Silicon chip writes 64 DNA sequences at once

A Harvard-led team has built a silicon chip that can synthesize 64 different DNA strands at the same time, according to a study published in Nature Electronics. The work points to a water-based route for making synthetic DNA, a material used in diagnostics, genome engineering and cancer research.

The research was led by Donhee Ham, a professor at the Harvard John A. Paulson School of Engineering and Applied Sciences, the school said. The chip uses electrical currents and enzymes in water to control where DNA-building reactions occur across its surface.

Most synthetic DNA is now made with phosphoramidite chemistry, a process Harvard SEAS described as capable of producing millions of sequences in parallel. That method relies on hazardous organic solvents and is usually carried out in specialized centralized facilities, according to the school.

Enzymatic synthesis offers a cleaner approach because it uses water and resembles the way cells build DNA, Harvard SEAS said. The method has been harder to scale, with earlier demonstrations producing roughly a dozen sequences at once, according to the school.

How the chip controls DNA growth

DNA strands are built one nucleotide at a time. After a nucleotide is added, a temporary blocking group stops the strand from extending until the next step, and that block must be removed through deprotection under acidic, low-pH conditions in water, according to the researchers.

The chip contains 64 synthesis sites. At each site, two ring-shaped electrodes surround DNA molecules fixed at the center, Harvard SEAS said.

When a site is switched on, the inner electrode produces protons that lower the local pH and allow the strand to keep growing. The outer electrode removes protons that spread away from the site, confining the acidic region so nearby reactions are not activated, according to the study summary.

By repeating the process through multiple cycles, the device produced 64 different DNA sequences, each up to 39 nucleotides long, Harvard SEAS said.

A device adapted from brain research

The electronics behind the device were first developed for a different purpose. Jeffrey Abbott, a former doctoral student in Ham’s lab, originally built the silicon system to record electrical activity from large groups of neurons, according to Harvard SEAS.

After the researchers redesigned the surface electrodes, they found the same current-control system could shape the chemical environment needed for DNA synthesis. Ham said the team redirected precision current injection from cells to molecules by replacing neuron-facing electrodes with ring-electrode pairs that localize pH.

The team also used the 64 DNA sequences made on the chip to encode a 169-byte text, Harvard SEAS said. The researchers described DNA data storage as a long-term possibility because it would require DNA production far beyond current volumes.

Woo-Bin Jung, a co-first author of the study who is now an assistant professor at Pohang University of Science and Technology, said enzymatic synthesis in water could matter for DNA data storage if far more than 64 sequences can be made in parallel.

Chemistry remains a barrier

The researchers tested denser chips with synthesis sites placed closer together to see whether the system could produce more sequences at once. Harvard SEAS said those tests did not succeed, although they showed the chip was still able to confine low pH to selected sites.

Han Sae Jung, a co-first author and postdoctoral researcher at Harvard, said the limit came from the deprotection chemistry. Low pH creates intermediate molecules that remove the blocking groups, and those molecules can move into neighboring synthesis sites, according to the researchers.

The project included researchers from Harvard, the Broad Institute, DNA Script and POSTECH. Harvard’s Office of Technology Development has filed intellectual property related to the platform, the school said.

This story draws on original reporting from ScienceDaily.