Silicon Chip Synthesizes 64 DNA Sequences in Water, Advancing Enzymatic DNA Manufacturing
核心洞察
Harvard (搜索)-led researchers developed a silicon chip that synthesizes 64 distinct DNA sequences in parallel using a water-based enzymatic method, replacing hazardous solvent-heavy phosphoramidite chemistry.
The chip uses precisely controlled electric currents and concentric ring electrodes to localize low-pH zones, enabling site-specific DNA growth at 64 synthesis sites with sequences up to 39 nucleotides.
The technology establishes a new benchmark for parallel enzymatic DNA synthesis, far exceeding previous systems that produced only about a dozen sequences at once.
A Harvard (搜索)-led research team has developed a silicon chip capable of synthesizing 64 different DNA sequences simultaneously using electricity and water, a method that could point toward a cleaner, more accessible future for DNA manufacturing and biotechnology. The work, published in the journal Nature Electronics, replaces the solvent-heavy chemistry commonly used in custom DNA production with a water-based enzymatic approach that more closely mimics how living cells naturally assemble DNA.
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). The project brought together researchers from Harvard (搜索), the Broad Institute (搜索), DNA Script (搜索), and later POSTECH (搜索).
A Water-Based Alternative to Phosphoramidite Chemistry
Synthetic DNA plays a central role in many areas of modern science and medicine, including diagnostics, genome engineering, cancer research, and the development of vaccines and gene therapies. Most synthetic DNA is currently produced through phosphoramidite chemistry, a well-established process that can create millions of sequences in parallel but relies on hazardous organic solvents and is usually carried out in large, centralized facilities.
Enzymatic DNA synthesis offers a gentler alternative. It takes place in water and more closely resembles the way living cells naturally assemble DNA. In the future, this approach could make DNA-writing devices smaller, safer, and easier to use. Until now, however, enzymatic methods have lagged far behind conventional chemistry in the number of DNA sequences they can produce simultaneously, with previous systems creating no more than about a dozen sequences at once.
The Harvard (搜索) team raised that number to 64 distinct sequences, with each one reaching a length of up to 39 nucleotides. The result establishes a new benchmark for parallel enzymatic DNA synthesis.
How the Chip Controls DNA Growth
DNA is built one nucleotide at a time. After each nucleotide is added, a temporary blocking group prevents the strand from continuing to grow. Before the next nucleotide can be attached, that blocking group must be removed in a process known as deprotection. In water, deprotection can be initiated by creating an acidic environment with a low pH.
The difficulty in parallel DNA synthesis is controlling exactly where and when that acidity appears. During each cycle, only the sites that are ready for the next nucleotide should experience a drop in pH. The Harvard (搜索) chip solves this problem using electricity. Its surface contains 64 DNA synthesis sites, each equipped with two concentric ring electrodes surrounding DNA strands fixed at the center.
When a particular site needs to receive a nucleotide, the chip sends current into the inner ring, producing protons and lowering the pH immediately around the DNA strands to allow enzymatic growth to continue. At the same time, the outer ring draws current in the opposite direction and consumes protons that begin to spread away from the site, preventing the acidic region from reaching neighboring DNA strands. By activating different sites during each synthesis cycle, the chip creates a changing pattern of low-pH zones that, over repeated cycles, build 64 separate DNA sequences.
From Recording Neurons to Manufacturing DNA
The silicon chip was originally developed in Ham's laboratory by former PhD student Jeffrey Abbott for large-scale intracellular recording from neurons. Researchers initially used the system to record activity from thousands of neurons and map hundreds of synaptic connections, with later versions capturing tens of thousands of connections.
By redesigning the electrodes on the chip's surface, Ham's team adapted the same electronic foundation for an entirely different purpose: directing 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."
A Possible Route to DNA Data Storage
The technology could eventually have applications in synthetic biology and medical diagnostics. The researchers also demonstrated a more futuristic possibility by using the 64 DNA sequences to encode a 169-byte text, providing a small-scale example of DNA-based data storage, a concept in which digital information is stored within DNA molecules.
DNA storage remains a long-term goal because it would require the production of enormous quantities of DNA. Yet that demand could make water-based enzymatic synthesis especially valuable, as the environmental impact of solvents and other chemical waste becomes a greater concern as the volume of manufactured DNA increases.
"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 (搜索)), 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 Becomes the Next Obstacle
After demonstrating 64-sequence synthesis, the researchers wanted to determine whether the technology could support even more DNA strands packed into a smaller area. They fabricated more closely spaced synthesis sites on the same silicon chip, but the denser design did not work as intended. Although the experiment failed, it revealed one of the study's most important conclusions.
At first, the researchers were confused because the electronics were successfully keeping the low-pH regions confined to the selected sites. Further experiments showed that the problem came from the deprotection chemistry rather than the chip. Low pH does not directly remove the blocking group from the growing DNA strand; instead, the acidic conditions produce intermediate molecules that carry out the deprotection step. Those molecules can drift into nearby synthesis sites, escaping the tightly controlled pH zones and causing reactions to spread beyond their intended boundaries.
"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 (搜索). "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."
The study, "Parallel enzymatic DNA synthesis using a semiconductor chip," was published on 17 June 2026 in Nature Electronics (DOI: 10.1038/s41928-026-01662-9). Harvard (搜索)'s Office of Technology Development has filed intellectual property related to the platform. The research was supported in part by the Office of the Director of National Intelligence (ODNI), Intelligence Advanced Research Projects Activity (IARPA), Horizon Europe, and Samsung Research Funding & Incubation Center for Future Technology of Samsung Electronics.