Some Delirious Musings on the Application of Phages
Lately, I’ve been spending a lot of my time working with (and thinking about) phages. Along the way, I had some ideas and wanted to share them with you.
Fair warning – this article touches on some more advanced ideas in microbiology. For those of you who aren’t familiar with what a phage is, feel free to check out this primer from Kurzgesagt – it’s really well-done.
If not, let’s begin.
Phages as Immune-Sensitization Agents
Normally, when bacteria breach our tissues, they get tagged by molecules called opsonins.
In essence, opsonins are the molecular equivalent of “Free Food” signs. They bind to the surface of pathogens and mark them to be engulfed by hungry phagocytes.
Phages are great at binding to specific bacteria – after all, this is their evolutionary specialty. What they tend to struggle with is killing the bacteria. When you pit a single phage against a colony of bacteria, for instance, the bacteria almost inevitably develop resistance.
Idea: What if you engineered phages to express opsonins on their surface? In practice, this would simply mean editing the genetic payload the phage manufactures these proteins on its own (i.e C3b or the constant fragment of the IgG antibody).
This way, we couple the phage’s ability to bind to bacteria with the immune system’s exquisite ability to destroy them.
Phages to Rapidly Characterize Urinary Tract Infections
Think of phages as entrepreneurs trying to capitalize a certain market (bacteria).
With this analogy, it becomes clear that the prosperity of a phage depends on the abundance of its bacterial host.
In the past, we’ve exploited this relationship quite elegantly to detect conditions like sepsis.
If a certain bacteria is thriving (as you might see in a budding infection), the numbers of its corresponding phage, as measured through cell-free DNA assays, will be disproportionately high. All other phages will be relatively unaffected.
As it is, this approach is designed to detect bacterial burden in the blood. Here, I’d like to propose an extension of this approach to detect urinate tract infections.
Idea: What if we developed phages that were small enough to enter the nephrons of the human kidney?
If someone’s bladder is colonized with a specific kind of bacteria, its corresponding phages will have a greater opportunity to replicate, and we’ll see those phages over-represented when we run them through urinalysis.
Phages as Bacterial Imaging Dyes
For the past few centuries, the methods we’ve used to image microbes hasn’t fundamentally changed. Whether we call it the gram stain or crystal violet, we’ve always used some form of colored or fluorescent chemical to hybridize and illuminate specific features on bacteria.
Idea: What if we could visually render bacterial samples with phages?
With some engineering (I.e. with luciferin or any colored molecule), phages could potentially offer a new level of resolution and tunability when imaging bacteria, letting us target them not only by species, but by individual molecules and phenotype.
What’s more promising, though, is that phages aren’t static. Unlike dyes, which struggle to image as they grow and replicate, phages can replicate with bacteria. Almost by design, they’re the perfect vehicles to see bacteria in real time.
An Invite for Dialogue
These were a few ideas I came up with on a flight from Denver to Toronto. Maybe the low oxygen content did strange things to my mind. If you’d like to challenge any of the claims I’ve made (or just share your thoughts), I’d love to hear from you.
Feel free to drop your comments in the thread, or email me at aaryanh@stanford.edu to continue our conversation async.
