Exclusive Interview with Professor Huang Zhen, Director of the International Selenium Nucleic Acid Innovation Institute: How Close Is the Global First-in-Class Selenium Nucleic Acid Technology to Commercialization?

Although the importance of the element “selenium” is well recognized, its effective application in molecular biology has long been hindered by insufficient technological capabilities. Although selenoproteins could already be expressed and prepared, it was not until more than three decades ago thatWayne Hendrickson, a professor and member of the U.S. National Academy of Sciences at Columbia University, has successfully applied site-specifically selenomethionine-labeled proteins to crystallographic structural biology., thus initiating the application of protein molecular structures involving the element "selenium."

Due to the long-standing belief in the chemical biology community that selenium-containing biological macromolecules, particularly selenium-modified nucleic acid compounds, are unstable and difficult to synthesize, site-specific synthesis of selenium nucleic acids had remained elusive. However, on New Year’s Eve 1999, in an unassuming laboratory at Brooklyn College of the City University of New York, site-specifically selenium-labeled nucleic acids (“selenium nucleic acids”) were successfully synthesized. Most surprisingly, the researcher was not a renowned figure in the field, but rather a scientist from mainland China:He is Zhen Huang, an Assistant Professor at the City University of New York. His independently led laboratory was the first in the world to successfully synthesize nucleic acids with site-specifically incorporated selenium atoms (selenium-modified nucleic acids).

In 1998, at the age of 34, Huang Zhen was appointed as an Assistant Professor at Brooklyn College of the City University of New York. Inspired by Academician Hendrickson’s research on selenoproteins, Huang Zhen, who possessed a profound background in chemical biology, decided to introduce site-specific selenium labeling into nucleic acids, thereby pioneering the field of crystallographic structural biology of selenium-derivatized nucleic acids. By incorporating selenium atoms at specific sites within nucleic acids to obtain selenium-derivatized nucleic acids, Professor Huang Zhen completely resolved a major “century-old challenge” in the crystallographic structural biology of nucleic acids—Challenges in the Accurate and Efficient Design of Derivatives and Phase-Universal Determination.Moreover, he discovered that selenium nucleic acids can also partially address the second "century-old challenge" in the field of nucleic acid crystal structure biology—Challenges in Atomic Modification Design and Crystal GrowthWhat’s even more exciting is that he later discovered the “medical” value of selenium nucleic acids.

In summary, the potential solutions offered by selenium-derivatized nucleic acids to two major challenges in the crystallographic structural biology of nucleic acids have created new opportunities for this field, as well as for drug target identification and novel drug design. However, at that time, systematic and large-scale studies of nucleic acid molecules had only been conducted for two decades, and the incorporation of selenium into these systems presented significant difficulties. Following Professor Huang Zhen’s pioneering work in the field of selenium-derivatized nucleic acids, many renowned researchers in the industry have continuously followed up and attempted further studies, yielding substantial results.

When Professor Huang proposed this research topic, everyone considered it whimsical. Academician Hendrickson had spent decades employing selenoproteins for structural elucidation and investigating their functional properties, whereas systematic and large-scale substitution studies of nucleic acids only began to take off in the 1990s. Introducing selenium atoms into nucleic acids for the purpose of nucleic acid structure determination was...This is at least 100 times more difficult than selenium atom incorporation into proteins and structure determination.

Consequently, Huang Zhen, who was merely an assistant professor at the time, was not highly regarded; the university provided only tens of thousands of US dollars as startup funding for his laboratory. Students also appeared uninterested in this niche area of research, with only a handful of undergraduates applying to join his lab. Nevertheless, he did not abandon his work due to external skepticism; instead, he immersed himself in laboratory research and embarked on studies of selenium-containing nucleic acids.

Chronic funding shortages have long plagued Huang Zhen. To cut costs, he would scour second-hand markets every weekend for usable laboratory equipment. He also hunted for bargains online, where securing items sometimes required winning fierce bidding wars. At the most difficult times, the lab lacked even the funds to purchase chemical reagents, forcing him to cover these expenses out of his own salary.

In 2001, the laboratory was operating at a deficit and faced closure, and the first manuscript on selenium nucleic acid research was rejected multiple times. Nevertheless, Huang Zhen remained undeterred and continued to advance his research.

Finally, a specialized nucleic acid journal decided to give his research on selenium-containing nucleic acids an opportunity for presentation.He was the first internationally to publish on site-specific synthesis of selenonucleotides and the first to propose concepts and methods for using selenonucleic acids to determine phase and structure.Although this paper was published in a small, specialized scientific journal (Nucleosides, Nucleotides, & Nucleic Acids, 2001, vol. 20, issue 9, 1723-1734), the future value and significance of the breakthrough it reported still attracted attention and interest. The publication helped the laboratory at the City University of New York headquarters secure approximately $10,000 in research funding, allowing the study of selenium-containing nucleic acids to continue.

With the publication of his papers, Huang Zhen’s laboratory gradually gained recognition, and its research funding and equipment allocations increased. About a year after the publication of the paper “Site-Specific Synthesis of Selenium-Containing Nucleic Acids,”Professor Huang Zhen published a paper in the premier chemistry journal Journal of the American Chemical Society (2002, vol. 124, No. 1, 24-25) on using selenium nucleic acids to validate nucleic acid structure determination.

Following Professor Huang Zhen’s pioneering development of selenium-labeled nucleic acids on the international stage, a wave of research into this technology swept through the academic community. Multiple laboratories around the world confirmed that selenium-labeled nucleic acids could be used to determine nucleic acid structures and began adopting Professor Huang’s technique. As a result, Professor Huang gained widespread acclaim and becameThe World’s Leading Pioneer in International Innovative Research on Selenium Nucleic Acids.

Over the following 25 years, Professor Huang continued to focus on research into selenium-modified nucleic acids. He discovered that incorporating selenium into nucleic acids significantly accelerated crystal growth, yielding crystals up to a thousand times larger in volume than those obtained by conventional methods. With these large crystals in hand, Professor Huang collaborated with others to perform neutron diffraction and structural determination of the nucleic acid crystals, thereby gaining deep insights into the reaction mechanisms. To date, only three successful cases of neutron diffraction-based structural determination of nucleic acids have been achieved worldwide.Professor Huang has become the pioneer in the efficient and rational design of large nucleic acid crystals.

The most distinctive feature of selenium-modified nucleic acids is that they enable more accurate base pairing and more precise molecular recognition.

The synthesis of selenium-containing nucleic acids is primarily achieved through the selective substitution of oxygen atoms within the nucleic acid structure, enabling site-specific incorporation of selenium atoms. This approach not only preserves the native structure of the nucleic acids but also enhances their functionality and properties. Originally, nucleic acid molecules exhibitHighly negatively charged, susceptible to enzymatic hydrolysis, conformational diversity, heterogeneity of prepared nucleic acid molecules, and the difficulty for nucleic acid molecules to arrange and pack in an ordered manner to form crystalsSuch issues can be largely resolved with the incorporation of “selenium atoms.”

Overall, selenium-modified nucleic acids not only ensure purity and homogeneity and strengthen intramolecular and intermolecular weak interactions, but also improve the speed and quality of ordered packing in molecular crystals. Furthermore, in molecular detection applications, theirThe specific manifestation is the improvement in the accuracy of base pairing and molecular recognition.

Any discussion of diagnostic testing inevitably revolves around the “Central Dogma of Molecular Biology.” This fundamental principle dictates that genetic information flows from DNA to RNA, and then from RNA to protein, thereby completing the processes of transcription and translation. This process is primarily mediated by base pairing. However, in conventional detection methods, nucleic acid molecules often suffer from insufficient recognition accuracy, leading to base mismatches that compromise test results. Selenium-modified nucleic acids, with their high-precision base pairing and enhanced molecular recognition accuracy, effectively address this limitation, thereby improving the accuracy of molecular diagnostics. Furthermore, they demonstrate significantly improved sensitivity and anti-interference capabilities in molecular detection.

Due to the insufficient precision of nucleic acid molecular recognition,The classic Watson-Crick (Nobel laureate) base pairing is referred to as “Stone Age base pairing,” whereas selenium atom-based base pairing represents “Artificial Intelligence (AI) Era base pairing.”

To facilitate understanding, Professor Huang drew an analogy between selenium-containing nucleic acids and the Five Elements theory in traditional Chinese culture: “Nucleic acids actually share similarities with the Five Elements.” Professor Huang compared the five elements found in nucleic acids—nitrogen (N), carbon (C), hydrogen (H), oxygen (O), and phosphorus (P)—to metal, wood, water, fire, and earth in the Five Elements framework. The interactions among these five elements, characterized by mutual generation and restraint, form a stable nucleic acid structure. The introduction of selenium is akin to adding a new element to the Five Elements system, which will bring significant innovative opportunities to nucleic acid research and applications.

During his student years, Professor Huang developed the method and technology for China’s first enzymatic production of sweet dipeptides. However, due to the limited capabilities of the industry at the time and prevailing conceptual constraints, his technology and methods failed to achieve industrialization. Even now, Professor Huang still feels a sense of regret whenever he recalls this experience.Therefore, upon the successful synthesis of selenium nucleic acids, he began to consider how to commercialize selenium nucleic acid technology and bring it to market.

After 25 years of laboratory research, Professor Huang has finally found a practical application for selenium nucleic acids in the market. He stated, “The development of selenium nucleic acid technology holds significant importance for precision diagnostics and drug discovery.” Currently, Professor Huang has applied selenium nucleic acids toHPV Testing, COVID-19 Testing, Brucella TestingandTumor Detectionand other areas, and has developed corresponding commercialized products.

Taking HPV testing as an example, the HPV detection technology developed based on selenium nucleic acid technology not only offers higher accuracy but also features a simpler sampling process. These advantages are all attributable to selenium nucleic acid detection technology.High Sensitivity, Accuracy, and Anti-Interference Capability。

Traditional HPV testing primarily relies on samples collected from the female cervix, a procedure that often causes physical discomfort. To improve the patient experience, researchers have proposed using urine or vaginal secretions for testing. However, due to the low viral load and significant sample interference in urine and vaginal secretions, traditional PCR methods fail to provide simple, effective, and accurate detection. In contrast, selenium nucleic acid technology offers sensitivity nearly 100 times higher than traditional PCR. Its high sensitivity, precision, and strong anti-interference capabilities enable accurate screening and detection of HPV in clinical samples of urine or vaginal secretions.

Under the HPV testing model designed by Professor Huang’s team, women need only provide a sanitary pad worn for 8–12 hours to complete sample collection for HPV testing. This approach is discomfort-free, simple, and rapid, thereby enhancing acceptability among women. Clinical data indicate that its diagnostic accuracy is comparable to that of conventional HPV testing. Professor Huang’s team is currently submitting clinical trial applications for this technology, with the aim of further introducing it to the market and improving the health outcomes of women at large.

The HPV test on the verge of commercialization is merely a microcosm of the application of selenium nucleic acid technology. Professor Huang told Chengguo Bureau:“The fundamental principles of molecular disease detection remain constant, and selenium nucleic acid technology serves as a versatile toolkit capable of addressing nearly all disease testing needs.”

Based on this, Professor Huang’s team will next leverage selenium nucleic acid technology to conduct research on early cancer screening and dynamic monitoring of minimal residual disease (MRD) after tumor resection, further strengthening the clinical application of selenium nucleic acids.

According to Professor Huang, the application of selenium nucleic acids is still in its infancy. It holds great promise for future advancements in point-of-care testing (POCT), innovative drug research and development, and even areas such as gene storage chips and nucleic acid computing. However, all these prospects will be built upon the foundation of rigorous molecular research.

As the world’s leading researcher in selenium nucleic acids, Professor Huang proudly stated, “China is currently at the forefront of global research in this field. However, to maintain our first-mover advantage, funding, talent, and market attention are all indispensable.”

The talents mentioned by Professor Huang refer to those whoMultidisciplinary Talents with Comprehensive Research Backgrounds. Selenonucleic acid research is inherently a technique that employs biochemical methods to address problems in structural biology; therefore, it requires researchers to possess not only a foundation in biological research but also an understanding of chemical research methodologies. Taking Professor Huang as an example, he originally specialized in analytical chemistry at Sichuan University and later obtained a master’s degree in bioorganic chemistry from Peking University, which has enabled him to conduct his research on selenonucleic acids with great proficiency.

In addition, apart from interdisciplinary talents in research, Professor Huang also mentioned“Researchers with an Entrepreneurial Vision”. Only by translating scientific achievements into clinical practice can more people appreciate the advancements in medicine. Therefore, Professor Huang believes that researchers should consider future applications and market trends at the project initiation stage. Only by planning ahead can they better facilitate the industrialization of their projects.

In the final part of the interview, Professor Huang boldly predicted: “With the rising prominence of high-precision molecular recognition, advances in nucleic acid–protein structural biology, drug innovation, and the application of AI technologies, we believe that research and industrialization of selenium-containing nucleic acids will soon reach a peak, and those who seize the first-mover advantage are poised to ride this wave to success.”