With the strong rise of bio-economy, three generations of sequencing has brought a new answer to life science, ＂Huaxia Great Health Meeting Room＂
Our reporter (chinatimes.net.cn) Wang Yu reports from Yu Na.
Recently, the first five-year plan of bio-economy in China-the "14 th Five-Year Plan for Bio-economy Development" was released, which indicates that bio-economy has become a brand-new economic form. The Plan points out that it is necessary to carry out cutting-edge biotechnology innovation, accelerate the development of Qualcomm quantitative gene sequencing technology, promote the new generation sequencing technology innovation marked by single molecule sequencing, and explicitly encourage the exploration of the third generation sequencing technology as an effective supplement to seek new solutions for complex gene mutation types beyond the scope of the second generation sequencing.
In fact, the third-generation sequencing is quite popular in recent years, which has attracted the attention of the whole industry, and many enterprises are actively deploying it. At the moment when the second-generation sequencing has become the Red Sea, everyone began to seek answers from the third-generation sequencing. So, how should this road of exploration go?
On the evening of June 8th, Dr. Gao Yang, chairman and general manager of Berry Gene, Wu Yingguang, general manager of PacBio Pacific Biotechnology, Sun Yuanyuan, general manager of Industrial Securities Great Health Research Center and chief researcher of pharmaceutical industry, and Li Gang, partner of Yikai Capital, visited the meeting room of Huaxia Great Health, and discussed frontier topics such as how to seize the beach in the era of bio-economy. The meeting room was presided over by Chen Yanpeng, assistant editor-in-chief of Huaxia Times and director of the Department of Big Health News.
The third generation sequencing has high growth.
Chen Yanpeng:
Third-generation sequencing is the focus of Berry’s gene layout. Berry’s gene is very forward-looking in this field. As early as 2019, it was announced that it had reached a long-term cooperation with PacBio Pacific Biotechnology, a well-known American third-generation sequencing company, on the development and clinical promotion of the third-generation sequencer, and the two sides jointly developed the third-generation sequencing platform. So what do you think, Gao Dong, is the thinking and planning of Berry gene in the layout of three generations of sequencing, and what is the force point of future clinical transformation?
Gao Yang:
We have laid out the field of three generations of gene sequencing, and in fact, we have gone through long-term research. What I want to explain is that the first generation, second generation and third generation sequencing technologies, unlike backwards compatibility in other fields, have their own technical characteristics and complement each other. Berry gene has been engaged in the diagnosis of rare diseases and genetic diseases for a long time. In this process, we found that some genetic diseases can not be effectively solved by first-generation and second-generation sequencing, let alone cost-effectiveness. Therefore, we are determined to bring more diagnostic methods to clinic with the most mature and stable third-generation sequencing technology in the world.
The layout of our third-generation sequencing is actually a state of scientific research first, hardware speeding up and products landing. Third-generation sequencing has developed for a long time in the field of scientific research, and there are a large number of scientific research documents, which have formed a technical demonstration in related fields. The hardware platform developed by Berry Gene and PacBio has entered the clinical trial stage of medical device registration. On the basis of hardware, we developed a genetic detection kit for thalassemia, and now it has entered the clinical trial stage.
We have observed that the acceptance of the third-generation sequencing products in China clinical market is very high. In the future, we will not only develop high-quality products, but also bring more cost-effective products to Chinese. We are confident to do a good job in screening and diagnosing a considerable number of patients with genetic diseases.
Chen Yanpeng:
PacBio Pacific Biotechnology is an advanced supplier of high-quality sequencing. Third-generation sequencing with high fidelity and long reading length has its unique advantages in technology, so in the era of bio-economy, there is a high-dimensional requirement for technological innovation. What do you think is the biggest problem that the third-generation sequencing technology will face?
Wu Yingguang:
The third-generation gene sequencing is very unique. It is very long and accurate. It can not only solve the problem of diagnosis, but also participate in solving the treatment problem (such as gene therapy) in the future.
In 2003, scientists published what was called the complete human genome sequence at that time, but there were about 8% blank regions without sequence data, which mainly included regions with highly repeated DNA fragments and regions with high GC content such as centromeres.
Until April, 2022, nearly 20 years later, Science published six papers in succession, and published the first complete gapless human genome sequence, which filled the missing "jigsaw puzzle" fragments in the past 20 years, mainly due to the great development of three-generation sequencing technology.
The third-generation sequencing technology has also greatly improved the ability of gene detection technology to solve clinical problems. Taking the diagnosis of rare diseases as an example, the conventional second-generation sequencing technology can only explain the pathogenesis of about 33% of rare diseases. The cooperation between PacBio and Children’s Hospital Mercy in the United States reveals that PacBio’s HiFi sequencing is expected to increase this percentage to 67% because of its excellent performance in SNV, Indel, SV and methylation.
Chen Yanpeng:
It is said that only by embracing the trend can we catch up with the trend. As a researcher in the secondary market, Mr. Sun, what do you think of the development trend and characteristics of the overall market of third-generation sequencing in the bio-economic era?
Sun Yuanyuan:
Our investment field is really concerned about the third-generation gene sequencing, and more capital will flood into this track in the future. From the perspective of the secondary market, I think the sequencing plate has strong growth and is a track with long slopes and thick snow. The growth of this track mainly comes from two points. First, it has a broad border, which determines that it has a long-term development space; Secondly, it belongs to intensive innovation, which determines that it has high growth and rich formats. In the future, a large number of sequencing projects will flood into the primary market, and then this track will get higher attention and financial support.
At present, human beings have extended the capability boundary of sequencing from the field of nucleic acid to the field of protein. From the perspective of technological innovation, as a new subdivision of sequencing, single-molecule sequencing has stronger technological innovation and faster technical iteration speed, and the downstream attention in this field is also very high. In the future, it will be promising in the growth track of sequencing.
Globally, the size of the third-generation sequencing market has reached 20 billion US dollars. Moreover, the penetration rate of the third-generation sequencer is only about 10% at present, and we think that the penetration rate will be further improved in the future. In the next few years, the global sequencing industry will maintain an average annual growth rate of 20%. The third-generation gene sequencing product of Berry Gene and PacBio Pacific Biotechnology is a good case of clinical transformation.
Chen Yanpeng:
At present, the third-generation gene sequencing is hot, and there will be more and more investment mergers and acquisitions on the third-generation sequencing in the market in the future. From a professional point of view, Mr. Li, as an investor, how do you think we should judge a high-quality third-generation sequencing enterprise target?
Li Gang:
I have been exposed to gene sequencing for quite a long time. I think that the first, second and third generation sequencing is not like a notebook chip. When a new generation comes out, it will completely iterate over the previous generation.
In fact, there are still many first-generation sequencing in clinical applications. For example, the first generation sequencing process is meticulous, there are many quality control links, it is not easy to be polluted, and the sequencing results are also very intuitive. If there is any doubt about the second-generation sequencing results, it will often be compared with the first-generation sequencing results. First-generation sequencing is still the gold standard in some scenarios. However, the first generation sequencing has a very big problem, that is, it takes a long time and costs a lot. Therefore, the second generation sequencing gradually rose. The second-generation gene sequencing technology has gradually entered the public’s field of vision. The second-generation gene sequencing technology is represented by Roche’s 454 technology, Illumina’s Solexa, Hiseq technology and ABI’s SOLiD technology. The second generation sequencing method firstly cuts DNA into small fragments randomly, and then connects adapter at both ends of these small fragments to make a DNA sequencing library.
The difference with the first-generation sequencer is that the second-generation sequencer adopts the synthetic sequencing method, that is, sequencing while synthesizing. While continuously extending primers by polymerase or ligase to obtain template sequences, the results of each round of reactions are collected and analyzed by fluorescence images, and finally the sequencing results of the whole sequence are obtained. The test speed is fast, the cost is low, and the high accuracy is maintained. Of course, the second-generation sequencer also has its shortcomings. Because of its technical route of cutting DNA into small fragments and amplifying it, the reading length of sequencing is short, and it will also bring various errors to sequencing during the amplification process.
The third generation sequencing technology refers to single molecule sequencing technology. When sequencing DNA, there is no need for PCR amplification, and each DNA molecule is sequenced separately. The third generation sequencing technology is also called de novo sequencing technology, that is, single molecule real-time DNA sequencing. The principle of the third generation sequencing technology is mainly divided into two technical camps:
The first camp is single molecule fluorescence sequencing, and the representative technologies are SMS technology of Helicos in the United States and SMRT technology of Pacific Bioscience in the United States.
The second camp is nanopore sequencing, and the representative company is Oxford nanopore company.
The research and development of third-generation sequencing needs a lot of financial support. I have made statistics. From 2019 to today, in more than three years, there have been about 24 cases of financing above designated size, with a total amount of about 12 billion yuan. Therefore, in terms of amount and quantity, the field of third-generation gene sequencing has grown very fast in the past three years.
Speed up the localization of sequencer
Chen Yanpeng:
We see that Berry Gene and PacBio are jointly developing three generations of desktop sequencers. At present, the topic of localization of sequencers is highly concerned. Gao Dong, how do you think to further speed up the localization of sequencers in the era of bio-economy?
Gao Yang:
Since localization is mentioned, I think the premise is to fully understand the China market.
In January of this year, we started to jointly develop three generations of desktop sequencer with PacBio. Why do you want to do this? Because the clinical market in China is multi-level, we should use hardware and appropriate kits to meet the multi-level needs. After investigation, we have come to a conclusion: the vast clinical market only needs sequencers to meet certain fixed applications. For example, the third-generation sequencer is mainly aimed at the variation of complex structure in clinic, which requires little sequencing quantity, but higher sequencing quality and intuitive data interpretation. In addition, the diagnostic ability of China hospitals for genetic diseases is still improving, and there is a great demand for desktop sequencers. When the third-generation desktop sequencer is successfully developed, it will be the first to be listed in China market in the form of localization.
To promote the localization process, this field is relatively new from the strategy of Berry Gene, and we are at the forefront in clinical transformation all over the world. We choose the best technical partners to locate and develop hardware platforms and kits suitable for China market. Only by meeting the clinical needs of China, the efforts to upgrade localization will be rewarded. Once the demand is met, the growth rate of the third-generation gene sequencing market at the clinical level will far exceed the scientific research level. I hope that in the future, in the field of third-generation sequencing, we can become a pioneer of technology, a promoter of the market, the backbone of hardware localization, and a bridge between clinic and patients.
Chen Yanpeng:
From the perspective of technology and application, Mr. Wu, what do you think will be the future direction of the third-generation sequencer, such as whether small and beautiful will become a big trend?
Wu Yingguang:
Clinical practice shows that the third generation sequencing can provide a higher health economic result. Take the third-generation thalassemia gene detection promoted by Berry Gene as an example. This is the first detection product based on the clinical application of third-generation sequencing technology in China. So far, our clinical tests show that the detection rate is almost 100%, and there are many mutations that cannot be detected in the first or second generation, all of which are detected by third-generation sequencing.
The second generation and the third generation are not a complete iterative or substitution process. I don’t think the technology of the third generation will stay in the small and beautiful stage, because it can really provide more answers and provide higher health and economic value, and it is bound to be applied in the mainstream.
Chen Yanpeng:
Because of its characteristics, third-generation sequencing is regarded as a new key to open the door. So in your opinion, what kind of "catfish effect" will the third-generation sequencing bring to the whole industry?
Sun Yuanyuan:
At present, the "catfish effect" can be seen. In the global sequencing market of nearly $20 billion, the downstream is developing faster than the upstream. According to the latest data, the downstream accounts for about 70% of the market. In the downstream market, the market growth rate of the clinical end is higher than that of the scientific research end, and the application scenarios of sequencing downstream are very diverse. In addition to being familiar with reproductive health, there are tumors, rare diseases and metabolic immunity in the clinical end. One of the characteristics of the third generation sequencing is that it has a good matching degree with many subdivision fields. In the future, the penetration of third-generation sequencing in the downstream segmentation field is worth looking forward to.
Chen Yanpeng:
In recent years, the market popularity of third-generation sequencing is getting higher and higher, and the industry also needs rapid, healthy and orderly development. What suggestions do you have for the policy level, Mr. Li?
Li Gang:
As far as regulatory policies are concerned, I think we should give these innovative enterprises with scientific and technological attributes a more relaxed environment. On the basis of strict standards for clinical trials of enterprises, enterprises should be given certain support in terms of technology, policy and even capital and listing.
Let the technology be applied to clinic faster.
Chen Yanpeng:
With the rapid development of third-generation sequencing and the continuous expansion of market scale, what roles do you think your enterprises play in this process?
Gao Yang:
In the field of third-generation gene sequencing, at present, it is a trend to transform from scientific research to clinical practice. Berry Gene is an enterprise that has been transformed and laid out in the clinical application of this gene sequencing field for a long time. We very much hope to seize and even lead the third generation of gene sequencing.
In this wave of clinical transformation, we hope to become the pioneer of third-generation sequencing technology, the promoter of the market and the backbone of hardware localization. We very much hope to develop a large number of products suitable for gene diagnosis and gene screening in China market by using the technology platform of third-generation gene sequencing. Berry Gene should play the role of a technical bridge between clinic and patients.
Wu Yingguang:
Since PacBio introduced high-fidelity sequencing technology in 2019, our business center has gradually shifted from traditional pure scientific research, especially in the field of animals and plants, to the field of human medical health. In my opinion, PacBio still has many very valuable things to do. First, at present, a considerable number of reference sets or various data and models of the human genome are basically based on ngs second-generation sequencing. With the establishment of a complete human reference genome, there are now many updates called pan-genomes, which we call disease-related databases, which will make our downstream clinical applications more accurate. Secondly, I think I can participate more in the clinical research of human genes and the health diagnosis industry, and deeply cooperate with Berry Gene, which can make the technology applied to clinic more quickly.
Sun Yuanyuan:
From the perspective of secondary market investment and research, our mission is to explore high-quality enterprises, grow together with excellent enterprises, and match the market valuation and enterprise value of enterprises.
At present, we also have a very strong team, our team now has 20 people, and the doctors in the team are also studying related sequencing majors in the United States. Third-generation sequencing is the long-term focus of our team. In the future, we also hope to serve as a bridge between enterprises and markets, so that more secondary investors can understand the potential and value of third-generation sequencing.
Li Gang:
As a bridge between capital and industrial enterprises, our investment bank has the largest medical and health team in China, with more than 70 people, all of whom focus on the medical and health field. Most people have professional backgrounds such as biology and medicine. Therefore, we hope that with the help of our familiarity with capital, industry and technology, we can effectively allocate capital and capital, and then these companies with promising technologies and development potential will develop and grow as soon as possible, providing more new medical technologies and treatments for patients in China and even around the world.
Sun Yuanyuan:
We pay more attention to the third generation sequencing, and the downstream application scenarios are assumed to be sorted. What do you think will be the next scenario?
Gao Yang:
Third-generation sequencing is first taken out to solve the screening and diagnosis of some relatively clear genetic diseases downstream. In the future clinical scene, we very much hope to achieve the screening of whole gene diseases and the diagnosis of unknown diseases.
Wu Yingguang:
In addition to the diagnosis discussed, I think the third-generation sequencing has a considerable prospect in the next treatment, especially in the field of gene therapy.
Chen Yanpeng:
Can you describe the future of the third generation sequencing technology in your mind in one sentence? What is your greatest expectation for it?
Gao Yang:
Third-generation gene sequencing has opened a brand-new door for our gene industry. I am very much looking forward to bringing some new ideas, new methods and new answers to practitioners in the whole industry.
Wu Yingguang:
Because the third generation sequencing is a typical single molecule real-time sequencing, its speed is actually very fast, and we hope to make further breakthroughs in this field.
Sun Yuanyuan:
I hope that the third generation sequencing can do what the second generation can’t do in the future and open up a pure incremental market.
Li Gang:
I expect the third generation sequencing technology and platform to be more accurate, faster and cheaper.
Editor in Charge: Guo Yilin Editor in Chief: Chen Yanpeng