (98.5% coupling efficiency). Besides, our semiconductor technology is expandable. We are now developing our next-generation semiconductor DNA chip and synthesizer. We foresee a few orders of magnitudes drop of unit DNA cost in the coming a few years.

 

Kostas: What is the environmental footprint of synthesizing DNA? Are there any steps in the process that can become more efficient and environmentally friendlier?

Cedric: Miniature synthesis scale is the key in semiconductor-based synthesis. Although currently the chemical waste produced during DNA synthesis on a chip-sized platform is negligible, the smaller the synthesis scale, the less waste will be produced. The other way is to increase the throughput and density of the DNA on a chip.

 

Kostas: Where do you see Genscript in the next few years? The market is getting more crowded…

Cedric: We foresee tremendous growth in synthetic biology in the next few years to decades. Fossil fuels are being depleted and the natural environment is becoming very fragile. Synthetic biology is the only answer to keep our life the same without the use of fossil fuels and organic chemistry. We know synthetic DNA is the beginning and also the foundation of the synthetic biology industry. There are many players in the market and the competition is getting strong. However, we don’t worry about it. Instead, we welcome everyone to the synthetic DNA industry and hope that we can work together to make the synthetic DNA more affordable and to help our synthetic biologists change the world. GenScript, has been the synthetic DNA market leader since 2010. The reason we continue to be the leader is that we invest heavily in research and we work closely with our clients and partners. We are the premium vendor selling the best quality DNA in the market at a very low price.

 

Kostas: What should we expect from the double Helix symposium?

Cedric: The Double Helix symposium is a conference where key opinion leaders and top researchers from both academia and industry will meet and share their wisdom on the latest trends in synthetic biology, providing a learning and networking opportunity for early career scientists. The focus this year will be how nucleotide engineering and genome engineering would impact the current industry and the advanced techniques and tools to manipulate DNA in order to achieve success in various applications. This event is free for researchers who receive Cloud Scientist membership from our platform. For more information about our featured speakers and how to join, visit: https://www.genscript.com/double-helix-symposium-2019.html

 

Dr. Cedric Wu is senior vice president of GenScript, where he leads the R&D team focusing on protein, antibody engineering, nucleic acid chemistry, genome editing, bioinformatics, data storage, semiconductor chip development and gene synthesis. He obtained a PhD degree in Cellular and Molecular Biology from University of Wisconsin – Madison, where he also received post-doc training in nucleic acid, surface and analytical chemistry. Dr. Wu possesses more than twenty years of combined experience working in academia, government and industry. He has invented and published more than 20 articles and patents, as well as numerous trade secrets. 

 

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