In a new study published in Nature Electronics, a Harvard led research team unveiled a silicon chip capable of synthesizing 64 different DNA sequences at the same time. Instead of relying on the solvent intensive chemical process commonly used to manufacture synthetic DNA, the device uses a water based enzymatic approach. Carefully controlled electrical currents trigger DNA building reactions at specific locations across the chip.

The research was led by Donhee Ham, the John A. and Elizabeth S. Armstrong Professor of Engineering and Applied Sciences at the John A. Paulson School of Engineering and Applied Sciences (SEAS).

A Cleaner Way To Manufacture DNA

Synthetic DNA is essential for many areas of modern science and medicine, including diagnostics, genome engineering, and cancer research. Today, most custom DNA is produced using phosphoramidite chemistry, a well established method that can manufacture millions of DNA sequences in parallel. However, that process depends on hazardous organic solvents and typically requires specialized centralized facilities.

Scientists have been exploring enzymatic DNA synthesis as a gentler alternative because it uses water and more closely resembles the way living cells naturally build DNA. The approach could eventually enable smaller, safer, and more widely available DNA synthesis systems.

Until now, though, enzymatic methods have lagged far behind conventional manufacturing in the number of DNA sequences they can produce simultaneously. Previous demonstrations had been limited to about a dozen sequences at once. The Harvard team's chip successfully synthesized 64 different DNA sequences in parallel, each as long as 39 nucleotides, establishing a new milestone for the technology.

How the Silicon Chip Writes DNA

DNA is assembled one nucleotide at a time. After each nucleotide is added, a temporary blocking group prevents additional growth. Before the next nucleotide can be attached, that blocking group must be removed through a process called deprotection, which is triggered by acidic conditions, or low pH, in water.

Producing many different DNA sequences at the same time requires lowering the pH only at selected locations during each synthesis cycle. The Harvard chip accomplishes this using tiny electrical currents.

Its surface contains 64 synthesis sites. Each site features two concentric ring electrodes surrounding DNA molecules anchored at the center. When a specific location is activated, the inner electrode generates protons that lower the local pH and allow the DNA strand to grow. At the same time, the outer electrode removes protons that spread outward, keeping the acidic region confined to that single site.

By repeating this process through multiple cycles, the chip independently builds 64 unique DNA sequences across its surface.

From Brain Research to DNA Synthesis

Interestingly, the chip was not originally designed to manufacture DNA.

Jeffrey Abbott, a former PhD student in Ham's laboratory, initially developed the silicon electronics for recording electrical activity inside large populations of neurons. After redesigning the surface electrodes, the researchers discovered that the same underlying technology could precisely control the chemical conditions needed for DNA synthesis.

"A defining feature of the chip was precision current injection, which we used to permeabilize neuronal membranes for intracellular access," Ham said. "At a certain point, we wondered whether that same current control could be redirected from cells to molecules, replacing the neuron-facing electrodes with ring-electrode pairs that could localize pH for DNA synthesis. It worked."

DNA Data Storage Could Be a Future Application

Beyond potential applications in synthetic biology and medical diagnostics, the team demonstrated another possibility by using the 64 synthesized DNA sequences to encode a 169-byte text.

Although DNA based data storage remains a long term goal because it would require manufacturing DNA at an enormous scale, the researchers believe water based enzymatic synthesis could become increasingly attractive as production volumes grow. Reducing solvent use could significantly lower the environmental impact of large scale DNA manufacturing.

"DNA data storage asks DNA synthesis to operate at a scale far beyond today's needs," said Woo-Bin Jung, co-first author of the study and now an assistant professor of chemical engineering at the Pohang University of Science and Technology (POSTECH), who carried out the work as a postdoctoral researcher in Ham's lab. "That is why enzymatic synthesis in water can matter. If far more than 64 sequences can be synthesized in parallel, it could offer an environmentally friendly route toward writing DNA at very large scale."

Chemistry Is the Next Obstacle

The researchers also wanted to learn how much further the chip could be scaled. They fabricated chips with synthesis sites placed closer together, hoping to increase the number of DNA sequences produced simultaneously.

The experiment did not succeed, but it revealed an important insight. The chip itself accurately confined low pH to the intended locations. The real limitation came from the chemistry used during deprotection.

Rather than directly removing the blocking groups, low pH generates intermediate molecules that perform the deprotection step. Those intermediate molecules can drift into neighboring synthesis sites, reducing the separation between reactions even though the pH remains tightly controlled.

"The chip did what we asked it to do: it localized low pH at selected sites," said Han Sae Jung, co-first author of the study and a former graduate student and current postdoctoral researcher at Harvard. "The limitation came from the deprotection chemistry, not from the silicon. That leaves a clear next step for the field -- develop a more direct acid-driven deprotection chemistry that can keep pace with the chip."

Collaboration and Research Support

The project was a collaboration among researchers at Harvard, the Broad Institute, DNA Script, and later POSTECH. Harvard's Office of Technology Development has filed intellectual property related to the platform. The study is titled "Parallel enzymatic DNA synthesis using a semiconductor chip."

The research was supported in part by the Office of the Director of National Intelligence (ODNI), Intelligence Advanced Research Projects Activity (IARPA), via 2019-19081900002, Horizon Europe, Hyperion project ID: 101115253, and Samsung Research Funding & Incubation Center for Future Technology of Samsung Electronics under Project Number SRFC-IT2402-09.