Antibody therapeutics have tremendous research and clinical value having the potential to combat different diseases such as cancers, HIV, autoimmune, hereditary, and more. The technologies used to discover these antibody-based drug candidates have transformed the way we use biology in both academia and labs globally. Antibody discovery requires biologics developers to rapidly generate, build and screen large numbers of candidate antibodies to maximize workflow efficiency and innovation. Scientists have more pressure than ever to simultaneously meet quality, throughput, and timeline pressures. Antibody discovery programs now require increasing levels of biological diversity in terms of the species and cell types that are screened for therapeutics against harder-to-hit targets, such as GPCRs and ion channels. High-throughput screening methods that analyze multiple antibody candidates quickly and effectively are critical to a successful discovery campaign. Emerging technologies, enhanced methodologies, and higher efficiencies are all required to support demanding development projects.

Antibody Discovery Advancements

Single-cell Characterization Platforms

Shortly after the development of next-generation sequencing, researchers began exploring the possibility of sequencing individual cells. For the first time, endogenous pairing of heavy and light chain variable sequences in a given B-cell repertoire became possible. Advances in microfluidic handling technology rapidly led to the development of optofluidic platforms capable of profiling single cells with relevant phenotypic, genotypic, and imaging information.

The impact of this development on the field cannot be overstated. In fact, the central role that single-cell analysis platforms, such as 10X Genomics Chromium or Berkeley Lights Beacon instruments, have come to play in current antibody development can trace a direct line back to these developments.

Genetically Engineered Hyperimmune Mouse Models

Transgenic humanized mice strains have been developed which can produce chimeric human-mouse monoclonal antibodies comprised of fully human Fab regions and mouse Fc regions. These animals can deliver robust and diverse immune responses, significantly improving the efficiency in which lead candidate antibodies can be obtained that meet difficult target specificity profiles.

High-throughput Biophysical Characterization Platforms

Advances in liquid handling automation have ushered in a new era of high-throughput lead candidate antibody characterization. Essential kinetic and affinity analysis, epitope binning, titer and concentration assessments can all be completed at a scale and pace that meets the challenging demands of current antibody development timelines.

Discovery Workflow Synergy

Thanks to these new tools, a high-throughput workflow has emerged which addresses the increased pressure on discovery pipelines to identify and validate high quality lead candidates for new therapeutics. Antibody discovery programs can now rapidly generate large numbers of lead candidate antibodies directed against complex membrane-bound targets by leveraging transgenic humanized mice. Paired heavy and light chain variable sequences from murine B cell repertoires can then be readily characterized and sequenced. Further downstream in this new workflow, bulk kinetic and binding analyses of expressed antibodies can be rapidly accomplished.

Break through to a new pace of discovery

To achieve high throughput required to meet development timelines, antibody discovery labs now must grapple with long wait times from synthetic biology service providers or hands-on, labor-intensive protocols often involving bacterial cultures, DNA extraction processes and quality control to build heavy and light chain constructs and amplify them before they are ready for expression. The optimal synthetic biology solution should help seamlessly connect high-content sequencing data from B cell discovery platforms to downstream high-throughput antibody screening and characterization workflows ensuring consistent and high throughput is maintained throughout the discovery process.

Fortunately, advances in automation technologies can transform a cumbersome and labor-intensive process, significantly increasing productivity for researchers. By automating manual processes that normally require expert personnel input, it allows researchers to find the information they need to make timely, well-informed decisions, and research projects proceed on schedule. This new workflow produces fewer errors and dramatically increases throughput. We believe that workflow optimization leveraging our technology can help address the throughput gap in antibody discovery head on.

Enabling Efficiencies in Antibody Discovery

Telesis Bio Solutions Address Key Bottlenecks in Antibody Discovery:

• Antibody cloning completed in days, not weeks: By optimizing synthetic biology workflows, the end-to-end time for heavy and light chain variable region cloning can be reduced from multiple weeks to a few days.
• Reduced process steps: Cell-free DNA amplification supplants tedious manual process steps associated with cloning, transformation, and E. coli culture and harvest during plasmid production.
• Workflow efficiency gains: By implementing the BioXp® system to provide hands-free, automated assembly of DNA sequences, cloning, and amplification in a single overnight run, antibody discovery programs can produce transfection-ready plasmids in a fraction of the time previously required.

Like this blog? Make sure to check out white paper on how you can accelerate antibody engineering timelines significantly.

The post How to Reduce Lead Synthesis Bottlenecks in Antibody Discovery appeared first on Telesis Bio.

Team member: Pavel Ryzhov, Field Application Scientist
Came aboard: April 2022

What do you do at Telesis Bio?
I work with the sales team to help our customers see the technical value of our instruments before and after the sale process. I also help our current customers to use the BioXp® system in the best way possible so they can accelerate their discoveries.

What is one of the most exciting projects you have worked on?
Unlocking the power of the BioXp within customers’ existing workflows. I don’t just do it with one customer; it happens regularly, it just takes different shapes with different customers. For example, I create a framework for their discovery process that utilizes our product applications adding the most value to our customers.

How do you feel Telesis Bio is shaping the future of technology?
Telesis Bio has developed tremendous technologies over the years, putting us in a unique position to significantly grow our application portfolio. These advancements allow us to tap into adjacent markets related to synthetic biology and capture more customer share in the market. We have a robust automation platform that operates using validated consumables and reagents that we continue to expand and provide value to many customers.

Telesis Bio’s mission is to inspire and empower scientists to accelerate their discoveries. How would you say you’re helping our customers meet their goals?
Our instrument, the BioXp system, fills a particular gap in the discovery process of our customers. However, because there are no other comparable solutions out there, my job is to help unlock as much value from what the instrument can do. When customers are fully-trained on experimental design with the BioXp system, they typically see multiple entry points where our synthetic biology products can benefit their research, which together amounts to a great acceleration in their discovery workflows.

How would you describe the company culture?
I like that I get to wear various hats while still focusing on what I enjoy the most which is science communications. It’s also great to collaborate with people across different departments that support other aspects of the business because that’s where they shine best and it’s a great balance.

What’s something fun about working at Telesis Bio?
The people that work with Telesis Bio are funny, and there is never a shortage of jokes. I also consider myself a fun person to work with and I bounce off other people’s energy which is great.

How would you describe synthetic biology to non-scientists?
Synthetic biology is our best approximation of real biology. It’s essentially a discipline that allows us to start creating biology in a test tube. It’s a technique that allows us to build DNA and other macromolecules like RNA and proteins outside of confines of living organisms. The main goal is to allow us to create better functionalities for medicines and other industrial applications like agriculture, material sciences, and climate change, etc.

What was the first thing you ever wanted to be when you grew up?
I wanted to be a dentist. I am glad I chose a different route and did science communications as it seems a much better fit for me.

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At the forefront of current drug development pipelines is the development of therapeutic antibodies directed against complex membrane protein families such as GPCRs and ion channels. Both these target classes offer significant therapeutic promise for a wide range of disease indications; however, they have also proven difficult to address with traditional antibody development approaches such as hybridoma and phage display.

To address these challenges, emerging technologies, enhanced methodologies, and higher efficiencies have all been required. Fortunately, critical technological and automation advancements that have been emerging over the past 15 years are synergistically reshaping the toolkit available to antibody discovery programs, but challenges remain.

In this article, we will not only review these key advances and their impact on the industry, but also highlight how complementary advances in synthetic biology are necessary to enable the speed and efficiency required in discovery workflows for complex antibody-based drugs and therapeutics.

Antibody discovery advancements

Single-cell characterization platforms

Shortly after the development of next-generation sequencing, researchers began exploring the possibility of sequencing individual cells. For the first time, endogenous pairing of heavy and light chain variable sequences in a given B-cell repertoire became possible.₃ Advances in microfluidic handling technology rapidly led to the development of optofluidic platforms capable of profiling single cells with relevant phenotypic, genotypic, and imaging information.

The impact of this development on the field cannot be overstated. In fact, the central role that single-cell analysis platforms, such as 10X Genomics Chromium or Berkeley Lights Beacon instruments, have come to play in current antibody development can trace a direct line back to these developments.

Genetically engineered hyperimmune mouse models

Transgenic humanized mice strains have been developed that can produce chimeric human-mouse monoclonal antibodies composed of fully human Fab regions and mouse Fc regions.₄ These animals can deliver robust and diverse immune responses, significantly improving the efficiency of obtaining lead candidate antibodies that meet difficult target specificity profiles.

High-throughput kinetics platforms

Advances in liquid handling automation have ushered in a new era of high-throughput lead candidate antibody characterization. Essential kinetic and affinity analysis, epitope binning, titer and concentration assessments can all be completed at a scale and pace that meets the challenging demands of current antibody development timelines.

Discovery workflow synergy

Thanks to these new tools, a high-throughput workflow has emerged that addresses the increased pressure on discovery pipelines to identify and validate high-quality lead candidates for new therapeutics. Antibody discovery programs can now rapidly generate large numbers of lead candidate antibodies directed against complex membrane-bound targets by leveraging transgenic humanized mice. Paired heavy and light chain variable sequences from murine B cell repertoires can then be readily characterized and sequenced. Further downstream in this new workflow, bulk kinetic and binding analyses of expressed antibodies can be rapidly accomplished.

BioXp 9600 system: the BioXp platform enables overnight automated synthesis of DNA fragments, clones, and variant libraries all with a push of a button – allowing discovery programs to drastically reduce their time to results.

The unaddressed challenge—Cloning throughput gap

Developing therapeutics against difficult target classes requires screening large pools of lead candidate antibodies. Thankfully, the advances discussed above in obtaining antigen-specific monoclonal antibody sequences make it possible to generate hundreds of candidate sequences rapidly. Downstream screening platforms now also enable rapid characterization.

However, between sequencing and screening lies an unaddressed process bottleneck: the cloning and expression of heavy and light chain variable sequences. To facilitate high production yields, codon-optimized lead candidate sequences must be synthesized and cloned into expression vectors. However, the infrastructure required to maintain adequate speed and throughput using traditional cloning techniques is a significant hurdle to antibody discovery pipelines. Despite the emergence of synthetic biology services to replace traditional molecular biology approaches for gene and plasmid synthesis, the standard turnaround time in the industry from submitting DNA sequences to having a transfection-ready plasmid is a suboptimal 4–5 weeks.

In an attempt to achieve high throughput across their entire workflow, antibody discovery labs have to grapple with either long wait times from synthetic biology service providers or hands-on, labor-intensive protocols often involving bacterial cultures, DNA extraction processes and quality control to build heavy and light chain constructs and amplify them before they are ready for expression.

There is a true market need for an optimal synthetic biology solution to seamlessly connect high-content sequencing data from B cell discovery platforms to downstream high-throughput antibody screening and characterization workflows to maintain consistent and high throughput throughout the discovery process.

If your antibody discovery program is limited by the speed of your capabilities in synthesis and cloning of lead candidates, you’re not alone. Contact our expert team to continue learning how Telesis Bio’s synthetic biology solutions can help you break free from traditional bottlenecks and significantly accelerate your antibody discovery pipeline.

References

1. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7. doi: 10.1038/256495a0.
2. Monoclonal Antibody Therapeutics Market: Expanding Cases of Cancer to Increase Growth Prospects of Market. BioSpace Nov 8, 2021.
3. DeKosky BJ, Ippolito GC, Deschner RP, Lavinder JJ,Wine Y, Rawlings BM, Varadarajan N, Giesecke C, Dörner T, Andrews SF, Wilson PC, Hunicke-Smith SP, Willson CG, Ellington AD, Georgiou G. Highthroughput sequencing of the paired human immunoglobulin heavy and light chain repertoire. Nat Biotechnol. 2013 Feb;31(2):166-9. doi: 10.1038/nbt.2492.
4. Integrated therapeutic antibody discovery solutions. Biopharmadeal makers.

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Cellular therapy research is booming with applications in cancer and further innovations on the horizon for infectious, autoimmune, and chronic inflammatory diseases. The progression in understanding the tumor microenvironment and how the immune cells infiltrate and kill tumor cells has resulted in advances in cancer immunotherapy research and treatments. Research focuses on the best targets for these therapies, as well as the engineering of cells to ensure safety and improve their efficacy, especially in difficult-to-treat areas.

Design iteration in adoptive T-cell therapy is a key challenge

Cell-based immunotherapy for cancer poses a discovery challenge, requiring researchers to balance synthetic biology complexity with the factors required for stability, manufacturing capability, immunological compatibility, and safety. Scientists need to design, build and test tens of dozens of cell receptors for tumor-associated antigen specificity and immune activation, optimize and then iterate before advancing candidates to development.

Design iteration for Chimeric Antigen Receptors (CARs) and screening T-cell receptors (TCRs) for tumor-associated antigen-specificity can be particularly challenging. The synthetic construction and assembly of CARs and TCRs and their introduction of these constructs into cells can often be the most time-consuming step in the process. High-throughput testing requires the quick assembly and integration of constructs into viral vectors for the transfection of cells used for screening assays. Traditional methods are not only time-consuming, taking several weeks to generate viral vectors for transduction, but also have limitations in quality control and are costly, limiting the number of CARs or TCRs researchers can test in a single iteration. To expedite the design-build-test cycle for CARs and TCRs, it is essential to improve and optimize this process.

Optimized discovery workflow for TCR screening and optimization

In a traditional workflow, the TCR construct is cloned, a lentiviral construct is generated, and this is then used to transduce T cell lines or primary T cells for candidate screening assays. This process generally takes up to six weeks and often involves external service providers for steps in this process. This entire process can now be sped up by weeks with an internal benchtop device able to create multiple candidate TCR mRNAs overnight for transfection and expression, reducing the time from establishing the sequence to functional testing of the TCR. While mRNA is an attractive alternative to viral transduction to generate transient, high levels of protein expression in primary T-cells/cell lines, generating mRNA quickly, efficiently, and cost-effectively has been a challenge with traditional synthesis methods. For example, you might perform a single-cell RNA sequencing analysis of specific sorted and/or expanded T cell populations to identify TCR sequences of interest. Based on this data, you can create heterodimeric TCR expression constructs in a matter of days and use these to electroporate RNA into T cell lines or primary T cells for functional screens.

Using a high-throughput automation platform for synthetic biology is a promising alternative approach that can substantially speed up the synthetic assembly processes. Genes are built based on a digital sequence, and clones, libraries, and mRNA can be created in a fraction of the time it takes using traditional methods. These methods are hands-free, and are possible using benchtop devices with a limited laboratory footprint so researchers can be more efficient and use their time on other valuable tasks. Using such a platform allows faster screening of constructs, enables rapid synthesis and testing of complex multi-domain constructs as well as broadens the scope of discovery. T-cell Receptor (TCR) therapy for cancer relies on selecting tumor-reactive T cells and assessing their TCR. Using a high-throughput in-house synthetic biology platform allows researchers to rapidly build candidate TCR constructs, enabling them to advance to candidate screening assays far quicker than traditional workflows.

A new workflow paradigm for CAR design-build-test discovery process

Beyond engineered T Cells, CAR T cell therapy has also shown tremendous potential for significant success in improving outcomes for several hematological cancers. Therapeutic applications are currently expanding to solid tumors and autoimmune and infectious diseases. In order to overcome issues with solid tumors’ immunosuppressive tumor microenvironment to find the best antigenic targets for therapy, research focuses on exploring targeting domains, improvements in the signaling domain, and other modifications to the construct, for instance, by adding sequences for cytokine production.

Additionally, innovations to develop off-the-shelf therapies using allogeneic cells may reduce costs, improve the quality of the cellular product, and make the treatment accessible to a larger group of patients. However, allogeneic cells risk graft-versus-host disease as they contain an original TCR that may be reactive to the patient’s tissues. To overcome this, CAR-T cells using allogeneic cells need to be constructed so that the endogenous TCRα gene is knocked out while the CAR transgenes are inserted via an adeno- or retroviral vector.

By being able to synthesize multiple gene fragments overnight, more CAR designs can be explored than previously possible. Construct designs can be rapidly iterated to identify the optimal characteristics for the CAR T cell. Multiple CAR or costimulatory constructs can be built simultaneously to accelerate candidate screening experiments.

Automating synthetic biology – a tool for accelerating novel cell therapy solutions

Automated synthetic biology solutions can provide solutions for both TCR-T and CAR-T, allowing researchers to accelerate the discovery phase of therapeutic development. As a developer of novel TCR-T or CAR-T therapies, your end goal might be to develop constructs targeting various antigens to assess tumor reactivity. Your process begins with selecting sequences for these constructs used to inform the construct development, after which those constructs are transduced into T cells for candidate screening experiments in vitro and in vivo. Traditional methods for the “build” part of this “design-build-test” cycle have several challenges and are not optimized to meet current development timelines.

This process is limited by the time it takes to get from a candidate sequence to a high-fidelity construct for use in screening assays. With automated synthetic construction from a digital sequence, the process can be conducted overnight, and has inherent error correction to ensure high accuracy. In addition, an in-house benchtop device performing this work for you circumvents the long turnaround times of service providers. This method allows you to have better control over your workflow timelines and broaden the scope of your experiments.

High throughput synthetic biology platforms offer fast, accurate, hands-free, end-to-end solutions to accelerate discovery workflows. These workflow solutions enable rapid candidate synthesis which in turn allow for faster screening through transient modulation of cellular phenotypes.

The post Removing bottlenecks in discovery workflows with synthetic biology solutions appeared first on Telesis Bio.

1. Tell me about when you went through the process of understanding what you wanted to automate. What was your inspiration? What was your objective? What did you want to achieve?
The development team wanted to create a next-generation platform for the BioXp which would allow for 3X the capacity of the existing 3250 system, allowing researchers to build more constructs in the same amount of time. In addition, we wanted to include the capability of more custom reagents and consumables to run on the instrument which will provide users with even more flexibility when integrating the system into existing workflows. Lastly, the system was designed to connect to future automation, including enzymatic oligo synthesizers.

2. Why is automating synthetic biology challenging?
Automating synthetic biology consists of precise fluid handling and accurate temperature control for thermal cycling and reagent storage. Transferring the golden hands of a very experienced molecular biologist can be a challenge. Because the system cannot see to the level of a human, it’s critical to ensure bubbles are not accidentally transferred, or random carryover is avoided at every step. This task can be daunting and requires a close relationship between the engineers developing the software and scripting with the biologist with the golden hands.

3. When you were first thinking about designing and automating synthetic biology as a novel application, what were you the most inspired by?
I’ve always been intrigued by how easily an experienced molecular biologist can cut, splice, amplify, purify and clone DNA. To collapse those steps on an automated platform where its “push button” is a real challenge. It always seemed wasteful to have an experienced biologist doing laborious things, so we aimed to make it as hands-off as possible.

4. You recently led the engineering team that developed the BioXp 9600 — the next-generation high throughput workstation for synthetic biology that builds on the capabilities of the award-winning BioXp platform. How does this version of the BioXp system differ from its previous iteration?
The BioXp 9600 project allowed us to build on the success of the 3250 system. For example, the system can store and use 960 additional disposable tips and has new custom reagent holders and storage for six more processing plates. This process provides flexibility for larger jobs such as mRNA and multi-fragment cloning. We also added bi-direction audio for future on-system training videos and customer service communications.

5. When you set out to design the system, what was your vision for the BioXp 9600?
Our vision for the BioXp 9600 system was that it was easy to use like the BioXp 3250 system but now with added capacity. We wanted the system to be as compact as possible since we know bench space is at a premium with most of our customers. Lastly, we wanted the system to have an attractive and unique industrial design.

6. Is there anything currently comparable to it in the biotechnology market? What would you say sets it apart?
Both the BioXp 3250 and the 9600 are unique in the market. There are many liquid handling systems available on the market, but there are no fully automated DNA assembly systems on the market. What is unique about the BioXp is that the reagents and all the scripting are finely tuned to give users a truly push-button experience for DNA construct synthesis.

7. In terms of design elements, what’s your favorite feature of the BioXp 9600 system?
My favorite feature of the BioXp 9600 is the user interface and how simple it is to use. We redesigned the entire user interface for the 9600 with a beautiful look that matches the industrial design of the enclosure.

8. How do you see this instrument impacting the development of vaccines and therapeutics?
We have been pleased with the response to the BioXp 9600 system. The system provides the capability for our customers to run higher numbers of candidates for screening for vaccines and therapeutics. The BioXp 9600 system is addressing the needs of those customers, helping them to speed up the delivery of these potentially lifesaving products to market.

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Team member: Silvio Cenzi, Senior Manager, Field Service Field Support
Came aboard: January 10, 2022

What do you do at Telesis Bio?
I lead a team of field service engineers globally. We support the daily needs of our customers.

How did you get into that kind of work?
I love science, and I’m passionate about teaching and troubleshooting technologies. I have always enjoyed being in a position where I can help others with troubleshooting. It’s quite rewarding to know that while I am supporting our customers, I am also contributing to bringing science a step closer to resolving some of the world’s most challenging problems.

How would you describe the company culture?
The Telesis Bio people are the most important part of what defines our company culture. The benefit of working for a smaller company is that everyone is very supportive and committed, and our CEO and VPs are accessible.

How would you describe synthetic biology to non-scientists?
I would compare it to a Swiss Army Knife. It’s a breakthrough technology that can speed up innovation in drug development, agriculture, and solving environmental challenges. Having synthetic biology at your fingertips is like switching from physical letters to emails to communicate; it allows genetic engineering to bypass tedious steps in the process.

What’s something fun about working at Telesis Bio?
There is a sense of community and support. We have team-building activities, BBQs, and happy hour events.

What was the first thing you ever wanted to be when you grew up?
I wanted to be a fighter pilot.

How do you see synthetic biology changing the world?
Imagine a world where food can grow in harsh environments, where designer microorganisms decompose plastic waste. Also, imagine doctors being able to engineer antibodies that would target only cancer cells without the side effects and curing rare and new diseases that have been falling through the cracks because of the high cost.

The post In our DNA: Silvio Cenzi, Senior Manager, Field Service Field Support appeared first on Telesis Bio.

What Cellibre does

We believe that biology is the most sophisticated and elegant manufacturing technology known to man, and we program biology to make products more sustainable, efficient, and reliable across various industries. Often people in the field of synthetic biology talk about sustainability. We don’t start there. Our key criteria for ensuring bio-based production are having large volumes, as biology is a scalable technology, so it’s all about large markets.

Secondly, we make sure we know what we’re getting ourselves into. Thirdly, we want to find supply chains that have major flaws. The goal is to solve issues and make products better, cheaper, and more convenient for the end consumers. We must ask ourselves if a biobased solution is economically viable or not. Can we compete with legacy supply chains in the marketplace to bring overall costs down? Our first application of this technology is in the cannabinoid space because it really does check all the boxes.

Cannabis industry focus

In large markets, most people think of cannabis as a recreational market like vape pens, beverages, etc. There’s also a large human therapeutic market as seen by evidence from GW Pharma and folks like that. There is also an animal health market for these molecules as well. We’re talking about the potential for hundreds of millions of kilograms in demand per annum across those three areas.

Additionally, their biochemistry is known. This plant has been sequenced. We understand the whole pathway, and we know how to turn those into valuable products known as cannabinoids.

Challenges with traditional agricultural methods

The supply chain for legacy agriculture is filled with problems. The plant itself makes over 400 chemicals simultaneously, so any product you get will be impure and inconsistent. The plant is a super sucker, so it takes everything it finds out of the soil and brings it into the plant, making it susceptible to contaminants like chemical residues or pesticides. There are also long unpredictable production cycles that go along with producing these molecules via traditional agriculture. Lastly, the prices for cannabinoids look a lot like medicines, not as commodities, like nutritional proteins or biofuels. The economics provide a floor and make the biobased solution more viable.

Cellibre changing the way cannabinoids are harvested

Traditional companies take an organism approach like the many great companies that have built tens of millions and in some cases hundreds of millions of dollars of infrastructure around engineering certain cell types. Whether that be saccharomyces cerevisiae, also known as bakers yeast, E. coli, or other bacterial systems. They typically do this by using fuels or specialty chemicals and taking that process and infrastructure to engineer cells to make various products. Essentially taking those square pegs and fitting them into round holes.

What we do differently here at Cellibre is rather than taking a cell approach, we take a product approach. If we want to make CBD we find out if there is a cell in nature that already makes the building blocks where the primary is to build the precursors that we need to make the product of interest. We then engineer those cells and allow nature to get us closer to the endpoint. This is the fundamental difference between us and other people trying to use biology for manufacturing and technology.

Telesis Bio partnership improving the enzyme engineering process

Our partnership with Telesis Bio starts not at the cell level, but down at the enzyme level. When we’re building these pathways and have different enzymes doing different chemical reactions, along those pathways, we want to both discover and engineer those enzymes. This can be a lengthy process. You design and build your constructs and once you have your constructs, you plate those cells and determine whether you have a proper build. After that, you do DNA amplification, which leads to enzyme production and analysis of those enzymes. Then you repeat the design-build-test process as you hear of from more engineering-focused focused disciplines.

When done traditionally, it’s a fairly long process. Because Telesis Bio’s solutions provide specificity and accuracy in their platform, we were able to accelerate this process and eliminate plating steps because we knew exactly what we were getting from them. This saved us almost a full week on each one of the cycles, which is a big deal from a time, IP, and cost perspective. When you think about how most people do protein engineering today, they’re doing what’s called pooled libraries, and that means they take hundreds of millions of constructs and pull those into a single tube. In the substrates, they screen those enzymes and find the winners.

Ultimately, most people are only sequencing and characterizing the winners. That could be problematic because of traditional oversampling issues, full data sets are only available for what you sequence. We only fully understand what those winners do, we don’t understand why things didn’t work which can be just as important. It’s especially cost-prohibitive for smaller organizations to sequence everything and get those complete data sets. Additionally, to do that screening and sequencing requires high throughput.

Benefits of using Telesis Bio’s library services

With Telesis Bio’s technology, we’re able to individually build constructs to do everything de novo. We can build large libraries on a de novo basis, as well as do very targeted libraries of de novo constructs. Telesis Bio’s technology can do this with a similar turnaround to pooled libraries. Additionally, the cost to do this is much lower than other technologies out there that we evaluated.

Once we have those libraries, we screen and find the winners. Interestingly, we can characterize both the winners and the losers because every single sequence is known as they were all built de novo. This means we get the same turnaround time and drastically lower costs of working with other providers. We also have the flexibility and fidelity to do both complex and simple designs. Because we have complete data sets, we can then flow back into our AI and machine learning algorithms, both for discovery and design. These clean data sets provide understanding not only into what works but what doesn’t work, which is crucial if you want to do in silico work that we as a field are so excited about.

Continue on for a brief case study on how this worked to get a sense of the different things that we were able to do with Telesis Bio’s technology in this discovery and engineering program. First, one of the key enzymes in the pathway for making a cannabinoid is the CBG synthase. We discovered an enzyme that had great activity and when put in the substrate made a little bit of CBGA and a lot of other stuff. Although the activity was great, we would rather engineer specificity vs. activity.

Went through our first library builds doing traditional site-saturation mutagenesis (SSM) with Telesis Bio’s technology we were able to flip that specificity the other way and even further to the point where it was almost 99% specific for the product of interest. In addition, we increased the activity. We then came to Telesis Bio and said we don’t want to just do point mutations we want to change entire sections of this protein and build these types of more complex libraries.

Time-saving solution

We did that with the team at Telesis Bio in very short order and resulted in almost a 5x increase in the activity of these enzymes while maintaining the specificity. Lastly, we did another round of engineering and we got it up to six times more active than what that original enzyme was. All of this was done from a kind of ideation discovery, all the way to these improvements, in less than three months.

Download the Cellibre’s case study

Over the course of time, we’ve continued to work with Telesis Bio and this enzyme is now ten thousand times more active than the original discovery. It was the flexibility and specificity that allowed us not only to do the simple high-throughput screening that we would normally do, but we were able to take more complex engineering approaches with Telesis Bio that led to these very significant discoveries for Cellibre.

With that, I would like to thank the entire team at Telesis Bio for their partnership in the continued innovation that they bring to us every day.

See the full recording here

Order libraries here

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BioXp system

How do complex targets challenge antibody development pipelines?

Nearly one-half of all FDA-approved drug targets are for GPCRs and ion channels. In a recent survey of top challenges in the field, difficult targets and the selection and screening required to identify leads against them accounted for nearly 80% of all responses. This means that antibody development pipelines had to adapt to meet this demand by embracing not only emerging technologies but also enhanced screening methodologies and higher workflow efficiencies.

What’s the BioXp system and how does it improve efficiencies across antibody discovery workflows?

The BioXp system is the world’s first fully automated synthetic biology workstation and provides a turnkey solution for generating gene fragments, clones, variant libraries, and mRNA starting from just a digital sequence. With all instrument builds taking less than 24 hours, the BioXp system enables numerous synthetic biology applications and is transforming workflows across antibody therapeutic development pipelines. The BioXp system enables researchers to build biology overnight.

Can you describe the BioXp workflow?

The BioXp system workflow is quite simple. First, you submit your digital sequences through our ordering portal. Next, you receive your BioXp kit, which will contain all the necessary consumables for your project. Then you load the instrument, which takes no more than a few minutes, and then finally press start. The BioXp system does the rest. Simply retrieve your products off the instrument and proceed to downstream experimentation.

Can you take me through the process of building and cloning DNA on the BioXp system?

The BioXp system constructs de novo synthesized DNA fragments up to a combined total of 7.2 KB in length and then clones them via Gibson assembly method into the linearized vector of your choice. Up to four unique fragments may be assembled into the final construct.

In particular, the two-fragment assembly cloning workflow provides an easy way to synthesize scFv fragments overnight by building VH and VL segments joined via a linker. If you would prefer to do your fragment cloning manually on the bench, up to 32 unique gene fragments can be built with each BioXp system run.

When compared to industry standard turnaround times for gene synthesis providers how much faster can the BioXp workflow enable time from sequence to transfection?

60-80% faster. Under ideal circumstances with synthesis providers, our customers have mentioned that they can receive the requested products within 2 weeks. Under typical circumstances, the turnaround times can take a month. With the BioXp system, this can be accomplished in less than one week.

How are Telesis Bio’s variant libraries designed for optimal results?

DNA synthesis time is independent of design complexity, constructs are built to specification (not as pools), every sequence is known from design, and there are no molecular biology constraints on protein engineering designs.

How has Cellibre been able to speed up its enzyme engineering process with these DNA libraries?

Cellibre is an agricultural biotech looking to address supply chain issues via bio-fermentation. They have partnered with our team to build multiple complex library designs for their enzyme evolution work. Not only were they able to engineer an enzyme with five times the activity of their starting one, but more importantly, they were able to drastically reduce the build-test cycle to weeks instead of months. Furthermore, they were able to rapidly synthesize complex designs that they were unable to obtain from other DNA synthesis providers.

Interested in learning more about how you can speed up and optimize your synthetic biology workflows? Visit our website to see how you can benefit from Telesis Bio’s synthetic biology solutions.

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Team member: Ken Williams, Bioinformatics Scientist Lead
Came aboard: February 2020

What do you do at Telesis Bio?

I develop the algorithms for the complexity checker, codon optimization, sequence synthesis, the SOLA (enzymatic DNA synthesis) project, DNA data storage, biosecurity, and NGS analysis. In addition to that, I also help troubleshoot customer sequences and I help with the design for myBioXperience, our new online portal we recently launched.

How did you get into that kind of work?

When I was a teenager, both of my parents got very sick. My dad caught a cold that I gave him which led to him developing Guillain-Barre syndrome, so all his antibodies started attacking his neurons. At the same time, my mom was also diagnosed with myotonic muscular dystrophy. I then lost about half of my family on my mom’s side to myotonic muscular dystrophy, which is what led to me being interested in molecular biology and genetics. As far as bioinformatics, I accidentally fell into it since it was the only biology program not impacted at UCSD. The great thing is I ended up liking it much more than being on the bench, which worked out quite well.

How would you describe the company culture?

We’re currently in a transition right now going from a startup to a small company. Ultimately, it’s a fun place to work, we have a huge diversity of work that we’re doing. It’s great that everyone is approachable and easy to talk to. We also have spontaneous events that dictate the culture of the company. I also like the people here who come from diverse backgrounds and bring different perspectives and expertise.

How would you describe synthetic biology to non-scientists?

Synthetic biology is essentially the catalyst to the future because we’re greatly able to expedite research for drug discovery. We will be able to cure diseases. We can do things like engineer algae and solve the climate crisis. We can even store data on DNA using synthetic biology.

What’s something fun about working at Telesis Bio?

There are so many projects that we’re working on. I enjoy interacting with so many people and expressing so many ideas to the various team members. I also like that’s a smaller company because everyone can make an impact.

What was the first thing you ever wanted to be when you grew up?

I wanted to be a civil engineer because I’m interested in that and there are so many moving parts and ways to optimize the way cities are built. I also wanted to be a front man for a thrash metal band.

How do you see synthetic biology changing the world?

Helping with drug discovery, curing diseases, alleviating the climate crisis, and really the possibilities are limitless.

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Team member: Sydney Kerr, Senior Research Associate
Came aboard: January 2021

What do you do at Telesis Bio?
I work on the SOLA (enzymatic DNA synthesis) project under Senior Director of Research and Development John Gill, enzymatically synthesizing DNA. My role in the project is to work on increasing throughput. We started working on a small number of samples doing a deep dive into individual sequences we were trying to build. Once we accomplished a robust build with the small sample sizes, we scaled it to a larger set of samples and genes.

How did you get into that kind of work?
I had always been interested in science. At first, I was interested in the material science trajectory of my career. When I was 19, I was diagnosed with Hodgins Lymphoma and battled out cancer throughout the end of my teen years. With that, I gained a newfound passion for life, health, and medicine. I wanted to put that personal journey to use to improve health and medicine for other people. I then studied nanoengineering with a focus in bioengineering at UCSD for my bachelor’s. I continued to pursue my master’s in nanoengineering with an emphasis in biomedical nanotechnology. After working for a small company called Cytologistics and Advanced Targeting Systems, I joined Telesis Bio, and it has been a great experience since.

How would you describe the company culture?
It’s supportive and collaborative. When I think of the company culture, I think of my supervisor John Gill. John has fostered a nurturing culture in his team, and it feels great to know that anytime we face a hurdle, we are encouraged to take a walk and take care of ourselves first. The people I see daily create a great culture, and it’s the best.

How would you describe synthetic biology to non-scientists?
I would describe it as making biology in a lab rather than in nature. We can make new or better biological systems, devices, and medicines that address problems we see in healthcare.

What’s something fun about working at Telesis Bio?
The people. The science is so amazing, but I love coming to work every day with people who I think are superheroes and have also become some of my best friends.

What was the first thing you ever wanted to be when you grew up?
I wanted to be a supercross rider when I was four. I also wanted to be a ballerina.

How do you see synthetic biology changing the world?
I think this synthetic biology revolution will increase access to the quality of medicine. I also think synthetic biology has a very graceful way of aiding human healing. Over time, we will see a big shift in health and wellness based on this synthetic biology we’re continuing to focus on.

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