How laser 'printing' builds DNA

The concept of using lasers to synthesize DNA with a specified genetic sequence intrigued me so much that I tried to describe it in my October Photonic Frontiers feature. After receiving a grant from the National Science Foundation, the company behind the idea, Cambrian Genomics (San Francisco, CA), has released new details on the process, and my speculation about its nature turned out to be wrong.

Previously, DNA synthesis has been a two-stage assembly process. First individual base pairs are assembled into "oligonucleotide" sequences of 60 to 100 base pairs. Then, a number of those longer chains are stitched together into the synthetic DNA. The process is time-consuming and costs 30 to 50 cents per base pair, a number which adds up for long sequences. I had thought they might be using lasers to manipulate the base pairs into place.

Instead, Cambrian Genomics uses microarray cloning to mass-produce a million oligonucleotides in parallel, a process that has been tried before, but was hampered by the high error rates of microarray synthesis. To overcome that problem, Cambrian synthesizes large volumes of oligonucleotide fragments on microarrays, then uses massively parallel DNA sequencing to sort the different DNA variants and identify those with the desired sequence. Then, says Cambrian founder and CEO Austen Heinz, "we use laser catapulting, also known as laser-induced forward transfer, to eject clonal DNA populations," which were identified as having the desired sequences. The process is a variation on laser capture microdissection, which can excise part of a cell and move it to a desired location without damaging DNA. High-speed laser pulses then eject beads carrying the desired sequences in the right order to assemble into genes on a 384-well plates, as shown in the diagram.

Cambrian Genomics process uses lasers to select oligonucleotides with the desired sequence.

The goal, Cambrian wrote in a summary of its application for a phase-one Small Business Innovation Research (SBIR) grant, "is to be able to recover tens of thousands of sequence-verified oligonucleotides in several hours from sequencer flowcells."  NSF announced on December 5, 2012, a $150,000 grant that will run through the first six months of 2013. Cambrian hopes that will open the door to disruptive reductions in the cost of DNA synthesis.