Graham Hatfull, Ph.D.

  • HHMI Professor; Eberly Family Professor of Biotechnology
  • Department of Biological Sciences

Education & Training

  • Ph.D. in Molecular Biology from Edinburgh University, U.K., 1981
  • B.S. in Biological Sciences from Westfield College, University of London, U.K. , 1978

Research Interest Summary

Molecular genetics of mycobacteria; site-specific recombination.

Research Categories

Research Interests

Mycobacterium tuberculosis kills more people than any other single infectious agent. Since antibiotics are available and the BCG vaccine is in widespread use, why do nearly three million people die each year from TB? The answer, in part, is that we really don't understand this curious bacterium or what parts of its genetic instructions make this such a deadly pathogen. At the heart of our strategies to understand mycobacterial genetics is the mycobacteriophages - viruses that infect the mycobacteria (an electronmicrograph of bacteriophage Bxz1 is shown to the left). These are easy to grow and manipulate and offer advantages over working with the slow-growing mycobacteria (such as M. tuberculosis) that can take up to a month to produce a colony on an agar plate. Phages are also rich sources of a wide variety of potential genetic and molecular tools that can be used to study - and to modify - their bacterial hosts.

Here's just a flavor of some of the current studies going on in the lab:

  • Bacteriophage genomics We have sequenced about half-a-dozen mycobacteriophage genomes and - in collaboration with Dr. Hendrix - an equivalent number of other phage genomes. These studies have not only provided some valuable insights into how this incredible collection of organisms have evolved, but fuels our mycobacterial investigations by continually providing new phage systems to study.
  • Mycobacterial Gene Expression We have identified novel strategies that the mycobacteria use for regulating gene expression. We have used these for developing tools for controlled expression of genes in mycobacteria and are now delving into the mechanisms of how these system works.
  • Site-specific recombination Several of the mycobacteriophages that we are investigating integrate their DNA into the host chromosome (and can excise them too). We are building a variety of mycobacterial vectors that use these systems to permit the integration of any desirable genes into mycobacterial genomes. We are also using these as model systems to investigate the molecular mechanisms involved in site-specific recombination and attempting to elucidate how phages dictate the directionality of these events.
  • Tools - Genetic and Clinical Studying the mycobacteria and their phages has great potential for the development of novel tools for their genetics but also for a more direct clinical involvement. Two systems we have been involved in developing are multivalent recombinant BCG vaccines and Luciferase Reporter Phages, but there are numerous additional strategies awaiting further development!

Representative Publications

Huang J, Ghosh P, Hatfull GF, Hong Y. (2011). Successive and Targeted DNA Integrations in Drosophila Genome by Bxb1 and PhiC31 Integrases. Genetics EPub

Bai, H., Sun, M., Ghosh, P., Hatfull, G. F., Grindley, N. D., & Marko, J. F. (2011). Single-molecule analysis reveals the molecular bearing mechanism of DNA strand exchange by a serine recombinase. Proc Natl Acad Sci U S A. 108, 7419-7424.

Rondon, L., M. Piuri, W. R. Jacobs, Jr., J. de Waard, G. F. Hatfull & H. Takiff, (2011) Evaluation of Fluoromycobacteriophages for detecting drug resistance in Mycobacterium tuberculosis. J Clin Microbiol.

Pope WH, et al. (2011) Expanding the Diversity of Mycobacteriophages: Insights into Genome Architecture and Evolution. PLoS ONE 6(1): e16329

Anderson WA, Banerjee U, Drennan CL, Elgin SC, Epstein IR, Handelsman J, Hatfull GF, Losick R, O'Dowd DK, Olivera BM, Strobel SA, Walker GC, Warner IM (2011) Science education. Changing the culture of science education at research universities. Science 331(6014): 152-153.

Alibaud, L., Alahari, A., Trivelli, X., Ojha, A. K., Hatfull, G. F., Guerardel, Y., and Kremer, L. (2010). T emperature-dependent regulation of mycolic acid cyclopropanation in saprophytic mycobacteria: role of the Mycobacterium smegmatis 1351 gene (MSMEG_1351) in CIS-cyclopropanation of alpha-mycolates. J. Biol. Chem. 285, 21698-21707.

Ojha, A. K., Trivelli, X., Guererdel, Y., Kremer, K., & Hatfull, G. F. (2010) Trehalose dimycolate (TDM) is the precursor for synthesis of free mycolic acids (FM) in mycobacterial biofilms. J. Biol. Chem. 285,17380-17389.

Hatfull, G. F., Jacobs-Sera, D., Lawrence, J. G., Pope, W. H., Russell, D.A., Ko C-C., Weber, R. J., Patel, M. C., Germane, K. L., Edgar, R. H., Hoyte, N. N., Bowman, C. A., Tantoco, A. T., Paladin., Myers, M. S., Smith, A. L., Grace, M. S., Pham, T. T. O'Brien, M. B., Vogelsberger, A. M., Hryckowian, A. J., Wynalek, J. L., Donis-Keller, H., Bogel, M. W., Peebles, C. L., Cresawn, S. G., Hendrix, R. W. (2010) Comparative genomic analysis of sixty mycobacteriophage genomes: Genome clustering, gene acquisition and gene size. J Mol Biol. 397, 119-143.

Traag, B. A., Driks, A., Stragier, P., Bitter, W., Broussard, G., Hatfull, G., Chu, F., Adams, K. N., Ramakrishnan, L., Losick, R. (2010) Do mycobacteria produce endospores? Proc. Natl. Acad. Sci. (USA) 107, 878-881.

Sampson T, Broussard GW, Marinelli LJ, Jacobs-Sera D, Ray M, Ko CC, Russell D, Hendrix RW, Hatfull GF. (2009). Mycobacteriophages BPs, Angel and Halo: comparative genomics reveals a novel class of ultra-small mobile genetic elements. Microbiology, 155, 2962-2977.

Payne, K., Sun, Q., Sacchettini, J., & Hatfull, G.F. (2009), Mycobacteriophage Lysin B is a novel mycolylarabinogalactan esterase. Mol. Microbiol., 73, 367-381.

Piuri, M., Jacobs Jr., W. R. & Hatfull, G. F. (2009) Fluoromycobacteriophages for Rapid, Specific, and Sensitive Antibiotic Susceptibility Testing of Mycobacterium tuberculosis. PLosOne. 4, e4870.

Stewart, C. R., Casjens, S. R., Cresawn, S. G., Houtz, J. M., Smith, A. L., Ford, M. E., Peebles, C. L., Hatfull, G. F., Hendrix, R. W., Huang, W. M., Pedulla, M. L. (2009) The genome of Bacillus subtilis bacteriophage SPO1. J. Mol. Biol. 388, 48-70.

Marinelli, L. J., Piuri, M., Swigoňová, Z., Balachandran, A., Oldfield, L. M., van Kessel, J. C. and Hatfull, G. F. (2008). BRED: A Simple and Powerful Tool for Constructing Mutant and Recombinant Bacteriophage Genomes. PLosOne. 3:e3957.

Ojha, A.K., Baughn, A.D., Sambandan, D., Hsu, T., Trivelli, X., Guerardel, Y., Alahari, A., Kremer, L., Jacobs, W.R., Jr., and Hatfull, G.F. (2008) Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harboring drug-tolerant bacteria. Mol Microbiol. 69, 164-74.

Hatfull, G. F., Cresawn, S. & Hendrix, R. W. (2008) Comparative Genomics of the Mycobacteriophages: Insights into bacteriophage evolution. Res. Microbiol. 159, 332-9.

Van Kessel, J.C. and Hatfull, G. F. (2008) Mycobacterial recombineering. Methods Mol. Biol. 435, 202-215.

Ghosh, P., Bibb, L. A., & Hatfull, G. F. (2008) Two-step site selection for serine-integrase mediated excision: DNA-directed integrase conformation and central dinucleotide proofreading. Proc. Natl. Acad. Sci. USA. 105, 3238-3243.

van Kessel, J. C., & Hatfull, G. F. (2008) Efficient point mutagenesis in mycobacteria using single-strand DNA recombineering: characterization of anti-mycobacterial drug targets. Mol. Microbiol. 67, 1094-1107.

Morris, P., Marinelli, L. J., Jacobs-Sera, D., Hendrix, R. W., & Hatfull, G. F. (2008) Genomic characterization of mycobacteriophage Giles: Evidence for phage acquisition of host DNA by illegitimate recombination. J. Bacteriol. 190: 2172-2182.