Translation - Phage Evolved Medicine with Travis Blum

Phage Evolved Medicine with Travis Blum

09/23/21 • 40 min

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.

Episode Notes:

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.

First Author: Travis Blum

Paper:

Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity

Episode Notes:

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.

First Author: Travis Blum

Paper:

Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity

Previous Episode

What boosts immune boosters? with Kevin Litchfield

Episode Summary:

Novel drugs that boost the immune system to fight cancer have become pharma darlings in the few short years since their approval. These drugs, known as immunotherapies, have so far focused on improving T cell responses and can be used to cure a multitude of different cancer types. Yet more often than not, immunotherapies have no effect on a patient, leaving doctors guessing on whether to prescribe the drug. To find the reason why some people respond while others don’t, Kevin and his team create a huge database of sequences derived from immunotherapy-treated patients. With it, he discovers biomarkers, mutational signatures, and immune profiles that correlate to response with the hopes that one day, these measurements form a diagnostic to ensure we treat the right patients.

Episode Notes:

About the Author

Kevin is a group leader at University College London and performed this work in the lab of Charles Swanton at the Francis Crick Institute. Dr. Swanton and his group are experts in studying the genome instability and evolution of cancer.
Kevin started his career as a mathematician but was always driven to apply his skills to improving medicine.

Key Takeaways

Immunotherapies aim to cure cancer by “taking the breaks off” your immune system, supercharging it to attack tumors.
Two immunotherapies known as checkpoint inhibitors (CPI), anti-CTLA-4 and anti-PD-1, work by enhancing T cells and have recently become blockbuster drugs for the treatment of multiple different cancer types.
These immunotherapies don’t work in many patients and medicine has yet to understand why.
Kevin aggregated DNA and RNA sequencing data across multiple studies to generate a dataset that contained over 1,000 CPI treated patients who did and did not benefit from treatment.
With this data, Kevin discovers mutational signatures, biomarkers, and immune profiles that correlate to whether a patient will respond to treatment.

Translation

Kevin finds measurable signatures of a patient’s cancer that could be used to determine whether a patient should receive CPIs.
This retrospective analysis will need to be validated as a prospective study to determine whether Kevin’s findings actually predict response.
More tumor data as well as information about the patient’s genetics is being brought in to improve the accuracy of this prediction.
Collaborations between academics, medical centers, non-profits, and industry partners will enable the findings to make an impact on patient outcomes.

First Author: Kevin Litchfield

Paper: Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Next Episode

Listening to Neurons with Sumner Norman

Episode Summary:

Brain machine interfaces untangle the complex web of neurons firing in our brains and relay the underlying meaning to a computer. These devices are being adapted to help patients regain motor control, monitor our mental well being, and may one day even make us more empathetic. State of the art methods to do this have massive trade-offs, either being high resolution yet requiring devices to be embedded in our heads or low resolution but non-invasive. Finding a key middle ground, Sumner uses advances in ultrasound to monitor the brain activity of monkeys performing specific tasks. With this data, he can not only record the brain activity associated with performing the task itself but also the intention of doing it before the subject even has a chance to move.

Episode Notes:

About the Author

Sumner started his career in mechanical and aerospace engineering, performing research on haptics and mechatronics.
This developed a love for how humans and computers interact, leading him to earn a PhD developing exoskeleton robots for motor learning and control.
Through this, he realized that to translate these technologies, we need better methods to get information out of the brain.

Key Takeaways

Ultrasound technologies are leveraged to monitor brain activity.
The signal that is generated when these methods “listen” to the brain is extremely complex and entangled, akin to trying to make out a sentence from across a loud stadium.
Sumner taught monkeys how to perform a task, reading the brain with ultrasound and using machine learning to decode the message.
With it, they were able to read which way the monkey intended to move, when the movement would occur, which way the monkey actually moved, and whether it would move its hands or eyes.

Translation

This technology has massive potential to help those suffering from motor impairment and could one day connect us all on a deeper level.
To get there, the device will need to be optimized to find the best way to maximize signal-to-noise but minimize invasiveness.
Additionally, advances in miniaturization, wireless connections, lowered cost of goods, and finding the right balance between AI and BMI control are needed to get this extremely new technology into the hands of everyone.

First Author: Sumner Norman

Paper:

Single-trial decoding of movement intentions using functional ultrasound neuroimaging