A Harvard-led team has demonstrated a silicon chip that synthesizes 64 distinct DNA sequences in parallel using water-based enzymatic chemistry, a breakthrough that could make DNA synthesis smaller, safer, and more accessible than current industrial methods. Published in Nature Electronics, the research represents a significant leap forward for enzymatic DNA synthesis, which has previously managed only about a dozen sequences at a time.

Why Does This Matter for Biology and Medicine?

DNA synthesis underpins modern biology and medicine, from diagnostics to genome engineering to cancer research. Today, most synthetic DNA is manufactured using phosphoramidite chemistry, an established industrial process that can produce millions of sequences in parallel but relies on hazardous organic solvents and centralized manufacturing facilities. The Harvard team's water-based enzymatic approach mimics how living cells naturally build DNA, offering a milder alternative that could eventually support smaller, safer, and more accessible DNA-writing instruments.

The research was led by Donhee Ham, the John A. and Elizabeth S. Armstrong Professor of Engineering and Applied Sciences at Harvard's John A. Paulson School of Engineering and Applied Sciences. The team's demonstration of synthesizing 64 distinct sequences in parallel, each up to 39 nucleotides long, sets a new benchmark for enzymatic synthesis.

How Does the Silicon Chip Actually Synthesize DNA?

The chip's design is elegant and relies on precise electrical control. DNA synthesis proceeds one nucleotide at a time, with each newly added nucleotide carrying a temporary blocking group that prevents further growth. To add the next nucleotide, that blocking group must be removed, a step called deprotection that can be triggered by lowering the pH in water.

The challenge in parallel synthesis is lowering pH only at the sites scheduled to receive the next nucleotide in each cycle. The Harvard chip solves this electrochemically. Each of the 64 synthesis sites on the chip's surface contains two concentric ring electrodes surrounding DNA anchored at the center. At a chosen site, the chip electronics drive current into the inner ring to generate protons, lowering the pH right at the DNA strands for enzymatic elongation. Simultaneously, the chip pulls current from the outer ring to consume diffusing protons, keeping the low-pH zone from spreading outward. In each cycle, the chip switches on this low-pH operation only at the sites due for a nucleotide, cycle by cycle growing 64 distinct DNA sequences.

"A defining feature of the chip was precision current injection, which we used to permeabilize neuronal membranes for intracellular access. 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," said Donhee Ham.

Donhee Ham, John A. and Elizabeth S. Armstrong Professor of Engineering and Applied Sciences, Harvard University

What Are the Practical Applications Beyond DNA Synthesis?

The team's work opens multiple pathways for innovation and real-world use. The 64 sequences synthesized in the study were even used to encode a 169-byte text, illustrating a longer-term possibility: DNA-based data storage. While DNA data storage remains a more distant application because it would require DNA synthesis at enormous scale, the water-based enzymatic route becomes increasingly attractive as the amount of DNA to be written grows, since solvent use and environmental burden become more important.

The research also has implications for portable diagnostic and exploratory tools. The article notes that for long-term space missions or away teams on other worlds, having a compact, reliable, power-efficient device capable of quick protein assays would be invaluable for crew health monitoring, characterizing life support system function, and surveying samples collected during surface expeditions. Such technology would need embedded artificial intelligence capabilities, much like the fictional Star Trek tricorder.

Steps to Scaling Enzymatic DNA Synthesis

• Increase Parallel Synthesis Sites: The team attempted to push the chip further by using more closely spaced synthesis sites on the same silicon chip, though this initial attempt failed, revealing important insights about the chemistry involved.
• Improve Deprotection Chemistry: Through painstaking experiments, researchers traced the limitation not to the electronics but to the deprotection chemistry used in the study, identifying a clear next step for the field.
• Develop Direct Acid-Driven Chemistry: The team concluded that developing a more direct acid-driven deprotection chemistry that can keep pace with the chip's electrical precision is essential for scaling beyond current limitations.

The team's discovery about the deprotection chemistry proved particularly illuminating. At first, the result of attempting denser synthesis was puzzling because the chip was localizing low pH well. Through careful experimentation, the researchers traced the problem not to the electronics but to the deprotection chemistry. Low pH does not directly remove the blocking group from DNA; instead, it generates intermediate molecules that perform deprotection. Those intermediates can drift to neighboring sites, escaping the very confinement that worked so well for the pH itself, and blur the boundary between sites.

"The chip did what we asked it to do: it localized low pH at selected sites. 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," explained Han Sae Jung.

Han Sae Jung, Co-first Author and Postdoctoral Researcher, Harvard University

What's Next for This Technology?

The research was a multi-institution collaboration including Harvard, the Broad Institute, DNA Script, and later Pohang University of Science and Technology (POSTECH). Intellectual property related to the platform has been filed through Harvard's Office of Technology Development. The work was supported in part by the Office of the Director of National Intelligence, the Intelligence Advanced Research Projects Activity, Horizon Europe's Hyperion project, and Samsung Research Funding and Incubation Center for Future Technology.

Woo-Bin Jung, co-first author of the study and now an assistant professor of chemical engineering at POSTECH, emphasized the environmental significance of scaling enzymatic synthesis. "DNA data storage asks DNA synthesis to operate at a scale far beyond today's needs. 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," Jung noted.

The silicon electronic chip itself was originally designed in Ham's lab by Jeffrey Abbott, a former PhD student, for population-scale intracellular neuronal recording. By reworking the surface electrodes, Ham's group has since widened the use of this same electronic backbone, from intracellular recording of thousands of neurons to orchestrating DNA synthesis, demonstrating the versatility of the underlying platform.