Biography

Dr. Marilena Fitzsimons Hall earned a B.S. in Chemistry in 1992 from McGill University in Montreal, Canada. She then earned her Ph.D. at the California Institute of Technology (NSERC Fellowship) where she worked in the laboratory of Dr. Jacqueline K. Barton. Her thesis involved the design of a synthetic deoxyribonuclease using a chimera of a DNA-binding rhodium complex and a short Zn2+-coordinating peptide. From 1998-2000, Dr. Hall carried out post-doctoral research at New England Biolabs in Beverly, MA, creating an artificial bifunctional intein capable of both protein splicing and homing endonuclease activity. During her post-doc, she was also an adjunct professor at Massasoit Community College, teaching general chemistry from 1999-2000. Professor Hall joined the Stonehill Department of Chemistry in the Fall of 2000. She earned tenure and was promoted to Associate Professor in 2008 and was promoted to Professor in 2018. She served as Director of the Biochemistry Program from 2008-2017 and is now serving as chair of the Department of Chemistry since 2017. She also served as Faculty Senate President from 2013-2017. 

Research Focus 

Professor Hall’s research program at Stonehill began by using phage-displayed peptide libraries to identify short peptides that could mimic the coordination of Zn2+ in zinc-containing metalloenzymes. Several Stonehill undergraduate students participated in screening the Ph.D.-7 and Ph.D.-12 libraries (displaying 7-mer and 12-mer peptides, respectively, from New England Biolabs) to identify putative zinc-binding peptides, developing a phage-ELISA assay to quantify the zinc-binding of individual peptides sequences, and characterizing the structure of Zn2+-peptide complexes using NMR.  

In screening the 7-mer peptide library against the zinc ion as the target, our lab became aware of a peptide with the sequence HAIYPRH that had also been selected through phage display in several other laboratories using completely different targets, suggesting it as a putative “target-unrelated peptide.” Interesting, the phage display community had recently become aware of target-unrelated peptides (TUPs): nuisance peptides that appear in the results of phage display experiments due to properties distinct from their affinities for the actual target. Menendez and Scott (Anal. Biochem. 2005, 336, 145-57) had compiled several sets of TUPs whose selection was attributed to their binding of other components of the screening systems employed in the panning of phage-displayed peptide libraries. In contrast, we demonstrated that the phage clone bearing the peptide HAIYPRH was enriched during panning experiments due to a dramatically faster propagation rate, which was traced to a G->A mutation in the Shine-Dalgarno sequence of the replicative gene II protein of the M13 phage. Thus, the displayed peptide HAIYPRH was merely coincident with the mutation, and it was the mutation that in fact led to the enrichment of the clone in the pool of phage and, consequently, to its target-independent appearance in numerous experiments. Our first publication (Brammer et al, Anal. Biochem. 2008, 373, 88-98) thereby offered a completely novel mechanism for the appearance of TUPs in a commercial M13-based library, with the HAIYPRH (G->A) clone introduced as the first known “propagation-related TUP,” in contrast to Scott’s “selection-related TUPs” (terms coined by Smith and coworkers, Anal. Biochem. 2010, 407, 237-240). 

Subsequent years saw increased interest in propagation-related TUPs, as evidenced by data-cleaning databases for phage display and several publications about the emergence of propagation-related TUPs in phage display libraries. Our follow-up paper (Nguyen et al, Anal. Biochem. 2014, 462, 35-43) introduced several additional single mutations in the 5’-untranslated region of gene II, not only in the Shine-Dalgarno sequence, but also in the operator sequence upstream of it. This repertoire of mutant phage clones spanned 24 different displayed peptides, many of which had previously been reported by other researchers in phage display experiments using various targets. The peptides displayed by these clones have the potential to be TUPs because the propagation advantages of the phage cause disproportionate increases in their concentrations during the amplification steps between rounds of panning. Because it is important for phage display practitioners to be aware of potential false positive results, we outlined a simple assay that could be used to determine if a clone identified in panning might indeed be a propagation-related TUP. 

Mutations arise in library phage due to a replication defect caused by the insertion of the lacZα gene in the (+) strand origin of the M13 phage variant used to construct the libraries (M13mp19). While the phage are completely viable, they propagate at a significantly slower rate than wild-type M13. Consequently, the phage are susceptible to various mutations that compensate for the replication defect. In our most recent paper (Zygiel et al, PLoS ONE 2017, 12(4), e0176421), we focused on the underlying cause of the replication defect and presented two completely new compensatory events: the ejection of the lacZα insert to restore the (+) strand origin and a silent mutation in gene IV, each of which restores the wild-type propagation rate. We also presented several new mutations in the gene II 5’-UTR, both spontaneously observed and synthetically engineered. We discussed the mechanisms by which these mutations increase the efficiency of replication initiation at the (+) strand origin in order to compensate for the defect. These studies have are of significant interest not only to the phage display community, but also to researchers who study bacteriophage life cycles, replication initiation, compensatory mutations, or other forms of epistasis. 

One recent follow-up project has involved analyzing the series of phage vectors initiated when Joachim Messing inserted the lacZα gene into the ori of wild-type M13 (M13mp1) and ultimately produced the M13mp19 vector, upon which the Ph.D. phage libraries are based (Messing et al, Proc Natl Acad Sci USA 1977, 74(9),3642–3646; Messing et al, Gene 1991, 100, 3–12; Noren and Noren, Methods 2001, 23(2),169–178). Among the vectors in the M13mp series, there are various genetic differences (both within the insert and outside of it, scattered around the genome) that may represent an earlier generation of mutations that first compensated for the lacZα insert. Our goal is to compare the propagation rates of the various M13mp phage in the series and assign any effects on propagation to specific genetic differences between the clones. Another area of interest is to attempt to place the lacZα insert in a less sensitive location in the intergenic region of the M13 genome (or to determine if, perhaps, such a thing does not exist). This ongoing proof-of-concept experiment has so far involved identifying locations, both upstream and downstream of the original location, that minimize the disruption of potentially sensitive features such as the sites of replication initiation and termination, the replication enhancer, the gene IV terminator, and the gene II promoter. 

Over numerous years, we enjoyed a stimulating and fruitful collaboration with Dr. Christopher J. Noren and Karen A. Noren before their retirements from New England Biolabs, and we remain ever grateful for their contributions. It is noteworthy, however, that the vast majority of the experiments have been performed by the amazing undergraduate students at Stonehill College! 

Education

  • B.S. Chemistry, McGill University
  • Ph.D. Chemistry, California Institute of Technology

Grants and Awards 

  • Research Corporation Cottrell College Science Award to fund project entitled Modeling the Zn2+ Coordination Site of Zinc Metalloenzymes Using Peptide Phage Display, 2003. 
  • Stonehill College Outstanding Faculty Service Award (individual), 2017. 
  • Stonehill College Diversity and Social Justice Award (NSF S-STEM FLC group), 2018. 
  • Stonehill College Outstanding Faculty Service Award (NSF S-STEM FLC group), 2020. 

Courses Regularly Taught 

  • Biochemistry I (BCH 343) 
  • Biochemistry Laboratory (BCH 345) 
  • General Chemistry I (CHM 113) 
  • General Chemistry II (CHM 232) 
  • Professional Ethics and Safety in Chemistry and Biochemistry (CHM 301) 

Selected Publications, Articles & Presentations

  • E.M. Zygiel, K.A. Noren, M.A. Adamkiewicz, R.J. Aprile, H.K. Bowditch, C.L. Carroll, M.A.S. Cerezo, A.M. Dagher, C.R. Hebert, L.E. Hebert, G.M. Mahame, S.C. Milne, K.M. Silvestri, S.E. Sutherland, A.M. Sylvia, C.N. Taveira, D.J. VanValkenburgh, C.J. Noren, and M. Fitzsimons Hall. “Various mutations compensate for a deleterious lacZα insert in the replication enhancer of M13 bacteriophage.” PLoS ONE 2017, 12(4), e0176421. https://doi.org/10.1371/journal.pone.0176421
  • K.T.H. Nguyen, M.A. Adamkiewicz, L.E. Hebert, E.M. Zygiel, H.R. Boyle, C.M. Martone, C.B. Meléndez-Ríos, K.A. Noren, C.J. Noren, M. Fitzsimons Hall. “Identification and characterization of mutant clones with enhanced propagation rates from phage-displayed peptide libraries.” Anal. Biochem. 2014, 462, 35-43. http://doi.org/10.1016/j.ab.2014.06.007 
  • L.A. Brammer, B. Bolduc, J.L. Kass, K.M. Felice, C.J. Noren, M. Fitzsimons Hall. “A Target-Unrelated Peptide in an M13 Phage Display Library Traced to an Advantageous Mutation in the Gene II Ribosome-binding Site.” Anal. Biochem. 2008, 373, 88-98. http://doi.org/10.1016/j.ab.2007.10.015
  • M. Fitzsimons Hall, C.J. Noren, F.B. Perler and I. Schildkraut. “Creation of an Artificial Bifunctional Intein by Grafting a Homing Endonuclease into a Mini-intein.” J. Mol. Biol. 2002, 323, 173-179.
  • K.D. Copeland, M.P. Fitzsimons, R.P. Houser, and J.K. Barton. “DNA Hydrolysis and Oxidative Cleavage by Metal-Binding Peptides Tethered to Rhodium Intercalators.” Biochemistry 2002, 41, 343-356.
  • R.P. Houser, M.P. Fitzsimons and J.K. Barton. “Metal-Dependent Intramolecular Chiral Induction: The Zn2+ Complex of an Ethidium-Peptide Conjugate.” Inorg. Chem. 1999, 38, 1368-1370.
  • M.P. Fitzsimons and J.K. Barton. “The Design of a Synthetic Nuclease: DNA Hydrolysis by a Zinc-binding Peptide Tethered to a Rhodium Intercalator.” J. Am. Chem. Soc. 1997, 119, 3379-80.
  • A.E. Grosser, M. Fitzsimons, L. Leonardi and J. Salha.  “Model for a Controlled-Release Drug Delivery Safety System with Permeable and Erodible Coatings.” J. Pharm. Sci. 1993, 82, 1061-3. 
  • "Propagating Undergraduates and Propagating Bacteriophage (and how being a Bartonite got me there)." Symposium in Celebration of the 60th Birthday of Jacqueline K. Barton, Division of Chemistry and Chemical Engineering, California Institute of Technology (Pasadena, CA), March 30, 2012.  
  • Kieu H. Nguyen, Heidi A. Weinreich, Michelle L. Houle, Christopher J. Noren, and Marilena Fitzsimons Hall, “Fast-propagating M13 bacteriophage clones containing gene II promoter region mutations.” Poster presentation. 239th American Chemical Society National Meeting, March 2010, San Francisco, CA. 
  • Marilena Fitzsimons Hall and Barbara Anzivino, “Research proposals and presentations in general chemistry: An extension of the guided-inquiry format.” Poster presentation. 239th American Chemical Society National Meeting, March 2010, San Francisco, CA. 
  • Leighanne A. Brammer, Benjamin Bolduc, Jessica L. Kass, Kristin M. Felice, Christopher J. Noren, and Marilena Fitzsimons Hall, “Detour in the Search for a Metalloenzyme Model: A Target-unrelated Peptide in a Phage Display Library.” Poster presentation. 234th American Chemical Society National Meeting, August 2007, Boston, MA. 
  • Marilena F. Hall and Barbara Anzivino, “Extending Guided-Inquiry Experiments to Research Proposals in General Chemistry.” Lecture as part of Center for Workshops in the Chemical Sciences (CWCS) symposium: Promoting Innovation in Chemical Education Through Workshops and Community Building. 233rd American Chemical Society National Meeting, March 2007.
  • “Characterization of a Target-unrelated Peptide in the Ph.D.-7 Phage Display Library.” Invited lecture as part of the Phage Display of Proteins and Peptides Course, Cold Spring Harbor Laboratory, November 12, 2006.
  • Marilena F. Hall and Cheryl S. Schnitzer, “How to Interview Well (and Keep Your Cool)” Oral Presentation as part of ACS Younger Chemists Committee (YCC)/Council on Undergraduate Research (CUR) symposium “How to Get a Tenure-Track Position at a Predominantly Undergraduate Institution.” 224th National American Chemical Society National Meeting, August 2002, Boston. 
  • M.P. Fitzsimons and J.K. Barton. “Rhodium Intercalators with Appended Peptides: Recognition and Reaction” Oral presentation. 212th American Chemical Society National Meeting, August 1996, Orlando. 
  • M.P. Fitzsimons and J.K. Barton.  “The Design of a Synthetic Nuclease: DNA Hydrolysis by a Zinc-binding Peptide Tethered to a Rhodium Intercalator”  Poster presentation. 212th American Chemical Society National Meeting, August 1996, Orlando.