A new DNA chip from the Weizmann Institute of Science produces dozens of viral antigens on silicon in a single experiment and rapidly maps the immune “fingerprint” of subjects – a tool that could accelerate the development of tests, vaccines, drugs and engineered antibodies with the help of artificial intelligence.
In 2020, as scientists around the world raced to decipher the coronavirus, in Prof. Roy Bar-Ziv The Weizmann Institute of Science has begun developing a new biological chip that could pave the way for faster response to future pandemics. The DNA chip the researchers created is capable of mapping our immune system's response to new viral threats much faster than existing technologies, and could thus aid in the development of tests, vaccines, and drugs that could curb the outbreak of new viruses. "During the pandemic, we realized that the tools we developed in the virus research laboratory could be converted to deal with pandemics, and in a short time, we made them relevant for dealing with pandemics," says Prof. Bar-Ziv about the findings Published this week in the scientific journal Nature Nanotechnology.
Until now, to understand which antibodies in the body recognize a particular virus and to what extent they bind to its various segments, researchers have usually had to first produce each of the virus's proteins in the lab, separate them, expose each to human antibodies, and observe what happens—a process that can take days or even weeks. To speed up the process, some labs are using a microfluidic chip that requires complex and precise operation of pumps and tubes.
The new biochip, on the other hand, developed under the leadership of senior faculty scientist Dr. Shirley Dauba, Dr. Aurora Dupin, and Dr. Ohad Wanshak from Prof. Bar-Ziv's lab, offers a much simpler approach. Instead of pre-producing each of the proteins or requiring a complex operating system, the new chip produces all of the proteins directly on its silicon surface – with each cell printed on its surface with a DNA segment that contains the instructions for creating a specific viral protein or part of it. To produce the proteins, the new chip does not require living cells; all the scientists need to do is add a mixture of biological molecules necessary for the translation process of the genetic instructions already printed on it.
"Each chip is capable of producing 30-40 protein fragments called viral antigens in a single experiment," explains Dr. Dupin. "When you add about one microliter of blood serum from a subject, less than a drop, it can reveal how the immune system responds to each of these antigens - that is, recreate the subject's unique immune fingerprint. Because each antigen appears in a different location on the chip, it can be measured separately how many antibodies have bound to it, and there is no need to run dozens of separate experiments to recreate the same fingerprint."
The chip is used not only to determine whether or not the antibodies bind to each viral antigen, but also how strongly they bind to them. "This provides us with a quantitative measure of the degree of immune protection of a subject, rather than just knowing whether or not they have antibodies that bind to a particular virus," explains Dr. Wanshak.
The scientists compared the performance of the new chip to the traditional ELISA test, which detects an antigen-antibody response, using blood serum samples from people who had COVID-19 and developed antibodies. They found that the new chip sometimes detects more subtle antibody responses that the traditional test misses. "The immune fingerprints of different people who were infected with the coronavirus turned out to be unique," adds Prof. Bar-Ziv. "For example, some people developed antibodies against the original strain of the virus that originated in Wuhan province, but not against the Delta and Omicron strains. The chip allows us to understand in depth the response of a human subject to the virus, and thus it is possible to predict what changes the virus may undergo that will make the antibodies present in each subject more or less effective."
Looking to the future, this approach could be used not only to deal with known viruses, but also to study antibodies against new viruses and develop effective treatments against them. "A significant portion of current drugs are based on antibodies," explains Dr. Dauba. "For example, if we find an antibody that binds perfectly to a new virus, we can block the infection and curb a potential pandemic. The chip could help us identify antibodies that could be used as a drug very quickly."
To demonstrate the chip's potential, the researchers recreated the reaction between the coronavirus envelope protein and the human ACE2 receptor – the one that allows the virus to enter human cells. The scientists labeled the viral protein and the human receptor with fluorescent markers, caused them to form on the chip, and observed how they specifically bind to each other. "This demonstration of purpose suggests that in the future the chip could be used to search for antibodies or other molecules that block the binding of a virus to its target in the human body," says Prof. Bar-Ziv. "If, upon introducing such an experimental treatment, the fluorescent signal on the chip weakens, this would indicate that the treatment is successfully preventing the virus from binding to the human protein. In doing so, the chip paves the way for learning about the relationships between viruses and human receptors and how the virus can be blocked from entering human cells."
The research group is currently collaborating with Sheba Medical Center to use the chip to track changes in the immune response of people who have contracted COVID-19 over time. By combining this tracking with information about the patients' medical histories, the scientists hope to identify which factors in people's medical histories shape their immune response to the virus, thereby enabling the development of better, more tailored vaccines for different populations in the future.
The next step will be to also harness artificial intelligence models. "We can use the chip to characterize artificial antibodies designed by computer models and test their binding efficiency to the target," says Prof. Bar-Ziv. "The chip makes the process of developing engineered antibodies with the help of artificial intelligence faster and more precise."
Prof. Bar-Ziv sees a future in which the new chip will enable real-time response to epidemics. "If a new epidemic breaks out tomorrow," he says, "we can take the genetic sequence of the new virus, produce its proteins on the chip, and test for antibodies immediately. This is a powerful tool in preparing for a future outbreak."
Also participating in the study were Dr. Valerie Nir, Maya Levanon, Dr. Noa Avidan, Dr. Yiftach Divon, and Steve Peleg from the Department of Chemical and Biological Physics at the Institute; and Seth Thompson and Prof. Vincent Noyarou from the University of Minnesota, USA.
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