bacteria

Season 4, Episode 1: Irresistible Cancer Therapies with Nick Goldner

Episode Contributors: Seth Bannon, Michael Chavez, Alex Teng, Nick Goldner

Episode Summary: Evolution is happening even at the cellular scale. Whether it's a virus, a bacterial pathogen, or a cancer cell, disease-causing agents are responding to the therapies we throw at them, updating their genes and molecular pathways to resist death. As a trained microbiologist, Nick Goldner and his co-founder Chris Bulow spent their years in grad school using -omics data to overcome antibiotic resistance in bacteria which led to their first company Viosera. As they struggled with the harsh realities of the antibiotics market, they stumbled upon the connection between bacterial and cancer resistance mechanisms. With this, they started resistanceBio which combines sophisticated tumoroids, intense patient sampling, and multi-omics to mimic the evolution of real tumors and ultimately find therapies that are irresistible.

About the Author

  • Nick Goldner is co-founder and CEO of resistanceBio, a company harnessing evolution to develop therapies that defeat treatment resistant tumors.

  • His interest in biotechnology was sparked by his own battle with treatment resistant bacteria.

  • Nick and his friend and labmate, Chris Bulow, knew they wanted to start a company and began Viosera to fight antibiotic resistant bacteria as graduate students.

  • Recognizing the inherent difficulty of bringing new antibiotics to market, they adapted their technology to cancer and spun-out resistanceBio.

Key Takeaways

  • Resistance is very similar in both cancer and bacteria – in response to a drug, both will change their phenotype in a way that reduces its efficacy.

  • Traditionally, we understand cancer resistance by growing cancer lines in a dish and evolving them over long periods in a way that is very different from what happens in the body.

  • Nick and his team developed ResCu, a method that cultures tumor cells as tumoroids that mimics how a tumor evolves during a patient's course of therapy.

  • Combining this with multi-omics, Nick and his team can untangle how the underlying resistance mechanism evolves over time.

  • The data that comes from this points resistanceBio toward therapies that will turn these resistances into vulnerabilities.

Translation

  • The drugs discovered through resistanceBio’s platform create cancer cures for people who currently have no options.

  • The data created through ResCu generate biomarkers ensuring that the right drugs are given to the right people.

  • With the foresight of how cancers evolve, resistanceBio could completely overcome the use of chemo and other non-targeted therapies that are hard on patients and instead have completely personalized therapies that are tailored to block all roads to resistance.

Company: resistanceBio

Season 3, Episode 3: Phage Evolved Medicine with Travis Blum

First Author: Travis Blum

Episode Summary: Enzymes that break down other proteins, or proteases, could be used as a powerful therapeutic if they could specifically chew-up disease causing entities. However many proteases are non-specific, breaking any protein in their path, while the specific ones target proteins that would provide no therapeutic benefit. Travis and his colleagues developed a riff on the method known as PANCE that utilizes bacteria and bacterial viruses known as phages to evolve proteins toward a specific goal. With it, he retrains the sequence-specific protease, botulinum neurotoxin, toward new targets and away from its original ones. The novel enzymes Travis generates have the potential to not only stimulate nerve regeneration but also deliver itself to the correct cell types for a whole new type of therapy. 

About the Author

  • Travis is a postdoc who performed this work in the lab of Professor David Liu at Harvard University. The Liu lab is famous for engineering and evolving proteins that can be utilized as massively impactful tools for overcoming diverse diseases.  

  • Travis’s teachers fostered a curiosity that created a passion for chemistry and ultimately led him to engineer new biochemistries. 

Key Takeaways

  • Proteases are enzymes that cut up other proteins.

  • Proteases can either be non-specific, a nuke obliterating any protein in their path,  or sequence-specific, a heat-seeking missile only cutting very specific protein motifs.

  • Sequence-specific proteases that target disease-causing proteins would make great drugs but therapeutically useful proteases rarely exist in nature.

  • Travis focuses on re-engineering the sequence-specific protease known as botulinum neurotoxin so that it cuts an entirely new, therapeutically relevant protein sequence.

  • Using a method called PANCE that utilizes bacteria and bacterial viruses (phages), Travis trains botulinum neurotoxin toward cutting a new target and leaving its original target alone.

Translation

  • Botulinum neurotoxin has a cutting domain that Travis engineered toward a therapeutically relevant target, and a targeting domain that delivers the protein toward neurons.

  • The enzymes generated could be used to cure neural pathologies but the PANCE could also be applied to change which cell type the protease targets, creating a highly programmable therapeutic protease platform.

  • The platform has a ton of interest from industry and Travis is continuing to work on it outside of academia so that these proteases make it to the clinic and impact patient lives.

Paper: Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity

Season 2, Episode 2: A New Era of Antibiotic Discovery with James Martin

First Authors: James Martin, Benjamin Bratton, Joseph Sheehan

Episode Summary: Bacteria are rapidly evolving ways to resist antibiotics, causing minor infections to become life-threatening events. Compounding the problem, new antibiotics have been incredibly challenging to develop and pharma is economically disincentivized to invest in finding them. James Martin and his colleagues Joseph Sheehan and Benjamin Bratton took on this challenge, developing an extremely potent antibiotic that targets multiple different classes of bacteria. James tells the story of identifying this antibiotic, understanding its potential, and pinpointing how its structure begets its function. Describing the state-of-the art CRISPR screens, proteomics, and machine learning methods they used, James calls for a new era of antibiotic discovery to meet the impending wave of superbugs.

About the Author

  • James Martin performed this work as a graduate student in Professor Zemer Getai’s lab at Princeton University.

  • James’s optimism and drive to understand a problem from all angles led him and his colleagues to develop one of the most potent antibiotics ever found.

Key Takeaways

  • Our arsenal of antibiotics will soon be worthless, as bacteria evolve ways to get around their killing effects.

  • Adding new antibiotics to this arsenal has been slow because they are challenging to discover and they have poor return on investment.

  • Synergizing a number of new biological tools available, like high throughput microscopy, CRISPR, and machine learning, new antibiotics can be developed and understood faster than ever before.

  • Applying this fresh take on antibiotic discovery, a novel drug is found that targets a wide-variety of bacteria and is difficult to evolve resistance to.

Translation

  • Moving this extremely potent compound to the clinic will require some smart biochemistry to make it a better drug.

  • The research of James and his colleagues demonstrates a paradigm shift in how antibiotic discovery pipelines are performed to more easily and rapidly find these new drugs.

Paper: A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance