Gabija, phonetically transliterated as "加比娅" in Chinese, signifies the hearth goddess in Lithuanian mythology, serving as the guardian deity of households.
In the realm of nature, there exists an immune system named after Gabija, which is widespread among prokaryotes, yet has long been shrouded in mystery, eluding human comprehension.
On March 13th, Professor Wang Longfei's team from Wuhan University joined forces with Professor Zhu Bin's team from Huazhong University of Science and Technology to publish a collaborative research paper in Nature, utilizing accelerated preview techniques. Through dissecting the structure of the Gabija system, they comprehensively revealed its mechanism of action against bacteriophages at the molecular level.
"Prior to our research, no one knew how it functioned. By employing techniques such as cryo-electron microscopy, we elucidated its structure in different states, finally unraveling the enigma surrounding the Gabija system," Professor Wang Longfei informed the Chinese Science Bulletin.
Professor Wang Longfei from Wuhan University (left) and Professor Zhu Bin from Huazhong University of Science and Technology (right) together. (Image provided by interviewees)
The "Guardian Goddess" Scissors: Unveiling the Mechanism of Gabija Immune System
Gabija immune system is the third most abundant prokaryotic immune system known in nature. It is widely present in prokaryotes, found in approximately 15% of bacterial and archaeal genomes.
Experts explain that while immune systems are generally complex, Gabija is remarkably simple. Comprising only two genes, GajA and GajB, it efficiently defends against various virulent bacteriophage infections, making it one of the most broad-spectrum, efficient, and concise immune systems in nature.
In 2018, Israeli scholars led by Rotem Sorek published a bioinformatics paper in Science, analyzing thousands of potential prokaryotic immune systems, including the Gabija system named after the Lithuanian mythological guardian goddess. However, the enzymatic functions and antiviral mechanisms of Gabija components remained undisclosed in Sorek's team's article. "We wanted to know how it kills viruses," said Zhu Bin, leading the postdoctoral fellow Cheng Rui in this research since 2018.
By 2021, the working mechanism of GajA was first discovered and verified by the team. After over two years of effort, by 2023, the working mechanism of GajB also came to light.
Gabija acts like "scissors," cutting the virus's DNA. However, the mechanism of this "scissors" is different from other previously discovered ones. "Once the virus enters the bacterium, it autonomously replicates its genome and transcribes RNA (ribonucleic acid), rapidly depleting metabolites like NTP (nucleoside triphosphate). GajA senses the change in NTP and starts using the 'scissors' to kill the virus. The DNA ends cut by GajA can further stimulate GajB, which, in turn, reduces the NTP levels. The two complement each other, forming a positive feedback mechanism," Zhu Bin told China Science Daily.
Discovering "New Things": The Joy and Pain
Unveiling the mystery of the "Guardian Goddess" was a process of facing challenges and climbing heights continuously. In the 2018 bioinformatics paper, the research team predicted the functions and working mechanisms of the Gabija system using computational analysis methods. However, through research, the team found that the activities of these two enzymes were unprecedented and different from the predicted results. "This research is entirely new, no one has done it before, and it's different from the predictions. We're basically starting from scratch," Zhu Bin said.
After Zhu Bin's team revealed the core enzyme function of the Gabija defense system in 2021, the Gabija immune mechanism garnered high attention from scientists in related fields internationally. While the joint team of Wuhan University and Huazhong University of Science and Technology further explored, four international teams had started similar research and began submitting to Nature. "Their paper review progress is faster than ours! This has made our work pace even more intense," Zhu Bin said. This "intensity" is understandable: typically, Nature only accepts one paper on the same topic, making the competition fierce.
A prestigious team from Harvard University submitted a paper to Nature in mid-April 2023. "We were two months behind them, submitting ours in mid-June," Wang Longfei said. The two teams were essentially "back to back" in their submission efforts.
"The first round of revisions came in July 2023, and the reviewers had high demands for our revisions," Wang Longfei recalled. The reviewers believed that the resolution of the activated conformation of the provided DNA was too low, and there were also some incomplete data situations. However, capturing the structure of Gabija bound with DNA was extremely challenging, with only four months for revisions. Could they succeed?
"While cryo-electron microscopy is very powerful, what's more crucial is the biochemical technology for handling samples," Wang Longfei told reporters, emphasizing the importance of sample quality. He further explained, "For us, the sample is like a child; it has its own preferences, like some prefer staying in an air-conditioned room while others like being outdoors in the heat. You have to figure out its preferences to keep the sample stable."
The team members worked day and night on various attempts, feeling disheartened after dozens of failed experiments. The first author of the paper, doctoral student Li Jing, fell ill twice due to the immense pressure during the revision stage. But once recovered, she immediately returned to work to continue the research.
By October 2023, nearing the final deadline for submitting revised results, they were getting closer. One evening, at 10 o'clock, another round of experimental results came out. Due to numerous previous failures, Wang Longfei didn't hold much hope for that experiment. However, during the final reconstruction that night, he unexpectedly found DNA inside.
This meant they had finally succeeded. The next day, after multiple confirmations, Wang Longfei shared the good news with the rest of the team, and everyone was excited.
After enduring many difficulties and hardships, as autumn arrived in Wuhan, they finally reaped the long-awaited rewards. "Among the four papers in the Nature series, only ours contained the structure of complexes with DNA or ATP. Based on these structures, we proposed the working mechanism of the Gabija system," Wang Longfei told China Science Daily.
"For me, the happiest moment is when I see something new," Zhu Bin said. In the face of the excitement and joy of unveiling the true nature of the unknown, the pain of the research process is insignificant.
From Harvard to Wuhan: Collaborative Efforts The collaboration between Wuhan University (武大) and Huazhong University of Science and Technology (华科) began from a friendship that lasted for over a decade.
Back then, both of them were doing postdoctoral research in the Department of Biochemistry and Pharmacology at Harvard Medical School. It was during a season in Boston when the red leaves were falling that Wang Longfei visited Zhu Bin's laboratory to borrow experimental materials. As they conversed, they gradually discovered that they were both Chinese scholars with similar interests and complementary aspirations. From then on, they embarked on several collaborations.
Zhu Bin returned to China earlier due to his wife being from Hubei province, and his own interest in biotechnology led him to join Huazhong University of Science and Technology. Many years later, Wang Longfei also planned to return to China, with many cities as potential destinations. Wuhan University extended a warm invitation, and preliminary intentions were established between the two parties. Over the phone, Zhu Bin suggested his old partner come to Wuhan so they could continue their research together. Ultimately, Wang Longfei joined Wuhan University and arrived in the city. On the second day of his return to Wuhan in 2021, they immediately met and discussed continuing their collaboration, leveraging each other's strengths to discover new insights.
Driven by curiosity and personality, Zhu Bin enjoys exploring niche research topics, delving into the "quirky things" in nature. Since conducting independent research, he has focused on biochemistry and enzymology, discovering many novel and peculiar functions of nucleases. In contrast, Wang Longfei's research area in structural immunology has always been a hot topic, garnering more international attention. He excels in revealing the detailed molecular mechanisms of complex biological systems. Their close and tacit collaboration began during their time at Harvard, where they previously discovered a unique DNA polymerase in underwater volcano viruses.
In their research on Gabija, Zhu Bin's team needed someone to help understand and demonstrate the immune and regulatory mechanisms of the Gabija system. Wang Longfei, who had just returned to Wuhan University, became the ideal partner.
In a restaurant in Wuhan's Optics Valley, Zhu Bin welcomed Wang Longfei, who had just returned to China. When discussing their Gabija research, they immediately hit it off. Both parties agreed that in this research, Wang Longfei's team would be responsible for detailed exploration of complex structure and regulatory mechanisms, while Zhu Bin's team would handle biochemical and enzymatic validations.
The Nobel Prize in Chemistry in 2020 was awarded for research on CRISPR gene editing, which was completed through collaboration between two scientists. Emmanuelle Charpentier, an expert in microbial genetics and biochemistry, and Jennifer Doudna, who excels in revealing molecular mechanisms through structural means, collaborated closely. Privately, Wang Longfei and Zhu Bin both felt that their partnership was similar to that of those two renowned scientists—one focusing on the front end and the other on the back end, working together to achieve results.
"Our collaboration still has great potential, and I believe it will bring even more surprises in the future," Wang Longfei told China Science Daily.
Mutual admiration between two prestigious universities in the same city
Wuhan University and Huazhong University of Science and Technology are two of the most prominent "twin stars" among many universities in Hubei province. While each university has its own strengths in academic disciplines, there is also an element of healthy competition, with professors sometimes silently vying to distinguish themselves. In recent years, there have been many exchanges and interactions between the two universities, but joint publications in top global journals are not very common.
Zhu Bin believes, "In scientific research, cross-unit collaboration is quite normal. Universities in the same city have more convenient communication, so why can't cooperation be closer? At least our collaboration is very smooth. There are no so-called 'taboos' speculated by some people. With fewer barriers, everyone can do research together and produce more results."
"Harvard and MIT are both top universities in the United States, and they often collaborate. Wuhan University and Huazhong University of Science and Technology can certainly do the same," Wang Longfei said. He told China Science Daily that initially, he had some concerns, fearing potential obstacles in collaborating on a "parallel track." However, in reality, they did not encounter any opposition.
Not only did Wuhan University not oppose the collaboration, but they also showed recognition. Wang Longfei cited an example: after the paper on Gabija was published, he and his team drafted a briefing to report to the university. In the initial draft of the briefing, they included Huazhong University of Science and Technology as a jointly completed unit, but did not include it in the title. After submitting the initial draft, Wuhan University quickly announced it, changing the title to: "Wuhan University collaborates with Huazhong University of Science and Technology to publish in Nature, this time on Gabija!" "Although Wuhan University is the first completion unit, they actively highlighted the contributions of Huazhong University of Science and Technology."
Interestingly, on the second day of Wuhan University's announcement, Huazhong University of Science and Technology also posted related news on its official social media platform, with the headline: "Huazhong University of Science and Technology publishes in Nature again! This time collaborating with Wuhan University!"
In the season of cherry blossoms, the two "Double First Class" universities in the same city exchanged calls in this way.
Related article link: https://www.nature.com/articles/s41586-024-07270-x.
