Tailoring phages for patients: Inside Baylor College of Medicine’s TAILΦR initiative

Issue 66 | March 6, 2020
10 min read
Capsid and Tail

TAILΦR (Tailored Antibacterials and Innovative Laboratories for phage (Φ) Research) is an academic, Baylor College of Medicine initiative dedicated to phage research, therapy, and technologies.

This week, a group of researchers led by Dr. Anthony Maresso at Baylor College of Medicine describe their new initiative, TAILΦR, which makes phages tailored to patients’ infections.

Also in this issue: new insights into phage-antibiotic synergy, resurrection of a class of single-stranded DNA phages, surprising findings about phage-host interactions, and more!

What’s New

Carmen Gu Liu (Baylor College of Medicine) and colleagues published a new preprint on phage-antibiotic synergy. They’ve created a comprehensive method for evaluating synergism, additivism, and antagonism for all antibiotic classes, (they’re calling it “synography”). They found that phage-antibiotic synergy is dependent on antibacterial mechanism of action, leads to reduced phage resistance emergence, is driven by phage burst size, and can be suppressed by serum and urine.

ResearchPhage Therapy

Paul Kirchberger (UT Austin) and colleagues published a new paper in eLife showing the resurrection of Gokushoviruses, barely-understood single-stranded DNA phages found in metagenomic datasets worldwide, in an experimentally tractable model system. They show that the virions can infect, lysogenize and persist cytoplasmically without collapsing their host cultures.

Research

Anushila Chatterjee (University of Colorado School of Medicine) and colleagues published a new paper in mBio investigating Enterococcus faecalis interactions with a virulent phage. They highlight roles for polysaccharide antigens and DNA mismatch repar in phage infection, and show that infection alters quorum sensing and polymicrobial competition gene expression. They conclude that phages can influence complex microbial behaviour that could have important collateral effects on communities.

ResearchPhage Genomics

Abul Tarafder (University of Oxford) and colleagues published a paper in PNAS showing how the phage Pf4 forms a sheath made of liquid crystalline droplets around its host, Pseudomonas aeruginosa, which protects it from antibiotics and more. This study combines electron cryomicroscopy, cryotomography, and more to thoroughly assess these occlusive sheaths. Check out the impressive images and videos!

ResearchBacterial virulenceAntimicrobial resistance

Patrick Secor (University of Montana) and colleagues published a review on Pf phages and what we know so far about their impacts on Pseudomonas virulence, immunity and chronic infections.

ReviewTemperate phages

Reminder: thinking of submitting an abstract for Viruses of Microbes 2020 in Portugal this July? The abstract deadline is coming up soon: March 16th!

ConferencePhage Research

STAT Madness has begun and there are 2 days left in round 1. Vote for the best biomedical innovations (in a “March Madness”-style format!). Phage therapy for alcoholic liver disease (UCSD) is in the running!

ContestPhage Therapy

Latest Jobs

The Department of Medical Microbiology & Immunology at the University of Alberta invites applications for a Tier 2 Canada Research Chair tenure-track position at the assistant professor level. Seeking outstanding candidates with a strong research program in virology or bacteriology; antimicrobial resistance and phage therapy are listed as specific examples.
The University of Copenhagen is hiring a research assistant to work on a project that involves developing mathematical models for lactic acid bacteria phage development in dairy fermentations.
The Edinburgh Institute of Zhejiang University is hiring a fully funded PhD position for a project on phage and phage therapy, involving both wet lab and bioinformatics.

Community Board

Anyone can post a message to the phage community — and it could be anything from collaboration requests, post-doc searches, sequencing help — just ask!

March 5, 2020

Boston PFU’s Second Meetup

The second meeting of Boston PFU (Phage Fanatics United) takes place March 19 at 5:30 pm at the Harvard Medical School Countway Medical Library. There will be food and two phage research talks (by Mia Liberman and Sian Owen). Doing phage work in the Boston area? Sign up for their Slack channel and mailing list here!

Phage meetup
March 5, 2020

Phage talks at the Global Virome in Health and Disease Keystone Symposium

The Global Virome in Health and Disease Keystone Symposium happened this week, and there were many phage talks! Check out the hashtag #ksvirome on Twitter to catch up. And in the spirit of openness, Rob Edwards (SDSU) made his crAssphage presentation for the event available online!

Conference
March 5, 2020

Q&A: making phage mutants

Important question: if I had a student who wanted to make an undomesticated bacteriophage mutant that could not make plaques, other than conditionally, is there a way other than bashing plaque isolates at two temperatures after random mutagenesis? — @markowenmartin

Check out responses, or add your own thoughts, via Twitter here!

MethodsQ&A

Tailoring phages for patients: Inside Baylor College of Medicine’s TAILΦR initiative

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Associate Professor
Baylor College of Medicine, Houston, TX, United States

Anthony William Maresso is a professor and scientist at Baylor College of Medicine in Houston, Texas. His research aims to understand how bacteria cause disease in their human hosts so as to discover and develop preventative vaccines and therapies for deadly infections. When not in the laboratory or teaching, he enjoys hiking, camping, fishing, woodworking, and gardening with his wife, Karen, and their three sons, Leo, Christian, and Maxwell.

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Graduate Student
Baylor College of Medicine, Houston, TX, United States
Tailor Service Center

Sabrina Green is a senior graduate student in Dr. Anthony Maresso’s lab in the department of Molecular Virology and Microbiology at Baylor College of Medicine in Houston, Texas. Her early research was on the pathogenesis of Extraintestinal pathogenic E. coli (ExPEC). Now she works to develop phage therapy to prevent gut-derived infections caused by ExPEC. She is currently the microbiome lead, social media lead and advisor for TAILΦR.

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Director of Operations
Tailor Service Center
Baylor College of Medicine, Houston, TX, United States

Austen Terwilliger is the Director of Operations for the TAILΦR service center at Baylor College of Medicine in Houston, Texas. His current research interests include developing technologies to rapidly discover, evolve, and purify bacteriophages. He’s an avid fisherman, weekend disc golfer, and occasional satirist.

How did you first get involved with phage research? What do you find most interesting about phages or phage therapy?

To some degree, we have always been interested in this topic. But only recently, the last five years or so did we ramp up our efforts. Really, our interest grew as the antimicrobial resistance crisis grew.

We remain in awe of the adaptability and evolvability of all life forms, especially microbes. The reason we keep having trouble with bacteria is not because we cannot come up with ways to stop them, it’s because they evolve to overcome these ways so fast. Their ability to change, essentially mutate, is their greatest attribute. In a population of billions of cells, theoretically only one is needed to overcome an antibiotic or vaccine; once it arises, natural selection chooses it to dominate the new ecological landscape. Then it spreads.

This is why phage research is so intellectually appealing – they compete in the original predator-prey dynamic – an evolutionary experiment as old as life itself that you can observe in real time; and, like bacteria, they mutate and evolve too. If we can harness this evolvability in a specific way, what we sometimes call in the lab “directed evolution”, we can adapt phage as quickly to their bacterial hosts as bacteria can adapt to our current antibiotics, if not faster.

Can you talk about the TAILΦR project at BCM. How is this going to change the state of phage therapy in the US today?

TAILΦR (Tailored Antibacterials and Innovative Laboratories for phage (Φ) Research) is an academic, Baylor College of Medicine initiative dedicated to phage research, therapy, and technologies. We strive to foster a collaborative environment between academia, industry, and medicine.

Bacteria change, but our medicines, like antibiotics, do not. Penicillin has the same structure it had when it was first synthesized in the 1940s. This idea explains the modern antibiotic resistance crisis. Evolutionary adaptation drives bacterial resistance to all of our drugs, vaccines, and engineering controls. When it comes to treatment, bacteria are a microbial “moving target”. We need medicines that adapt and change quickly to hit that moving target. TAILΦR was founded because we believe in a personalized, rapid approach whereby we use phage developed specifically against the patient’s strain as a means to their therapy. We bank these phages and classify them by type of infection and the institution they come from. The objective is to generate the largest bank of adapted and tailored phages to all bacterial infectious disease problems and allow physicians around the world access to this bank to help solve their own patients’ problems.

If resistance arises during therapy, we will use our directed evolution procedure and technologies to identify new phages that target the resistant strains. We specifically seek phages that have enhanced activity and work in the microenvironments where the infection occurs – blood, urine, sputum, at the mucosal surface, on catheters, or on prosthetics. We also search for phages with enhanced activity towards biofilms and/or edit “bad” bacteria from our diseased microbiomes. Also, we have a high-throughput method to screen for antibiotics and phage that synergize with each other. We believe this phage-antibiotic “1-2 punch”, using adapted phage with antibiotics targeted to a specific type of infection, give the best chance at clinical success.

Bacterial resistance to antibiotics and phage therapy is inevitable, but a personalized approach maximizes a phage’s capacity for change to constantly antagonize their bacterial targets. We will work with doctors, hospitals, insurance companies, and regulatory agencies to advocate for this personalized approach while developing the methodologies, facilities, and libraries to make it successful.

Frankly, all medicine will eventually head in this direction. We already see it with cancer therapy (T-cell for example) and the use of gene therapy to fix very specific mutations in one’s genome. TAILΦR is essentially the infectious diseases version of this approach. We hope to provide a model for all medicine to follow.

Have you started makes phages for patients? Treating patients?

Yes, we have at least a dozen or more cases ongoing at this time and each of them is a little different and brings its own challenges.

TAILΦR itself, as a unit, does not treat patients. Specifically, we are a collection of scientists that discover, characterize, and evolve phages for potential treatment, create and vet therapeutic cocktails, then ship therapeutic-quality cocktails to the treating physicians. Our main purpose is to use our skillset and expertise to offer hope, essentially to lay the basic science foundation for making informed decisions.

Who is funding this project?

TAILΦR is funded by the Baylor College of Medicine, foundational grants, and contracts with companies. The leadership of BCM is outstanding. They are always open to creative ideas to push medicine’s boundaries forward. They are the main reason TAILΦR can flourish in these early stages. We are also building a fee-for-service arm to consistently supplement these resources on an “at-cost” basis.

Are you looking to work with collaborators?

We have several partners already, but we are actively seeking industrial and pharma partners to help take these approaches to the next level. If there are companies that wish to develop our adapted phages for specific bacterial problems, we welcome working with them. Like all new medicines, pharma ultimately brings them to the market for large-scale use. Our objective is to give pharma the very best chance at having phage survive the rigors of clinical trials. We welcome collaborations with anyone – scientists, doctors, hospitals, institutions, and companies.

Please contact us at [email protected].

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