High-throughput methylation non-invasive detection technology: Professor Zhang Wei rewrites cancer early screening

release time：2019-08-05

[Gade Chemical Network Technology Application] This month, an article related to high-throughput methylation non-invasive detection technology in Nature Genetics magazine has received attention from domestic and foreign media. Developed by Professor Zhang Wei and his team at the Department of Bioengineering at the University of California, San Diego (UCSD), this technology not only detects cancer, but also determines where tumors grow in the body, providing a new direction for early diagnosis of cancer. At the heart of this technology is a new combination of tumor ctDNA liquid biopsy and methylation detection, with methylated CpG islands in DNA as specific detection tags. The advent of this article marks a major step forward in liquid biopsy technology. So what is the story behind this technology? What are the difficulties of liquid biopsy technology from scientific research to product transformation? What elements should future entrepreneurs seize? With these questions, Bio-Exploration interviewed Professor Zhang Wei. 1. From the routine to the “Aura of Light”, this “Nature Genetics” is more perfect. Professor Zhang Wei has been engaged in the research of methylated haplotypes for many years. He began to contact the subject of population genetics haplotype analysis when he followed graduate students in Jinli, and he wrote a software in 2003. Published in the journal Bioinformatics, the software is still in use today. In 2007, after Professor Zhang Wei went to UCSD as an assistant professor, he began to work on methylation targeted sequencing. He applied haplotype analysis technology to methylation sequencing data for the first time. In 2010, he published the first article in Genome Research. An article on methylation haplotype analysis. However, due to the limitation of sequencing technology, he analyzed only more than 2000 CpG islands of several cell lines, and the analysis method was limited. Later, he led the team to focus on deeper methylation haplotype analysis, with more sample types and covering the entire genome. It was not until the summer of 2016 that they closed their work and dropped the article. Professor Zhang Wei told the reporter, "In the initial stage of submission, we have been separating the detection of tumor presence and tumor tissue into two parts for analysis. After the article was accepted, we suddenly found the idea of ​​combining the two before the final draft, and found that Together, the sensitivity and specificity of the analysis are higher, which was completely unthinkable. We also suddenly realized that in fact, where the tumor grows, it will compete with the normal cells on the side for nutrition, leading to normal cell death and releasing DNA to In the circulatory system, there is a feeling of 'Eureka moment' in mind." 2, from "not trusted" to breaking through the tradition, rewriting the cancer early screening The advent of this technology is not always smooth. Professor Zhang Wei said, "The biggest difficulty is that the amount of DNA is too small. Because the amount of free DNA in the plasma is relatively small, no one believes in our technology when we start to take patient samples for verification. The people in the sample library are only willing to give us hundreds. Microliters of plasma, the free DNA inside is very pitiful. We had to use a single-cell methylation sequencing method to build a sequencing library with a few nanograms of DNA. The amount of DNA injected was small, and the data coverage was also very high. Low. So we spent nearly two years on data analysis, tried various methods, and finally found a way out, forming our unique patent technology today, and its detection sensitivity is particularly high." High-throughput methylation non-invasive detection technology has significant differences and advantages over traditional liquid biopsy. He said, "Most of the liquid biopsies currently used in clinical practice are based on DNA mutations and cannot provide tissue specificity. We The method is detected by observing the DNA methylation modification. This method can give three kinds of information: Is there a tumor? What is the tumor burden? Where is the tumor? This is the information that is not visible from the DNA mutation. The early screening of tumors is of great significance. In addition, we have used methylated haplotypes in technology, which can break through the limitations of traditional single-point detection methods and have obvious advantages in sensitivity." The follow-up of liquid biopsy for the treatment of tumors has gradually matured. Professor Zhang Wei believes that “the biggest change next is the early screening of high-risk healthy people or general healthy people. Non-invasive positioning of tumors is a very important part of early screening. At present, the method seems to have the highest positioning accuracy. Although it is only a technical prototype, it is believed that after several rounds of optimization and verification, there will be a breakthrough in early screening. Many tumors may be resected at an early stage. Healed. This is the direction of our efforts." 3, from technical prototype to product conversion, hard bones sip The research and development of technology is of an exploratory nature, funded by government research funding, and the results are published in the form of articles. Once the technical prototype is made, it is time to enter the transformation phase. Professor Zhang Wei said, "Transformation is completely different from the early exploration. The difficulty here is far more than the early development of technology prototypes. The development of products is a systematic project, and the requirements for the products to be used in patients are even higher. The technology of the products. The development of stereotypes, clinical validation, and FDA/CFDA approval are all hard bones, and the corresponding professional team needs to take a sip." The technical patent of Professor Zhang Wei’s team has already submitted an application in the United States through UCSD in 2014, and has since expanded the scope of application and granted the exclusive patent to Suiyuan Gene. He told reporters, "Many top investment institutions, including Asia Lilly, have a special recognition of our technical value. We are fully committed to helping us convert technology prototypes into products and complete the clinical validation approval process as soon as possible. The industrialization of scientific research results in universities has been countless successful cases in the United States, and there are more and more successful examples in China. I hope that this project can also be one of the successful cases." 4, future entrepreneurs, to be "higher, faster, cheaper" Whether it is international or domestic, liquid biopsy is very attractive to entrepreneurs. Professor Zhang Wei said, “If future entrepreneurs have new ideas in the aspects of 'higher, faster and cheaper', then there will be huge room for development. High refers to detection sensitivity and specificity. Fast is the detection cycle. Now, from blood draw to seeing results for days or even a week or two, if technology can shorten this process to one or a few hours, then this technology is certainly competitive. Cost is also important, especially when it is early When the direction of the sieve is promoted, only the cost is low enough to benefit most people." Capital has always been a concern of entrepreneurs. So what kind of technology is more likely to get the favor of capital? Professor Zhang Wei said, “First, technology must be excellent and performance should have obvious advantages. Second, technical implementation must Simple, too complex technology is poorly operability, difficult to promote, and the amount of users is not large; third, there must be technical barriers, including the corresponding patents and know-how (technical know-how); fourth, the technical team must Continuous innovation, continuous self-improvement, streamlining processes, improving performance, reducing costs, and developing next-generation technologies." At the end of the interview, Professor Zhang Wei told reporters that "the future trend is to put molecular liquid biopsy technology into routine physical examination."