Current Research

Graham Hatfull's project uses bacteriophage discovery and genomics—phage hunting—to engage undergraduate and high school students in authentic scientific research. Student researchers identify previously unknown bacteriophages (viruses that infect bacteria), analyze their genomes, and design experiments to determine the function of specific bacteriophage genes.

In 2002, we established the Phage Hunters Integrating Research and Education (PHIRE) program. Our goal was to develop a platform in which novice scientists—primarily undergraduate and high school students—could become engaged in authentic scientific research. The research focuses on the discovery and comparative genomics of bacteriophages, viruses that infect bacteria, and takes advantage of the abundance and diversity of the phage population. Each student in the program isolates a novel virus from the environment, names it, and learns how it is related to other viruses through genomic characterization. The initial steps are technically and conceptually simple, but the project becomes more complex and abstract as it progresses. The excitement of discovery and the power of project ownership motivate students to tackle the more challenging tasks.

The phages we have focused on are the mycobacteriophages—viruses that infect mycobacterial hosts including Mycobacterium tuberculosis. They can be used to address questions of viral diversity and evolution, and also to develop genetic and clinical tools for understanding and controlling mycobacterial diseases. However, the primary host we use is M. smegmatis, a relatively fast-growing and non-pathogenic relative of M. tuberculosis. The PHIRE program thus seeks to satisfy the scientific goal of exploring the comparative genomic analysis of a collection of phages known to infect a common host, and the educational goal of developing a platform for engagement of novice students in authentic scientific research.

Students in the PHIRE program learn that the chance to engage in cutting-edge scientific exploration comes with the responsibility to teach others how to do the same. Because each student follows a parallel set of procedures and protocols, advanced students in the program have the opportunity to mentor those who are just starting. We also expect students to coauthor submission of their annotated phage genome sequence to the public databanks and to coauthor manuscripts for publication in peer-reviewed scientific literature.

From examination of the PHIRE program, we have identified seven attributes that we hypothesize are beneficial towards achieving the goal of engaging novice students in authentic research, and which should be generally applicable to other programs in other disciplines sharing this goal. These are

  1. Technical simplicity, especially at initial stages
  2. Conceptual simplicity transitioning to complex operations
  3. Compatibility with flexible scheduling
  4. Multiple achievement milestones
  5. Parallel project structure
  6. Authentic, publishable research
  7. Project ownership providing strong motivation

These key features of the PHIRE program suggested that it lends itself to broader dissemination. In 2002, HHMI established the Science Education Alliance (SEA) to facilitate such dissemination and adopted the PHIRE program as the first main initiative. From this was born the SEA Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) program, establishing a two-term, course-based research experience for freshman undergraduates.

The program started with 12 institutions in 2002 and added institutions each year since. Today there are 72 schools involved, with more than 2,000 students in the current year (2013 - 2014). Faculty and Teaching Assistants are trained in two one-week workshops, one focusing on the first term that involves microbiology and molecular biology approaches, and a second for the bioinformatic methods.

Data coordination is facilitated by a database and web site at where students can deposit information about the phages they discover and access all the data for broad comparative genomic analyses.  Other tools include the program Phamerator (developed Dr. Steve Cresawn at James Madison University) for comparing phage genomes and the genes they encode. The number of fully sequenced mycobacteriophage genomes now exceeds 650, spanning remarkable diversity given that these all infect exactly the same host strain of M. smegmatis.

SEA-PHAGES students benefit significantly from the program and score as well as or better on all 20 learning gains of the CURE III survey compared to the SURE students, reflecting benefits at least equivalent to those accrued through a summer-long apprentice-based undergraduate research experience. SEA-PHAGES students also showed enhanced retention in STEM, and strong performance in other classwork.

Research in the Hatfull Lab

My lab is interested in the exploration and exploitation of mycobacteriophages, viruses that infect mycobacterial hosts such as Mycobacterium tuberculosis. Discovery and genomic analysis of a large set of mycobacteriophages—all known to infect a common M. smegmatis host—reveals them to be enormously genetically diverse and containing vast numbers of genes of unknown function with no homologues in the sequence databases. Nevertheless these phage genomes contain many genes related to host genes suggesting that they may act to modify the physiology of their hosts. Mycobacteriophages are therefore rich topics for discovery and genomic analysis, presenting an effective platform for an introduction to research for novice scientists. They also present an abundance of mysteries about gene function, regulation, and evolutionary mechanisms. Approaches such as mutagenesis, transcriptomics, and ribosomal profiling, hold promise to resolve these mysteries.

Mycobacteriophages represent terrific toolboxes for mycobacterial genetics. On one hand, they have evolved to efficiently introduce their DNA into their bacterial hosts and can thus be used as vehicles to introduce transposons, reporter genes, and recombination substrates into M. tuberculosis. On the other hand, many of their component parts function as well-oiled machines, and can be adapted for use to modify their hosts; these include integration systems for inserting foreign DNA into bacterial genomes, mycobacterial-specific recombineering, and non-antibiotic selectable markers.

Last updated May 2014

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