Zhongshan Sixth Hospital's Prof. Yu Huichuan on QASM: Pioneering 'From 0 to 1' Innovation and Practical Translation in DNA Methylation Detection

DNA methylation plays a crucial role in biological processes such as the regulation of gene expression, maintenance of chromatin structure, genomic imprinting, and X-chromosome inactivation.

Changes in DNA methylation accompany every stage of biological development and aging. They not only contribute to shaping the characteristics of different species and determining inter-individual differences, but also interact with the surrounding environment, playing a regulatory role in the progression of diseases such as carcinogenesis, inflammatory lesions, and degenerative disorders. Therefore, DNA methylation biomarkers have broad applications across multiple fields, including general health, forensics, human biology, and archaeology.

The team led by Professors Wang Jianping, Luo Yanxin, and Yu Huichuan from the Sixth Affiliated Hospital of Sun Yat-sen University (hereinafter referred to as “the Sixth Affiliated Hospital”) has successfully developed“Third-Generation Technology for Detecting Genomic Methylation Levels at Single-Base Resolution—QASM (Quantitative Analysis of Single-CpG Methylation)”, and was selected for the Chinese Society of Biotechnology’s “2021 First High-Value Patent Project Pool in the Biomedical Field.”

QASM is not only applicable to CpG islands, which are rich in CpG sites within gene promoter regions, but is particularly suitable for the quantitative analysis of DNA methylation in CpG-poor regions. In the broader health sector, this technology can be employed for disease biomarker detection, prenatal diagnosis, infectious disease testing, species identification, the upgrading of existing in vitro diagnostic kits, and basic scientific research.

Seizing the opportunity presented by the 2022 Second Biomedical High-Value Patent Project Selection and the National Conference on Medical-Engineering Integration and New Medical Technologies / Science and Technology Innovation China Industry Matchmaking Meeting, VCBeat Orange Bureau, at the invitation of the conference organizing committee, conducted an interview with Professor Yu Huichuan, the primary inventor of the project.

Five years ago, Professor Yu Huichuan’s team, which has been deeply engaged in DNA methylation research, was carrying out a National 973 Program project to screen and validate methylation biomarkers for early-stage colorectal adenomas and adenocarcinomas.

OASM technology was developed against this backdrop. The detection performance of “first-generation” and “second-generation” methylation-specific PCR technologies (MSP and qMSP) is limited to CpG island regions rich in CpG sites, whereas the “third-generation” QASM technology can detect CpG-poor regions outside of CpG islands.

CpG-poor regions account for more than 99% of the genome, yet the CpG sites within them remain unexploited.Professor Yu Huichuan told us that they generally refer to this region as the “dark matter of the epigenome.”If technologies capable of detecting CpG-poor regions outside CpG islands can be developed, it will enable large-scale screening of additional methylation biomarkers in the population, thereby delivering substantial value and driving significant advancements in the field of disease biomarkers.

Thus, an “adventure” began. This adventure was not only a technical breakthrough in scientific research but also a departure from the research team’s psychological comfort zone.

“Should we undertake such an endeavor?” For a research team with a background in clinical medicine, previous medical projects had progressed very smoothly, even to the point of being routine. Had they followed the well-trodden path of their predecessors, the research would undoubtedly have proceeded without difficulty. However, the prospect of pioneering uncharted territory left everyone feeling somewhat apprehensive.

It is easy to assume that stepping out of one’s comfort zone requires nothing more than a modicum of courage. However, in situations involving choices, this pressure is actually multiplied. When it comes to practical implementation, teams must genuinely engage with novel concepts and technologies they were previously unfamiliar with and had few opportunities to encounter. This entire process not only involves interdisciplinary collaboration across multiple basic sciences and coordination among various stakeholders but also demands the perseverance to maintain long-term focus despite the inherent isolation.

Despite the numerous challenges and difficulties encountered during the project, which required the team to continuously seek solutions, each breakthrough fortunately served as a pleasant surprise, motivating everyone. QASM is ultimately not only applicable to CpG islands in gene promoter regions but also particularly suitable for quantitative DNA methylation analysis of isolated CpG sites in CpG-poor regions. Furthermore, this technique does not require control reactions or methylated standards as references, offering high accuracy while being more cost-effective and rapid.

The QASM technology has gained peer recognition, with research findings published in Clinical Chemistry, a top-tier journal in laboratory medicine. Meanwhile, based on this technology, the team has applied for two domestic invention patents and two international PCT invention patents, one of which has been granted expedited approval.

When introducing the project, Professor Yu Huichuan stated that QASM is an invention derived from the fundamental logic of methylation detection technology; therefore, all fields related to DNA methylation have the potential to become application scenarios for this technology.

The broad application prospects driven by foundational innovation are a key reason for the translational development of this technology. Currently, this technical approach has been applied to the detection of methylation markers in CpG-poor regions of the tumor genome, and has been utilized across eight internationally renowned medical centers—including The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University Cancer Center, the University of Washington, the University of Toronto, and the University of Melbourne—to detect novel DNA methylation tumor biomarkers in cancer specimens.

The current applications of this technology are primarily focused on the field of gastrointestinal tumors, a characteristic closely associated with The Sixth Affiliated Hospital of Sun Yat-sen University, where the research team is based. The hospital hosts one of the largest gastrointestinal tumor diagnosis and treatment centers in China and has led the development of multiple national guidelines, including the “Chinese Guidelines for the Diagnosis and Treatment of Colorectal Cancer” and the “Chinese Guidelines for Screening, Early Diagnosis, and Early Treatment of Colorectal Cancer.”

With the hospital’s support, the project is currently in the stage of translating research outcomes into practical applications. In the field of scientific and technological achievement translation, relatively few outcomes are successfully implemented, and the process is fraught with challenges. After participating in numerous technology transfer activities, Professor Yu Huichuan also shared his candid insights with us:

At times, matchmaking events resemble more of a networking mixer., stakeholders may consider a broader range of factors, such as expanding industry resources. This could be a step toward promoting the commercialization of scientific and technological achievements beyond local boundaries. However, we also hope to see greater participation from key figures involved in frontline R&D. In-depth exchanges between these parties would enable investors and enterprises to gain a more concrete understanding of technology transfer and its prospects.

QASM technology serves as the foundational logic and cornerstone tool with the potential to become the next-generation method for early disease screening, diagnosis, and treatment efficacy monitoring. The project is currently seeking collaborations with biotechnology enterprises both in China and abroad to further refine the technology, expand its applications, and achieve product commercialization.

Furthermore, we also learned thatIn the process of advancing translation, this project continues to generate new results.. For example, building on the development of QASM technology, the research team has constructed a CD8+ MeTIL digital cell classifier that is better aligned with clinical application scenarios. This classifier can accurately quantify the numbers of different T-cell subsets in human tissues or blood through three simple PCR reactions, thereby predicting the sensitivity of tumor patients to immunotherapy. Furthermore, the research team is currently integrating QASM with the latest digital droplet PCR technology.

In recent years, numerous physicians, medical institutions, and universities in China have begun to participate in and promote the translation of medical innovation achievements into practical applications, with corresponding incentive measures and supporting policies continuously being refined.

Professor Yu Huichuan strongly endorses this trend, believing that physicians, as the originators of clinical needs and the executors of clinical applications, have always occupied a central role in medical innovation. By participating in the translation of medical innovations into practical outcomes, physicians can also realize their social and personal value beyond the realms of scientific research and clinical practice.

China’s innovation model in the healthcare sector is gradually shifting from imitating foreign products to developing its own novel medical technologies tailored to domestic needs.

Amidst this wave, and inspired by the experiences of the QASM technology project, Professor Yu Huichuan stated,In future research endeavors, we will continue to make greater efforts to tackle critical bottlenecks in the discipline by starting from fundamental logic and principles, striving for more original breakthroughs from 0 to 1.。

At the end of the interview, we became curious about “How Professor Yu Huichuan, a dedicated researcher, spends his day,” and he kindly satisfied our curiosity:

As a new day begins, he first turns on his computer as usual to check and respond to emails from across China and overseas, typically numbering around 20 to 30. He then arranges or adjusts the day’s research plan according to the progress of his research group. Subsequently, he implements the plan, makes adjustments based on actual circumstances, and continues this cycle of execution and adjustment...

It was not until around midnight, after compiling the day’s results, that the day’s work finally came to an end.

When asked whether scientific research ever feels repetitively tedious, Professor Yu Huichuan paused, as if reviewing his daily routine once more, and then replied: “In fact, each day is different.”