The Draft Human Genome Sequence Unveils the Era of Future Precision Medicine.

Let’s begin with the central dogma: genetic information flows from DNA to RNA, and then from RNA to proteins. This process accomplishes the transcription and translation of genetic information, resulting in a corresponding order-of-magnitude increase in informational complexity. From a genetic perspective, humans possess only approximately 20,000 genes; however, through mechanisms such as transcriptional regulation and translational modifications, the informational complexity increases by one to two orders of magnitude. Subsequently, via post-translational modifications and protein–protein interactions, proteins execute their respective functions in biological processes.

Therefore, within the broader context of life processes, genes function more like a blueprint that primarily outlines the probability of future events. In many cases, the detection of genetic mutations and expression levels cannot directly reflect the activity of disease-related proteins or the status of the immune system. Consequently, such data often fail to accurately predict drug efficacy or guide new drug development and clinical medication.

Taking cancer as an example, a patient may carry a mutation in an oncogene; however, it remains uncertain whether this mutation will lead to abnormal proliferation and subsequently result in tumor formation. Therefore, determining whether it will truly cause cancer requires the integration of multifaceted information for comprehensive prediction.

However, at the protein level, whether proteins are expressed and their expression levels often do not align with information from the genomic and transcriptomic levels. Protein modifications play a more critical role in functional regulation, particularly phosphorylation, which often indicates whether a protein is activated and is closely related to tumorigenesis. Protein modifications and activity cannot be detected or predicted at the genetic level. Although studying proteomics involves a vast amount of interaction data compared to genomics, the advantage lies in the fact that once the relationship between key proteins and related diseases is understood, it can be directly applied to clinical practice.

Genomic technologies have created tremendous value over the past decade. Looking ahead, proteomics holds equally broad developmental potential, and the era of proteomics-driven precision oncology is gradually dawning.

Although the functional significance of phosphorylated kinases, which indicate whether representative proteins are activated, has become relatively clear after decades of basic research and their importance is widely recognized, there has been a persistent lack of efficient and stable detection technologies. Jiahua Yaorui Technology (Zhuhai) Co., Ltd. (hereinafter referred to as “Jiahua Yaorui”) employs multiplexed targeted proteomics mass spectrometry to support new drug development and enhance the efficacy of precision medicine.

Jiahua Yaorui is a proteomics company focused on early cancer screening and pharmaceuticals. Its founder and CEO, Dr. Naizhong Zheng, holds a Ph.D. in Cell Biology from Peking University. He conducted research at Peking University for many years, primarily focusing on tumor metastasis, neural development, and gene editing. His papers have been published in journals such as PNAS and Genetics.

In 2015, Zheng Naizhong, as a co-founder of MyGenomics (which has since filed for an IPO on the Hong Kong Stock Exchange), led the company from its inception to establishment. It was during his tenure at MyGenomics, where he delved deeply into the field of genomics, that Zheng observed that many challenges in oncology were being addressed through genomic technologies as the field advanced.

However, most genomic applications primarily detect predictive markers, which do not reflect the actual state of biological activities. This limits genomics to addressing only 20% of the issues, while the majority require the involvement of proteomics technologies to analyze proteomic markers.

A large number of unmet clinical needs urgently require new technologies for resolution.

In 2019, Zheng Naizhong founded Jiahua Yaorui with proteomics at its core, marking a transition from gene sequencing to protein sequencing. Reflecting on this cross-disciplinary entrepreneurial venture, Zheng noted, “In fact, these two technologies share the same origin, both stemming from the work of British biochemist Frederick Sanger. Sanger was awarded the Nobel Prize in Chemistry twice, in 1958 and 1980, for his contributions to protein and DNA sequencing, respectively. Both technologies are of Nobel-caliber significance and have laid the research foundation for the field of precision medicine.”

Not only do their core technologies share the same academic lineage, but Jiahua Yaorui’s key personnel are also all alumni of Peking University.

Professor Li Shuncheng, Chairman and Chief Scientist and the senior disciple of Zheng Naizhong, studied under Professor Tony Pawson (a fellow of the British, American, and Canadian Academies of Sciences, and an eight-time Nobel Prize nominee). Previously, Professor Li’s research group developed and pioneered a method utilizing superbinders specific to protein interaction domains. Since 2006, Professor Li has published more than 50 papers in academic journals such as Nature, Cell, Molecular Cell, Science Signaling, PNAS, and The EMBO Journal. He has also served as the Canada Research Chair in Proteomics and Cancer Mechanisms since 2006.

In May and June 2013, Professor Li Shuncheng published two consecutive articles as the corresponding author in *Molecular Cell*, a subsidiary journal of *Cell*. As of 2020, Dr. Li Shuncheng had published more than 120 articles in high-impact international journals.

In addition, Professor Li Shuncheng serves as the Director of the Biomass Spectrometry Laboratory at the Schulich School of Medicine & Dentistry, Western University, Canada. He pioneered the establishment of the school’s first high-throughput biology laboratory, which is equipped with advanced instrumentation for the research, development, and application of chip technologies, covering peptide synthesis, protein expression and purification, microarray printing, detection, and data analysis. Professor Li’s laboratory employs mass spectrometry to decipher the mechanisms of protein modifications in cancer and to develop super-affinity binders for applications in cancer research, diagnosis, and therapy.

In addition to Zheng Naizhong and Li Shuncheng, Jiahua Yaorui’s partners, including Xiao Yun and Liu Yi, are also alumni of Peking University, each boasting over 15 years of experience in clinical research and the IVD sector. The team members at Jiahua Yaorui have known each other for many years and possess interdisciplinary and cross-industry expertise in both scientific research and industry.

Led by its core team, Jiahua Yaorui has redefined the molecular subtyping of tumors at the protein level, leveraging proteomics technologies and building upon the draft map of the human proteome published in Nature in 2015.Four areas for optimization to make traditional proteomics research methods more suitable for clinical application.

First is the complexity of sample preparation.Conventional proteomics imposes stringent requirements on sample quality, necessitating intact protein tertiary structures for detection; therefore, only fresh-frozen tissue samples can be used. Phosphorylation signals are difficult to detect in other sample types (Phosphoproteomics is the most direct diagnostic approach for tumors.Aberrant phosphorylation modifications can lead to various diseases, including cancer and neurodegenerative disorders. Understanding the process of protein phosphorylation helps elucidate the mechanisms underlying human physiology and pathogenesis, thereby facilitating its translation into drug development and pathological diagnosis.

Secondly, traditional mass spectrometry instruments are complex to operate., low automation and high demands on operators hinder large-scale adoption in hospitals. Typically, prior to mass spectrometry analysis, researchers employ ion-exchange chromatography or affinity capture chromatography, such as metal oxide affinity chromatography, to enrich phosphopeptides from digested proteins. However, these enrichment methods suffer from inherent limitations in intermolecular interactions, leading to steric hindrance and diffusion constraints at the solid-liquid interface.

Furthermore, conventional methods are only suitable for detecting high-abundance proteins., but the abundance of phosphorylated proteins is low, making low-abundance proteins prone to being missed in detection, yet these are often the most promising biomarkers.

Finally, traditional antibody-based methods struggle to achieve high throughput and broad applicability, as enhancing antibody sensitivity and specificity is a challenging process.Antibodies, by recognizing surface antigens of proteins, inherently lead to higher rates of false positives and false negatives. As a biased method, they are difficult to employ as tools in proteomics.

Jiahua Yaorui leverages its patented SH2 Superbinder technology (a tyrosine phosphorylation-modified protein enrichment technique) to enable detection of denatured proteins without relying on their tertiary structure.Testing can be performed on formalin-fixed paraffin-embedded (FFPE) tissue sections, formalin-fixed samples, biopsy samples, and blood samples. Jiahua Yaorui’s antibody-based biased protein enrichment technology effectively enhances sensitivity, specificity, and stability in clinical applications.

By employing tyrosine phosphorylation-based protein enrichment technology, it is possible to directly detect the activation of drug targets for targeted therapies and immunotherapies. This approach provides comprehensive profiling of tyrosine kinase phosphorylation, integrates targeted proteomics analysis strategies, and enables proteomic analysis of trace samples. It accurately determines the activity status of drug target proteins or immune system regulatory proteins, thereby providing valuable information for the precise application of targeted drugs and immunotherapy.

In terms of applications, the current directions for the application of tyrosine phosphorylation-based protein enrichment technologies can be divided into two major fields: pharmaceuticals and clinical practice.

In pharmaceutical applications, leveraging tyrosine phosphorylation-based protein enrichment technology enables the systematic mapping of all tyrosine kinase pathways and immune response signaling pathways, as well as the definition of molecular subtypes of tumors. Furthermore, it facilitates quantitative analysis to elucidate pathogenic mechanisms and causes of drug resistance, thereby identifying novel therapeutic targets and biomarkers.

In clinical applications, phosphoprotein enrichment technology can identify protein targets for targeted therapy and immunotherapy in each patient, guiding personalized medication; it can also track changes at the protein target level associated with drug resistance and recurrence, thereby informing adjustments to treatment regimens.

Jiahua Yaorui’s patented technology enables end-to-end applications, spanning from novel drug target discovery to clinical companion diagnostics.Currently, the core PCT patent has been approved, and the Chinese patent has been granted.

Currently, the primary services offered by Jiahua Yaorui are largely focused on providing CRO services to innovative pharmaceutical companies and collaborating with clinical experts to conduct prospective studies.

Regarding specific development stages, Zheng Naizhong introduced: “Currently, in the clinical direction, Jiahua Yaorui is transitioning from research services to Laboratory Developed Tests (LDTs), a process marked by technological stabilization and gradual scale-up. In the pharmaceutical enterprise sector, bolstered by supportive policies, the development trajectory of innovative drugs in China has become clear. The domestic landscape has evolved from an initial phase of fast-follow strategies to one where innovative pharmaceutical companies are now genuinely willing to pursue novel targets and explore mechanisms that have not been previously studied.”

“These needs cannot be addressed by traditional CROs; therefore, we are actively collaborating with companies such as Thermo Fisher Scientific to leverage proteomics for driving innovation at the source. In the clinical domain, we have established partnerships with dozens of large tertiary Grade A hospitals, including Peking Union Medical College Hospital, to facilitate patient screening for clinical trial enrollment and provide companion diagnostics.”

When discussing future development, Zheng Naizhong stated: “In the current phase of growth, Jiahua Yaorui is collaborating with innovative pharmaceutical companies and clinical experts to help advance the precision of cancer medical care and promote the establishment of industry standards for proteomic mass spectrometry testing.”

“We will also concurrently develop in vitro companion diagnostic (IVD) products on our immunotherapy platform, leveraging continuously accumulated data to accelerate biomarker discovery and the R&D of innovative drugs. Ultimately, the dual strategic initiatives of Jiahua Yaorui will successfully converge, accumulating data on clinical disease targets and extensive drug target information. Once these data streams are integrated, Jiahua Yaorui will leverage this unified data ecosystem to facilitate strategic alignment and connectivity.'Medicine', 'Pharmaceuticals'"These two vast fields have achieved translation based on targeted proteomics."

From research services and pharmaceutical CROs, LDTs, and IVDs to innovative drug development, and from genomics to proteomics, how will Jiahua Yaorui further contribute to the advancement of precision medicine in the future? We wait and see.