Designer DNA and Bugs as Drugs
Bug Printer: naulicrea via Envato
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The advent of the revolutionary gene-editing technology, CRISPR, has added a new dimension to drug discovery, with new and exciting ways to fix genetic diseases and identify therapeutic targets. For more on CRISPR and its impact on drug discovery, listen to our previous episodes: S407: A brief history of CRISPR: how we learned to edit the genome and S408 Making better medicines: unlocking the promise of genomics for drug discovery.
Despite the technological advances brought by CRISPR, one major bottleneck remains in drug discovery. It is the same bottleneck the scientists at Genentech encountered nearly three decades ago: DNA synthesis.
The ability to design genetic sequences and synthesise them precisely, quickly and at scale would enable us to create libraries of precisely designed antibodies, proteins, and nucleic acid drugs without the hassle of finding related molecules in nature and coaxing them into the structures and functions we need to treat disease.
While DNA sequencing has moved forward at lightning speed over the past few decades, and we can now sequence DNA in hours for a few hundred dollars, DNA synthesis techniques have not seen equivalent advances. If researchers want to synthesise DNA in the laboratory, they are still stuck with a slightly more up-to-date version of the laborious process that has been used since the 1980s - carefully adding one nucleotide at a time using a method called phosphoramidite synthesis.
Several companies are now working on chip-based technologies that promise quick, accurate DNA synthesis in small, user-friendly desktop devices - effectively DNA printers that take the genetic code you want from letters typed into a computer to molecular reality.
The devices create DNA stands in multiple parallel micro-reactions on silicon chips using the same basic process of adding each nucleotide step by step. But they create DNA strands in thousands of multiple, precisely controlled parallel microreactors in pixels or virtual wells that act as independent DNA synthesis sites. The result is a highly automated, high yield, and accurate process that can create long strands of DNA on demand.
New DNA synthesis technologies are now promising to open up biological engineering and unleash a new era of drug discovery, where we can rapidly produce and screen libraries of potential new synthetic drugs, including antibodies, hormones, enzymes, proteins or DNA based therapies.
Perhaps the most obvious applications given the current coronavirus pandemic could be vaccines for infectious diseases, with DNA printers capable of producing genetic codes for sections of viruses or other pathogens that can be incorporated into vaccines to generate an immune response.
One company is pursuing the idea of providing vaccine printers in doctors surgeries or hospitals, which could be invaluable in future pandemics. Researchers are also trying to use the printers to create personalised cancer vaccines which harness the power of a patient's own immune system in their fight against cancer.
Currently, DNA synthesis is often limited to sequences of around 200-300 DNA letters in length, much shorter than most genes. But as technologies advance and the size of DNA sequences that we can produce continues to increase, we can begin to think about building complete genes, or even whole genomes and designer cells to open up new avenues in drug design, including creating precisely engineered cells, gene therapies and even entirely new microorganisms designed to fight disease - a concept known as ‘bugs as drugs’.
Precision DNA printing could also open the door for more unusual DNA therapies created through ‘DNA origami’, folding strands of synthetic DNA into tiny nanoparticles with powerful properties. One example, so-called spherical nucleic acids, look a bit like tiny pom-poms, with strands of DNA coming out of the centre, and are being developed to treat diseases like skin and brain cancer.
Once we have complete control over the code of life and we can manipulate, print, and edit it with ease, the possibilities are almost endless.
References:
Accelerating Drug Discovery Through Synthetic Biology - Kirsty Maclean, PhD, Technology Networks
The Power of Spheres - Chad A. Mirkin, Christine Laramy & Kacper Skakuj, Nature
How CRISPR is transforming drug discovery - Andrew Scott, Nature
Synthetic biology – reimagine drug discovery - Stephanie Brooking, Drug Discovery Today
Synthetic biology's clinical applications - Mike May, Science
Codex DNA takes vaccine printing from concept to reality - Mary Ellen Schneider, Bioworld
Spherical nucleic acids: A whole new ball game - Sarah C. P. Williams, PNAS
