NEW YORK – BGI is entering new territory as the group’s researchers unveiled their first nanopore sequencer in a preprint this week.

纽约——BGI正在进入一个新领域，该组织的研究人员本周在预印本中发布了他们的第一个纳米孔测序仪。

The Chinese omics conglomerate has granted the global rights to commercialize and distribute the technology to affiliate company MGI Tech, which is staying mum for now about its commercial roadmap.

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Xun Xu, director of BGI Research, a unit of BGI Group, said his organization sees a lot of benefits in developing a nanopore sequencing platform. 'It is also very complementary to the short-read [technology we have],” he said. Xu’s team described its nanopore sequencing technology in a preprint in BioRxiv this week.

华大基因集团旗下华大基因研究所所长徐迅说，他的组织认为开发纳米孔测序平台有很多好处它也是对短读（我们拥有的技术）的补充，”他说。Xu的团队本周在BioRxiv的预印本中描述了其纳米孔测序技术。

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Named CycloneSeq, BGI’s platform is similar in principle to that of Oxford Nanopore Technologies. Both technologies use helicase motor proteins and protein nanopores to read DNA molecules, generating current signals that can be translated into sequences using deep learning models. However, Xu noted that BGI, which has been developing its nanopore technology for a decade, has put its own spin on the protein engineering, chip design, sequencing chemistry, and basecalling algorithm.

BGI的平台名为CycloneSeq，原则上与Oxford Nanopore Technologies的平台相似。这两种技术都使用解旋酶运动蛋白和蛋白质纳米孔来读取DNA分子，产生电流信号，可以使用深度学习模型将其转化为序列。然而，徐指出，十年来一直在开发纳米孔技术的BGI已经在蛋白质工程，芯片设计，测序化学和碱基检出算法方面取得了自己的进展。

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More specifically, Xu said the motor protein and pore deployed in CycloneSeq were evolved from bacterial proteins derived from samples collected in BGI’s previous deep sea expeditions. “We are continuously putting efforts into collecting samples from extreme environments all over the world,” he said, including an expedition to the Mariana Trench in 2021.

更具体地说，徐说，CycloneSeq中部署的运动蛋白和孔是从BGI之前深海探险中收集的样品中提取的细菌蛋白进化而来的。“我们正在不断努力从世界各地的极端环境中采集样本，”他说，其中包括2021年对马里亚纳海沟的考察。

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In their paper, the BGI researchers noted that their motor protein, a helicase that unwinds double-stranded DNA, can achieve a speed of approximately 380 bp per second. Meanwhile, their pore protein can translocate single-stranded DNA and generate currents “with high signal complexity and good signal-to-noise ratio,” according to the preprint..

BGI研究人员在论文中指出，他们的运动蛋白（一种解开双链DNA的解旋酶）可以达到每秒约380 bp的速度。同时，根据预印本，它们的孔蛋白可以转移单链DNA并产生“具有高信号复杂度和良好信噪比”的电流。。

The sensor chip features a high-density microwell array that holds the nanopores. Each microwell and sensor unit is spaced approximately 200 µm apart, and sensor units are arranged in a honeycomb pattern to maximize density and enhance sequencing throughput.

传感器芯片具有高密度微孔阵列，可容纳纳米孔。每个微孔和传感器单元的间距约为200µm，传感器单元以蜂窝状排列，以最大程度地提高密度并提高测序通量。

Moreover, the BGI team designed the microwells to have small diameters, boosting the signal-to-noise ratio and improving sequencing accuracy.

此外，BGI团队设计的微孔直径较小，提高了信噪比，提高了测序精度。

To improve data quality, Xu said BGI developed so-called nanopore local chemistry (NCL) sequencing, where the chemical environment on each side of the nanopore is asymmetric. It involves the controlled release of magnesium ions, which are embedded within the flow cell rather than supplied with the sequencing reagents.

为了提高数据质量，徐说，BGI开发了所谓的纳米孔局部化学（NCL）测序，其中纳米孔两侧的化学环境是不对称的。它涉及镁离子的控制释放，镁离子嵌入流通池中，而不是与测序试剂一起提供。

After applying the transmembrane potential, magnesium ions are translocated through the nanopore, maximizing their concentration near the pore. Together with ATP, the magnesium ions fuel the unwinding and translocation of DNA molecules through the nanopore. .

施加跨膜电位后，镁离子通过纳米孔移位，使其在孔附近的浓度最大化。镁离子与ATP一起促进DNA分子通过纳米孔的解旋和易位。

Lastly, Xu said the team developed a basecalling algorithm trained with deep learning models using unlabeled data, which were then fine-tuned for enhanced accuracy. The CycloneSeq sequencer can also perform sequencing and base calling at the same time, according to the paper.

最后，徐说，该团队开发了一种基本调用算法，该算法使用未标记的数据进行深度学习模型训练，然后对其进行微调以提高准确性。。

According to BGI, when tested with E. coli DNA, CycloneSeq cumulatively generated more than 50 Gb of data with 107 hours of sequencing on a single flow cell. For human genomic DNA, the platform was able to produce long reads with an N50 of 33.6 kb, while achieving a raw read accuracy of 97 percent. .

据BGI称，当用大肠杆菌DNA进行测试时，CycloneSeq在单个流通池上进行107小时的测序，累积产生超过50 Gb的数据。对于人类基因组DNA，该平台能够产生N50为33.6 kb的长读取，同时原始读取准确率达到97%。

“If everything works as it is written in the paper, then it is pretty cool,” said Christopher Vollmers, a professor at the University of California, Santa Cruz and a nanopore sequencing expert. “It would be behind where [Oxford Nanopore] is today by a few years in terms of throughput and accuracy, but it's not way off.”.

加州大学圣克鲁斯分校教授、纳米孔测序专家克里斯托弗·沃尔默斯（ChristopherVollmers）表示：“如果一切都按照论文中的描述进行，那就很酷了。”。“就吞吐量和准确度而言，它将落后于[牛津纳米孔]今天的水平几年，但离它还有很长的路要走。”。

Vollmers pointed out that BGI has not yet made publicly available important information such as sequencing data, raw nanopore signals, as well as the basecalling code and its training dataset, making it impossible for the community to independently verify the technology’s performance. “There is a whole bunch of things missing from this paper,” he said.

Vollmers指出，BGI尚未公开重要信息，例如测序数据，原始纳米孔信号，以及碱基检出代码及其训练数据集，这使得社区无法独立验证该技术的性能。他说：“这篇论文缺少很多东西。”。

“As it stands, this is not a real paper … this would have been a great white paper.”.

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Kin Fai Au, a professor at the University of Michigan and a long-time nanopore sequencing user, said he feels “positive” and “excited” about BGI’s nanopore sequencing technology overall. Still, based on his experience, there tends to be a discrepancy between the advertised metrics from sequencing companies and the technology’s real-world performance.

密歇根大学（University of Michigan）教授、长期纳米孔测序用户金辉（Kin Fai Au）表示，他对BGI的纳米孔测序技术总体上感到“积极”和“兴奋”。不过，根据他的经验，测序公司公布的指标与该技术的实际表现之间往往存在差异。

Therefore, external benchmarking is still necessary to evaluate CycloneSeq’s true performance. “Some of the figures [in the study] are too good for me, but we will wait for the third-party evaluation,” he noted. .

因此，仍然需要外部基准来评估CycloneSeq的真实表现。他指出：“研究中的一些数字对我来说太好了，但我们将等待第三方的评估。”。

BGI did not disclose the format of a commercial nanopore sequencer in its paper. Xu said there will likely be a few platforms developed using the CycloneSeq technology, with one of the first being a “shoebox-sized” instrument that can accommodate two flow cells.

BGI在其论文中没有披露商业纳米孔测序仪的格式。徐说，可能会有一些平台使用CycloneSeq技术开发，其中第一个平台是可以容纳两个流通池的“鞋盒大小”仪器。

According to Xu, BGI Group, formally named BGI Shenzhen, has established a new subsidiary called Hangzhou BGI Xufeng Technology that holds the IP related to CycloneSeq. Earlier this year, BGI Xufeng granted the exclusive rights to commercialize and distribute CycloneSeq globally to BGI Group-affiliate MGI Tech.

据徐介绍，华大基因集团（正式名称为华大基因深圳）成立了一家新的子公司，名为杭州华大基因旭峰科技，拥有CycloneSeq相关的知识产权。今年早些时候，华大基因旭峰将CycloneSeq全球商业化和分销的专有权授予了华大基因集团旗下MGI Tech。

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“By distributing nanopore sequencing products, MGI will be able to provide users with a comprehensive long-read and short-read sequencing tool, not only facilitating the expansion of long-read sequencing equipment for existing customers but also helping to broaden downstream sequencing applications,” an MGI spokesperson said in an email.

MGI发言人在一封电子邮件中表示：“通过分发纳米孔测序产品，MGI将能够为用户提供全面的长读和短读测序工具，不仅有助于为现有客户扩展长读测序设备，而且有助于拓宽下游测序应用。”。

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She declined to answer specific questions regarding CycloneSeq’s commercial roadmap at this time, including its price and availability, noting that the company will disclose its plans for CycloneSeq at an official launch in early September.

她拒绝回答有关CycloneSeq商业路线图的具体问题，包括价格和可用性，并指出该公司将在9月初的正式发布中披露其CycloneSeq计划。

It also remains unclear whether BGI's nanopore patents overlap with those of Oxford Nanopore, which is widely perceived to have a tight grip on nanopore sequencing IP. Both Xu and Oxford Nanopore declined to comment on the subject.

目前还不清楚BGI的纳米孔专利是否与牛津纳米孔专利重叠，牛津纳米孔被广泛认为对纳米孔测序IP有严格的控制。。

Even if CycloneSeq proves its performance, BGI and MGI will likely have much legwork to do to drive the technology’s adoption in the US, especially against the backdrop of a deteriorating US-China relationship and looming legislation that proposes to target both entities’ products and services.

即使CycloneSeq证明了其表现，BGI和MGI也可能要做大量的立法工作来推动该技术在美国的采用，尤其是在美中关系恶化以及即将出台的旨在针对这两个实体的产品和服务的立法的背景下。

“It's cool that it exists, but I'll probably never use it — not because I wouldn't want to, but because I probably won't have the opportunity,” Vollmers said. “That's the truth with the US-China relationship.”

“它的存在很酷，但我可能永远不会使用它-不是因为我不想，而是因为我可能没有机会，”Vollmers说。

“The US may not allow BGI to sell their service or their machines in the country,' Au said. 'In that case, we have no way to utilize this technology.”

Au说：“美国可能不允许BGI在美国销售其服务或机器。在这种情况下，我们无法利用这项技术。”

Even within China, BGI will face domestic competition from the likes of Qitan Tech, a nanopore sequencing startup that purportedly launched a handheld, low-throughput platform in 2021.

即使在中国国内，BGI也将面临来自奇坦科技（Qitan Tech）等国内竞争。奇坦科技是一家纳米孔测序初创公司，据称于2021年推出了一款手持低吞吐量平台。

Some researchers believe the emergence of new players in the nanopore sequencing market, including a platform Roche reportedly has been working on for years, might move Oxford Nanopore to re-assess its commercial strategy.

一些研究人员认为，纳米孔测序市场新参与者的出现，包括据报道罗氏多年来一直在开发的平台，可能会促使牛津纳米孔重新评估其商业策略。

According to Scott Tighe, technical director of the University of Vermont Advanced Genomics Lab, Oxford Nanopore increased instrument prices a lot lately, and 'this might cause them to think twice.” The company 'forces users to buy their instruments bundled with reagents and flow cells,' he said in an email.

佛蒙特大学高级基因组学实验室技术主任斯科特·蒂格（ScottTighe）表示，牛津纳米孔（Oxford Nanopore）最近大幅提高了仪器价格，“这可能会让他们三思而后行。”他在一封电子邮件中说，该公司“强迫用户购买与试剂和流通池捆绑在一起的仪器”。

'This is a terrible, terrible model and is quite upsetting for potential [Oxford Nanopore] users since we often buy instruments separate from consumables.”.

“这是一个非常糟糕的模型，对潜在的（牛津纳米孔）用户来说非常令人不安，因为我们经常购买与耗材分开的仪器。”。

Even so, Tighe does not think BGI, which is “11 years behind in nanopore, and in no position to gain any market share,” will pose a real threat to Oxford Nanopore at this point.

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“I think once they get a peer-reviewed paper out and a few hundred units out to people, maybe in five years we’ll learn more,” Tighe said. “Until then, I don’t think Oxford has any concerns.”

Tighe说：“我认为，一旦他们发表了一篇同行评审的论文，并向人们发布了几百个单元，也许五年后我们会学到更多。”。“在那之前，我不认为牛津有任何担忧。”