Translation

Could all the leading COVID19 vaccines have a fatal flaw in their design? A dizzying number of vaccines are being developed to protect society from the dangers of COVID19, each with its own benefits and pitfalls. At HelixNano, Nikolai Eroshenko and his team are designing a special type of vaccine with increased attention to ensuring that this protective medicine doesn't accidentally improve the virus's ability to infect cells or drive the immune system to cause collateral damage. Nikolai describes how vaccines work, why so many are being developed to fight SARS-CoV-2, and how technological advances have allowed us to develop them faster than ever before. Most importantly, Nikolai calls on all vaccine developers to put more effort into their design and testing pipeline such that they don’t accidentally help the virus become more deadly. 

About the Author

• Nikolai earned his PhD under Professor George Church, one of the founding fathers of synthetic biology. The lab is renowned for developing high throughput methods to design, build, and test bioengineered parts.
• The technology Nikolai designed in the Church lab was spun out into a company, HelixNano, to design next-generation vaccines to treat and prevent cancer.
• When the COVID19 pandemic hit, Nikolai and HelixNano made an all-hands-on-deck pivot to create a COVID19 vaccine without the possibility of triggering antibody-dependent enhancement, an effect that can cause a vaccine to increase the deadliness of SAR-CoV-2.

Key Takeaways

• Vaccines train an immune response by creating specialized T cells and antibodies that protect people from future infections of the virus.
• A mechanism called antibody-dependent enhancement, or ADE, could allow current vaccines to accidentally help SARS-CoV-2 infect people who have received it.
• Nikolai calls on vaccine developers to improve their measurement capabilities so that they can catch the potential for ADE early.
• The current boon of new biotechnology has allowed us to test and measure the effectiveness and safety of these lifesaving technologies faster than ever before.

Translation

• Nikolai and his team focus on one specific type of vaccine that uses RNA to elicit an immune response.
• Using RNA allows for fast design-build-test cycles that HelixNano uses to rapidly screen for novel vaccine properties.
• HelixNano is developing a vaccine that is specifically designed to minimize the chance of ADE.

First Author: Nikolai Eroshenko

Paper: Implications of antibody-dependent enhancement of infection for SARS-CoV-2 countermeasures. Nature, 2020.

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Powered by synthetic biology, Pierce Ogden makes ALL possible mutations to an adeno-associated virus (AAV) outer shell and rapidly screens them to dissect their attributes. Pierce discusses the technological advances that make this breakthrough screen possible and the novel properties that were discovered. AAVs are rapidly becoming the prefered way to perform gene therapy, correcting cells that carry disease-causing mutations through genetic modification. This technology forms the basis for company Dyno Therapeutics.

About the Author

• Pierce performed this work as a postdoc at Harvard University in the lab of Professor George Church. Professor Church is one of the founding fathers of synthetic biology and the lab is renowned for developing high throughput methods to design, build, and test bioengineered parts.
• In his role as Co-Founder & CSO at Manifold Bio, Pierce utilizes his multiplexing expertise to uncover the design principles of protein therapeutics and make new drugs faster than ever before.

Key Takeaways

• Gene therapy uses genetic information as a drug, correcting cells that carry disease-causing mutations.
• The inability to deliver these genes to the correct cells limits the widespread adoption of gene therapy.
• Adeno-associated viruses (AAVs) are an extremely promising way to deliver DNA to human cells. Their outer shell, or capsid, can be engineered for increased safety, specificity, and shelf-life.
• Using advances in DNA synthesis technology, all possible single mutations to the AAV capsid are generated.
• With a DNA barcode read through next generation sequencing, this AAV library was simultaneously tested cheaply and quickly to find mutations with improved properties.
• Increased thermal stability, evasion of immune responses, and specificity toward the brain were all found. 

Translation

• Pierce demonstrates that smart usage of our synthetic biology toolbox can allow millions of protein variants to be tested simultaneously, in direct opposition to the “tested in parallel” model that has dominated high-throughput biology.
• Manifold Bio takes this idea of DNA barcodes coupled with simultaneous screening and points it toward the field of protein therapeutics.

First Author: Pierce Ogden

Paper: Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design. Science, 2020.

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Commodity molecules are vital ingredients for everything important to our modern world including food, energy, and medicine. However, creating these molecules still largely relies on old processes that suffer from low yield, laborious methods, and unsustainable inputs and byproducts. Tina envisions a world where all molecules are created quickly, easily, and sustainably through enzymes, biology’s chemical catalyst. Here, Tina describes how she used an extremely powerful method called directed evolution to build a novel enzyme that can create the non-canonical amino acid 4-cyanotryptophan, a fluorescent molecule that is extremely difficult to make with traditional chemistry. 

About the Author

• Tina performed this work as a postdoc in the lab of Nobel Laureate Professor Frances Arnold at Caltech. The lab is world renowned for developing the methods around directed evolution and applying them to create proteins that do unnatural chemistries.
• Tina is now the co-founder and CEO at Aralez Bio whose focus is on developing efficient, sustainable alternatives to chemical manufacturing through enzyme engineering.

Key Takeaways

• Enzymes are proteins that induce specific chemical reactions to occur. They can create molecules much more efficiently and sustainably than using traditional chemistry
• One class of molecules, called non-canonical amino acids, are extremely important precursors to drugs and have specific properties that make them desirable for biotech.
• Making highly pure non-canonical amino acids is difficult with traditional chemistry, requiring many time-consuming reactions and toxic byproducts. But nature has yet to generate an enzyme that can create these.
• A process called directed evolution mimics nature’s process by heavily mutating a starting enzyme and sequentially pushing it to make a molecule of interest.
• When using directed evolution, “you get what you screen for”. Said another way: the outcome of the process is highly dependent on how the experiment was run and what was optimized for.
• With directed evolution, the non-canonical amino acid 4-cyanotryptophan is generated overnight with no harmful byproducts; something that would take a team of chemists months to do.

Translation

• The evolved enzyme that creates 4-cyanotryptophan became the cornerstone technology of Aralez Bio.
• Tina spent the last parts of her postdoc defining customers and building a team to launch the company.
• Through enzyme engineering, Aralez Bio plans to replace many unsustainable and time consuming chemistries that currently plague commodity molecules.

First Author: Christina Boville

Paper: Improved Synthesis of 4-Cyanotryptophan and Other Tryptophan Analogues in Aqueous Solvent Using Variants of TrpB from Thermotoga maritima. Journal of Organic Chemistry, 2018.

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Protein engineering has been dominated by two opposing paradigms; directed evolution, a massive screening technique, and rational design, a completely computational approach. Surge has fused these two paradigms by developing a machine learning technique that discovers an optimal protein design by training on a low number of engineered proteins. Here, Surge discusses how this hybrid method works, how it enabled the creation of better fluorophores and enzymes, and what this method will unlock next.

About the Author

• Surge performed this work as a graduate student at Harvard in the lab of Professor George Church. George is one of the founding fathers of synthetic biology and the lab is known for developing high throughput methods to design, build, and test bioengineered parts.
• As CEO and co-founder of Nabla Bio, Surge is now focused on pointing the algorithms and methods developed in his academic work toward building proteins that can improve human health or protect the environment.

Key Takeaways

• Methods from natural language processing algorithms (like Siri or Alexa) are adapted to understand how nature builds proteins.
• These machine learning algorithms distill fundamental structural, as well as  evolutionary and and biophysical properties about proteins.
• Fusing these models with real world data enables us to make proteins with improved or novel functionality.
• By checking how a few mutations (low-n) affect the function of a protein, Surge evolved proteins in a computer to make better fluorescent proteins and enzymes.
• These models know a lot about proteins in general and can therefore be applied to a wide variety of tasks that improve human health and protect the environment.

Translation

• This methodology dramatically reduces the time, cost, and labor of evolving proteins, making it a perfect tool to create commodity proteins.
• Based on this technology, Surge co-founded Nabla Bio whose goal is to engineer supernatural proteins that enable biology to solve the world's biggest problems.

First Author: Surojit “Surge” Biswas

Paper: Low-N protein engineering with data-efficient deep learning. bioRxiV, 2020.

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