A research team at Harvard University has developed a silicon chip capable of synthesizing 64 distinct DNA sequences simultaneously, utilizing a water-based enzymatic approach that promises to make DNA production cleaner and more efficient.
CAMBRIDGE, MA — In a groundbreaking study published in Nature Electronics, a team of researchers from Harvard University has introduced a silicon chip that can synthesize 64 different DNA sequences at once. This innovative technology marks a significant advancement in the field of biotechnology, transitioning silicon chips from their traditional role in computing to a new function in DNA synthesis.
The project was led by Donhee Ham, who holds the John A. and Elizabeth S. Armstrong Professorship of Engineering and Applied Sciences at the John A. Paulson School of Engineering and Applied Sciences (SEAS). The research team has developed a method that utilizes carefully controlled electrical currents to trigger enzymatic DNA building reactions across the chip, thereby eliminating the need for the chemical solvents commonly used in traditional DNA manufacturing processes.
A Cleaner Way to Manufacture DNA
Synthetic DNA plays a crucial role in numerous scientific and medical applications, including diagnostics, genome engineering, and cancer research. Historically, the production of custom DNA has relied on phosphoramidite chemistry, a method known for its ability to produce millions of DNA sequences in parallel but also for its dependence on hazardous organic solvents and centralized facilities.
In contrast, the enzymatic DNA synthesis approach being explored by scientists uses water and mimics the natural process by which living cells construct DNA. This method holds the potential to make DNA synthesis smaller, safer, and more accessible. However, previous enzymatic methods have been limited in their capacity, typically producing only about a dozen sequences simultaneously. The Harvard team’s silicon chip represents a pivotal advancement, achieving the synthesis of 64 unique DNA sequences in parallel, each comprising 39 nucleotides.
How the Silicon Chip Writes DNA
The assembly of DNA occurs one nucleotide at a time, with each added nucleotide temporarily blocked to prevent further growth. To allow the next nucleotide to attach, this blocking group must be removed through deprotection, which is facilitated by acidic conditions (low pH) in water. The Harvard chip innovatively addresses this by lowering the pH selectively at specific locations during each synthesis cycle, controlled by tiny electrical currents.
The chip features 64 individual synthesis sites, each equipped with concentric ring electrodes surrounding anchored DNA molecules. When a specific site is activated, the inner electrode generates protons, lowering the local pH and enabling the DNA strand to grow. Simultaneously, the outer electrode removes protons that spread outward, ensuring that the acidic area is confined to just that single site. By repeating this process across multiple cycles, the chip independently constructs 64 unique DNA sequences on its surface.
From Brain Research to DNA Synthesis
Interestingly, the silicon chip was not originally intended for DNA synthesis. Jeffrey Abbott, a former PhD student in Ham’s laboratory, initially designed the electronics for recording electrical activity within large populations of neurons. Upon redesigning the surface electrodes, the researchers realized that the technology could be adapted to control the chemical conditions necessary for DNA synthesis.
“A defining feature of the chip was precision current injection, which we used to permeabilize neuronal membranes for intracellular access,” said Ham. “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.”
Potential Applications in Data Storage
Beyond its implications for synthetic biology and medical diagnostics, the research team demonstrated the potential of using the synthesized DNA sequences to encode a 169-byte text. Although DNA-based data storage remains an ambitious long-term goal, the researchers believe that the water-based enzymatic synthesis approach could become increasingly viable as demand for DNA production grows. Reducing solvent use could significantly mitigate the environmental impact associated with large-scale DNA manufacturing.
“DNA data storage asks DNA synthesis to operate at a scale far beyond today’s needs,” noted Woo-Bin Jung, co-first author of the study and now an assistant professor at the Pohang University of Science and Technology (POSTECH). “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.”
Identifying Future Challenges
The research team continues to explore how to further scale the technology. They fabricated chips with synthesis sites positioned closer together in hopes of increasing production capacity. While the experiment did not yield the anticipated results, it provided valuable insights. The chip effectively confined low pH to designated areas, but the chemistry involved in deprotection posed a limitation.
According to Han Sae Jung, co-first author of the study and a former graduate student currently engaged in postdoctoral research at Harvard, “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.”
Collaborative Efforts and Future Research
This research was a collaborative effort involving scientists from Harvard, the Broad Institute, DNA Script, and POSTECH. Harvard’s Office of Technology Development has filed for intellectual property rights related to this new platform. The study is titled “Parallel enzymatic DNA synthesis using a semiconductor chip” and was funded, in part, by the Office of the Director of National Intelligence (ODNI), the Intelligence Advanced Research Projects Activity (IARPA), Horizon Europe, and Samsung Research Funding & Incubation Center for Future Technology of Samsung Electronics.
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