Scientific research in the field of life sciences has been "out of the circle" frequently recently. At the end of 2021, a new achievement successfully attracted people's attention - in December 2021, the news of "Southeast University 'writing' its motto into DNA" was crazily swiped on major platforms. This achievement was published in the international journal science advances. Professor Liu Hong's team from the school of Bioscience and medical engineering of Southeast University and the State Key Laboratory of Bioelectronics reported a fully integrated DNA data storage system, which realized the integration of data writing and reading on a single electrode through the synthesis of DNA molecules on the electrode surface and in-situ sequencing, and successfully put the school motto "rest in the highest excellence!" It is stored on the electrode surface in the form of DNA molecules and read out. This is the original "Romance" of engineering.
This "brain opening" research result has laid a foundation for the development of high-throughput integrated automated DNA storage system in the future. With the advent of the era of big data, the global data generation is increasing exponentially, and the data storage system based on DNA molecules is considered to be a feasible solution to the future "data crisis", and it is also a good example for BT to solve it problems.

For the future track of DNA data storage, entrepreneurs with keen sense of smell have long paid attention to its commercial value, and twist Bioscience (NASDAQ: twst), a leader in DNA synthesis, is one of them. DNA based data storage was already part of Twist's plan before its launch in 2018. In November 2020, twist announced that it had formed an alliance with Illumina, a global gene sequencing giant, Western Digital, a leader in data storage industry, and Microsoft to jointly promote the development of DNA data storage and create a comprehensive industry roadmap. In May 2021, twist announced that it had successfully synthesized 200 base pair oligonucleotides on its DNA chip developed for data storage. It is reported that the size of these silicon-based chips is only 1 µ M. Dr. Emily lepraust, CEO and co-founder of the company, said at that time that this is a considerable achievement and the longest DNA synthesized on the smallest silicon-based chip in history. However, the company believes that in order to truly realize commercialization, the size of the chip needs to be reduced to 150nm, so there are still many key technologies to break through.

1.1 # technical platform
Twist's DNA synthesis platform highly miniaturizes the traditional chemical DNA synthesis reaction, reduces the reaction volume by 1 million times, and improves the throughput by 1000 times, so that 9600 genes can be completely synthesized on a single silicon chip; In the same physical space, the traditional synthesis method can only synthesize one gene on a 96 well plate. At the same time, the high-throughput DNA synthesis technology platform greatly reduces the use of reagents. Compared with the traditional oligonucleotide synthesis, the reagent consumption can be reduced by 99.8%, and the synthetic products are almost zero waste in the subsequent assembly process.
The chip is combined with the company's proprietary software system, expandable business infrastructure and e-commerce platform to create an integrated technology platform. Compared with peers, twist significantly reduces the cost of DNA synthesis, ensures the quality and accuracy of synthesis, realizes automation and improves throughput.
Comparison between traditional 96 well plate DNA synthesis (left) and twist bioscience silicon chip DNA synthesis platform (right)
Twist is using its unique technology to manufacture a wide range of products based on synthetic DNA, including synthetic genes, high-throughput sequencing (NGS) preparation tools and antibody libraries for drug development. At the same time, twist is also looking for longer-term opportunities in the digital storage of DNA data and the development of biological products. The company's products have been widely used in health care, industrial chemicals, agriculture, academic research and many other industries.

1.2 existing product line: derived from synthetic biological tools + ngs tools
Twist's existing product line is derived from synthetic biology tools and ngs tools, mainly including synthetic biology products, IgG protein, NGS tools, synthetic virus control and infectious disease research tools, drugs and target discovery solutions.
Synthetic genes can be used in chemical / material, food / agriculture, treatment, diagnosis, product development of data storage and academic research. Synthetic genes mainly include two kinds: one is cloned gene, also known as DNA carrier, with a length of up to 5000 base pairs; The other is a non cloned gene fragment, which can be put into the vector with a length of up to 1800 base pairs, and the error rate is as low as 1:7500 base pairs.
Oligonucleotide pool (or primer pool) can be applied to high-throughput targeted sequencing, CRISPR gene editing, mutation experiment, DNA origami (nano folding of DNA to construct two-dimensional and three-dimensional shapes in nano space), calculation and data storage in DNA, and high-throughput gene detection for studying cell signal pathway, gene regulation and cell regulatory element structure. Twist provides a variety of customized oligonucleotide pools (or primer pools), ranging from hundreds of oligonucleotides to more than 1 million, and can provide oligonucleotides with a length of up to 300 nucleotides, with an error rate of only 1:2000 nucleotides.

IgG protein
Based on twist automatic synthesis platform and antibody discovery expertise, the company launched an IgG protein product for customers focusing on drug discovery and development. In the process of antibody discovery, antibody fragments must be reassembled into complete IgG. Twist can provide IgG in high throughput to eliminate this bottleneck in the process of antibody discovery.
High throughput sequencing (NGS) tool
Twist ngs products are mainly used to diagnose and detect various indications through liquid biopsy, including rare diseases, sars-cov-2 and cancer. It can also be used in population genetics research and biomarker discovery, translational medicine, microbiology and applied market research. This part of customers mainly include diagnostic companies and hospitals, research institutions, agricultural biotechnology companies and consumer genetics companies. In addition, the company can also provide various ngs tools, including library preparation kit, human exome kit, integrated and customized panel, twist high-quality target enrichment alliance panel combination, methylation detection kit for cancer, rare diseases and genetic diseases, and rapid hybridization solution.
Synthetic virus control products and infectious disease research tools

In order to cope with the rapid spread of covid-19, twist launched a new synthetic virus control product line using its DNA synthesis platform, providing the fully synthetic sars-cov-2 RNA reference sequence as a positive control for the development of NGS detection and reverse transcription PCR (RT-PCR) detection products. The sars-cov-2 control developed by twist is now included as a reference on the website of the U.S. Food and drug administration. In addition to SARS-CoV-2, the company provides a wide range of respiratory virus reference products, including influenza, respiratory syncytial virus (RSV), rhinovirus, SARS, MERS and other coronaviruses, providing quality control for the development and validation of diagnostic reagents, thereby avoiding the use of live virus samples by researchers. In addition, there are sars-cov-2 research panel, twist respiratory virus panel and pan virus research panel, which are used to detect pathogens in scientific research scenarios. All products in this part can be used for environmental detection and monitoring. At the same time, it also provides insight into the complete sequence information for monitoring the evolution of virus and the source of virus strain.
Drug and target discovery solutions: accurate DNA library, identification and validation of antibodies for diagnosis and treatment of covid-19
Twist's technology platform can customize the variation of each antibody sequence and systematically build an accurate antibody library to target the whole target region. The company can create single site libraries in which we change a single amino acid within the sequence or single site saturation libraries in which we change every amino acid within the sequence to provide more comprehensive antibody discovery methods, and can also introduce mutations at multiple sites on the same gene according to specific proportions and combinations, To create a combinatorial library. These libraries can be used for antibody engineering, affinity maturation and humanization, so as to simplify downstream screening and identify more lead molecules.
Twist has also developed a comprehensive antibody optimization solution that can optimize multiple characteristics of a given antibody at the same time. Use the software program specially developed by the company to optimize the antibody targeting and make it meet the specified standards of drug development; And expanded the ability of its high-throughput and highly diversified antibody library. At present, the solution is being used by twist to design, construct and test highly diversified and strictly controlled antibody libraries. After screening, only known sequences existing in human DNA are left, which reduces the defects caused by traditional optimization methods, and creates a "Library of Libraries" composed of many different independent libraries. These antibody libraries have natural composition, It is expected to produce better candidate drugs and have a high degree of synthetic diversity. It can optimize the characteristics of a variety of antibodies at the same time, and find antibodies with high affinity and specificity for drug targets.

In 2020, twist launched antibody discovery using its biopharma platform to identify potential research antibodies to diagnose and treat covid-19. Twist later tested several candidate antibodies in live viruses and continued to advance a group of antibodies through preclinical research. In September 2021, covic (Coronavirus immunotherapy alliance, a non-profit cooperative research institution connecting academia and industry) confirmed that the antibody tb202-3 developed in twist completely blocked the binding of sars-cov-2 spike protein to human ACE2 receptor through blind test. The research results were published in the top academic journal Science (DOI: 10.1126 / science. Abh2315). Studies have shown that tb202-3 can be combined with most known mutations, except for l452r mutations in Delta and epsilon variants. In addition, twist has also developed a new nano antibody tb339-031, whose structure and titer are similar to tb202-3, and can bind and neutralize Delta and epsilon variants. At present, it is in the later stage of early drug discovery and verification.
1.3 biopharma: from service provider to preferred partner
Twist biopharma Department of twist bioscience was launched in 2017 to provide end-to-end solutions in the discovery and early development stage of therapeutic biological products. The disease fields include cancer, neuroscience, immunooncology, infectious diseases, dog / cat diseases, etc. the product types include monoclonal antibody, double antibody, nano antibody, ADC, engineered protein, etc. The department makes profits by establishing antibody discovery programs with partners in various ways. In this process, twist biopharma quickly develops high affinity antibodies for one or more targets according to demand. These partnerships typically have three elements:
Twist uses antibodies to discover "Library in Library" and authorizes it to customers.
Twist is responsible for the discovery, validation and optimization of new candidate antibodies for specific targets.
The customer pays the annual technology license fee to twist; And with the completion of the corresponding work, twist will receive the project milestone payment; When the customer's project is promoted and the product is commercialized, twist will receive the development milestone payment. In many cases, twist also receives royalties for products from partnerships.
In addition, for Twist's internal development work, the company screened out several potential targets and determined the antibodies against these targets. The company plans to carry out out out license for these compounds in the later stage of preclinical development, so as to optimize the advance payment income and obtain higher milestone payment and royalties. By giving out licenses to experts in biotechnology product development and commercialization, twist can continue to focus on polishing and upgrading the company's proprietary technology platform. To date, twist has developed antibodies against Adora 2a, glp1r (agonists and antagonists), sars-cov-2, tigit, PD-L1, CXCR4, CD3 and several undisclosed targets.
As of December 31, 2021, twist biopharma has established relationships with 42 partners, with 52 active projects and 39 completed projects, of which 50 include milestone payments or royalties. These partners include Boehringer Ingelheim, Takeda pharmaceutical, adicet bio, Kyowa Kirin, inventx, Neogene therapeutics, etc. In addition, twist biopharma has established cooperation with companies providing complementary technologies to expand the opportunities and scope of the sector.
On November 22, 2021, twist announced that it had reached a final agreement with abveris to acquire abveris for us $190 million. The company is a private in vivo antibody discovery service company, which uses its proprietary diversimab hyperimmune mouse model to provide comprehensive antibody discovery and characterization services, which can be combined with twist's antibody optimization solution to develop high-quality biological products and quickly promote clinical development, Seven antibodies in its assets have entered the stage of clinical development.
1.4 in the era of data explosion, redefine data storage with DNA
At present, the demand for data creation and storage continues to grow exponentially. The industry is seeking to discover new storage technologies to improve the storage capacity by more than 100 times. DNA data storage is an ideal solution to realize high-density, economic, sustainable and energy-saving long-term data storage, so as to realize "cold storage" of massive data. At present, the DNA data storage technology developed by twist has reached the GB storage level, and the integrated DNA data storage chip with a size as small as 1 µ m is used as the proof of concept. In addition, the company is working on designing alpha integrated chips with TB storage level.