Molecular Medicine Israel

Tiny Answers to Big Questions

The most abundant biological entities on Earth still have a few tricks up their sleeve, and a recent surge of research is reinvigorating the field. With the potential to dramatically expand known protein sequence space, give insights into unprecedented biological processes, and provide means to wipe out antibiotic-resistant superbugs, bacteriophages may be tiny, but they are mighty.
Bacteriophages, the ubiquitous and extremely diverse viruses that infect bacteria, are estimated to outnumber their bacterial hosts by a factor of ten. Anywhere bacteria thrive—from deep-ocean hydrothermal vents, to Arctic permafrost, to our own intestines—phages are abundant. With 1023 phage infections happening every second on Earth, it is clear that the extreme evolutionary pressures imposed by phages have shaped bacterial evolution. By transferring genetic material between bacteria, phages profoundly influence the emergence and spread of antibiotic resistance and virulence traits.

Decades ago, phages helped scientists make many of the seminal discoveries in molecular biology and genetics. From the revelation that DNA is the hereditary material of cellular life, to the existence of a triplet code in translation, to foundational principles in DNA replication and recombination, phages were an integral part of the molecular biologist’s toolkit. Although they are often underappreciated, we can largely thank phages for the field of molecular biology itself.

The phage legacy carries on even today, a century after their discovery. Notably, the study of interactions between bacteria used in the dairy industry and the phages that infect them led to the first evidence of the true function of CRISPR-Cas systems (Barrangou et al., 2007). Through ten years of intense research, these fascinating bacterial defense systems have been developed for genome engineering applications in countless eukaryotic organisms—even human embryos—and their potential impact on biomedical research, agriculture, and therapeutics is astounding.

But phages aren’t just tools we can use to study fundamental biological processes. Apart from being the most abundant biological entities on the planet, phages are also the most diverse. Although many of us may conjure images of phage lambda or T7 from undergraduate textbooks, these well-studied examples are nowhere close to being representative. With more genome sequences becoming available at an unprecedented pace, scientists have a wealth of genetic “dark matter” to explore. Phages remain one of the largest untapped resources of completely novel genetic material, which is sure to contain many surprises.

By exploring this incredible diversity, we are still learning unexpected things about what makes phages such effective bacterial killing machines. Early in 2017, a study in Nature reported the first evidence that phages communicate with each other. By producing and sensing small peptides as chemical messengers, phages make decisions about whether to proceed with the lytic or lysogenic infection cycle based on the abundance of phages present, in a mechanism analogous to bacterial quorum sensing. Although many different phages have this system, the sequence-specific production and recognition of the communication peptide ensures that each type of phage speaks and understands its own “language.” By controlling the dimerization of a phage-encoded transcriptional regulator, the peptide concentration can elicit different transcriptional responses, tuning the infection dynamics depending on the phage population density (Erez et al., 2017).

A study published in Science demonstrated that some phages assemble a specialized compartment within their host’s cytoplasm to facilitate spatial and temporal control over the phage replication cycle. This nucleus-like structure, composed of a phage-encoded protein shell, sequesters the phage genome and machinery involved in DNA replication and transcription. Remarkably, the authors observed phage capsids (heads) docking on the surface of the compartment to be packaged with phage DNA, then retreating back to the cytoplasm to assemble with tails into mature phage particles (Chaikeeratisak et al., 2017). It remains to be determined how common this process is, how different components are trafficked in and out of the compartment, and whether it may play a role in protecting phages from bacterial defenses like CRISPR during the infection process.

Apart from investigating these intriguing, natural biological processes, research into phage infection mechanisms has laid the groundwork for novel therapeutics. For many years, phage-based therapies for bacterial infections only gained traction in former Soviet nations, where a lack of western antibiotics necessitated the use of alternative treatments. No phage-based therapies have yet been approved in the United States for infectious disease treatment, but with the rise of antibiotic-resistant infections, many scientists are turning their attention back to nature to harness the incredible power of phages to kill bacteria. Just this spring, news articles emerged about a patient in San Diego, California, with a severe systemic bacterial infection that was resistant to all antibiotics. Doctors had run out of options to fight the infection, and as a last resort, the patient was treated intravenously with an experimental cocktail of phages. Remarkably, the patient awoke from his septic-shock-induced coma within three days of treatment and was later released from hospital with no apparent adverse effects of the phage injections (University of California, San Diego, 2017). Despite being only a single patient, this success will undoubtedly fuel future efforts into phage therapy.

Phages really have it all: an impressive track record in molecular biology, a wealth of completely novel and unexpected biology, and a new renaissance of therapeutic potential. It has never been clearer that groundbreaking phage research is sure to carry on for the next hundred years and beyond.

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