In 2020, as scientists around the world were racing to understand COVID-19, Prof. Roy Bar-Ziv and his team at the Weizmann Institute of Science started developing a DNA chip that could not only quickly show how our immune system responds to this coronavirus but open new possibilities for swiftly responding to future viral outbreaks.
The genetically programmed, cell-free biochip, described recently in Nature Nanotechnology, can rapidly synthesize, map and test proteins, making it possible to determine how antibodies interact with viruses. It delivers data faster than conventional methods and reveals which viral fragments antibodies target and how strongly they bind to these fragments.
“During the pandemic, we realized that tools developed by our lab could be repurposed for exploring viruses and become immediately relevant,” says Bar-Ziv.
“”If a new outbreak emerges tomorrow, we could take that virus’s genetic sequence, make its proteins on the chip and test antibodies immediately”
Studying how the immune system reacts to a virus is a more complex task than a quick diagnostic test revealing whether a person is infected with that virus or not. To understand which antibodies recognize a virus and how strongly they bind to it, researchers must usually produce each viral protein separately, purify it and then test it against antibodies – a process that can take days or even weeks. Some labs use miniature fluid channels that speed up the testing, but these setups are complex and rely on precise pumps and tubing.
The biochip created by Bar-Ziv’s team offers a much simpler way to perform the testing. The method requires no pumps or tubes and can be quickly adapted for a new virus. Its development was led by Senior Staff Scientist Dr. Shirley Daube, along with Drs. Aurore Dupin and Ohad Vonshak, from Bar-Ziv’s lab in Weizmann’s Chemical and Biological Physics Department.
Use of the biochip requires no ready-made proteins; instead they are synthesized by the chip directly on its own silicon surface. Each section on the chip contains a small patch of printed DNA that carries the genetic instructions for a specific viral protein or protein fragment, such as those belonging to several variants of the coronavirus, including the various versions of its outer spike and inner shell. When the researchers add a cell-free mix of the biological molecules typically found inside cells, that DNA is translated directly into the corresponding protein.
Each biochip can produce 30 to 40 viral proteins or fragments. It uses about one microliter of serum – less than a drop – to reveal an individual’s immune fingerprint across dozens of viral targets, or antigens. Since each antigen appears at a different position on the chip, the team can separately measure how much antibody binds to each one.
“We don’t need to grow or purify anything in advance – each spot on the chip makes its own protein or protein fragment,” says Dupin. “With dozens of these antigens on the same chip, we can test many of them at once, in a single experiment, instead of running separate tests for each one.”
From the interactions between these proteins and antibodies, researchers can determine the binding strength, or affinity – meaning, how firmly an antibody grips its target. Stronger binding typically means a more effective immune defense. “Measuring how strongly each antibody binds to its target gives us quantifiable results instead of just a yes-or-no answer,” explains Vonshak.
The team compared their biochip data with standard ELISA (enzyme-linked immunosorbent assay) results on human serum samples. They found that their chip often detected antibody activity that standard ELISA tests missed, suggesting that traditional assays can sometimes omit subtler antibody reactions.
The team used this setup to test interactions between COVID-19 proteins and human antibodies against the virus. “From person to person, we saw very unique immune signatures,” says Bar-Ziv. “Some people had antibodies against the original Wuhan variant but not against the Delta or Omicron variants. Since the chip helps us understand in-depth different people’s responses to the virus, we can also tell if changes in a new variant might make their antibodies less effective.”
Looking ahead, this same approach can be used to study antibodies to other viruses or to develop new therapeutics. “Many medicines today are based on antibodies,” explains Daube. “If one binds perfectly to the virus, it can block infection. Our system could be used to find those candidates faster.”
To demonstrate the chip’s potential, the team recreated the interaction between the coronavirus spike protein and its human receptor, ACE2 – the step that allows the virus to enter human cells. Both the spike protein and the receptor were produced on the chip and bound specifically to one another. This suggests that the platform could be used to screen potential therapies directly on the chip by adding antibodies or other drug candidates that would block that binding. If the signal weakens, it would mean that the antibody was preventing the virus from attaching to the receptor.
“Our chip opens the door to testing how viruses interact with human receptors – and how we might block those interactions with new treatments,” Bar-Ziv says.
The team is currently starting a collaboration with Sheba Medical Center to track immune responses in COVID-19 patients over time using the new chip. By linking antibody data to patient histories, they hope to identify immunity patterns that could guide the development of future vaccines.
Artificial intelligence is the next step. “We can use the chip to analyze antibody sequences designed on a computer and test their properties with a very short turnaround time,” says Bar-Ziv. “The chip can make the AI design process faster and more precise.”
Bar-Ziv envisions a future in which this tool enables a real-time pandemic response. “If a new outbreak emerges tomorrow, we could take that virus’s genetic sequence, make its proteins on the chip and test antibodies immediately. It’s an incredibly powerful tool for preparedness.”