george church

Season 2, Episode 1: Engineering the Immune System to Kill Senescent Cells with Corina Amor Vegas

First Author: Corina Amor Vegas

Episode Summary

Hundreds of iterations of immune cells that are engineered to kill cancer have already been designed. Corina reached outside of this box to use the same synthetic biology principles to engineer T cells to attack senescent cells, a cell type that contributes to diseases of aging. Corina walks us through how her engineered T cells know the difference between a diseased cell and healthy tissue, how she stumbled upon the chimeric antigen receptor that made this possible, and how these new T cells are being moved from academia to the clinic.

About the Author

  • Corina is a physician scientist who performed this work under Professor Scott Lowe at Memorial Sloan Kettering in New York City. Dr. Lowe and his team are world experts in dissecting how functional changes in a cell make them go from healthy to cancerous.

  • Corina became fascinated with translation biotechnology after seeing her mother survive a life threatening disease using a new therapy in a clinical trial.

Key Takeaways

  • T cells are the part of the immune system that have the ability to target and kill other cells in the body in a way similar to drug sniffing dogs. 

  • Using the hottest tool in synthetic immunology, the chimeric antigen receptor (CAR), T cells can be engineered to target and attack almost anything we like.

  • A major hurdle to engineering these cells is finding something to target that is overrepresented in disease cells and virtually absent in healthy cells.

  • When targeted to senescent cells, these T cells can kill precancerous cells and reverse diseases related to aging and poor diet.

Translation

  • Corina’s research contains excellent demonstrations of these cells working in preclinical models, mice that mimic human diseases.

  • To move to human trials, Corina must update the therapy to attack human versions of the cells and begin to work toward understanding its safety and efficacy.

  • Corina believes the best people to take on this challenge are the researchers who have intimate knowledge of the method and who care deeply about the disease it could cure.

Paper: Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 2020

Season 1, Episode 4: Designing A Better COVID19 Vaccine with Nikolai Eroshenko

First Author: Nikolai Eroshenko

Episode Summary

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.

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

Season 1, Episode 3: Evolving AAVs for Gene Therapy with Pierce Ogden

First Author: Pierce Ogden

Episode Summary

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.

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