Associate Professor
Ph.D., University of Michigan, 1993

Program Affiliation: Molecular Biology & Genetics | Microbiology

Research Groups Affiliation: Biochemistry | Microbiology

The genetic code is the Rosetta stone of modern Biology, animating fields from Evolutionary Biology to Proteomics.  Despite the enormous power inherent to the code, our ability to create coding sequences de novo is extremely limited.  The proteins we study are largely the ones provided by Nature, or slightly modified versions wherein key amino acids that affect structure or function are varied.  We posit that the ability to create coding sequences in a straightforward combinatorial fashion, i.e., to create libraries of artificial genes comprising only selected codons, presents a powerful starting point for re-imagining the origin and applications of the genetic code.  We find that open reading frames comprising limited codon sets represent a versatile tool for defining the relationship between primary amino acid sequence and higher order protein structure using a reductionist approach. 

We have developed a robust and technically simple method for constructing libraries of open reading frames comprising only codons selected by the operator.  The SynthOMIC (Synthesis of ORFs by Multimerizing In-frame Codons) strategy maintains the reading frame inherent to the input codons with exceptional fidelity.  It further allows for libraries of ORFs to be constructed with broad control over variables such as the identity of translated amino acids, overall protein hydropathy and charge distribution.  The SynthOMIC methodology excludes redundant regions of protein sequence space and can be used to introduce complex structural patterns within coding sequences.  We are using this strategy to achieve three primary aims.  First, we want to define lower limits on the number and identity of amino acids in polypeptides required to adopt secondary, tertiary and quaternary protein structure.  To this end we have identified simple motifs not found in Nature that mediate protein multimerization.  We predict that highly stable tertiary structures without close precedent in Nature will emerge from selections for structure applied to libraries with low amino acid diversity.  Second, we are developing limited alphabet polypeptides for use as diagnostic or therapeutic molecules by selecting for specific interactions with a target molecule.  The properties of such proteins may be fine-tuned to modulate the strength of the interaction or the stability of the interacting protein.  Third, we are generating restricted codon sequences free of terminators to test the plausibility of the hypothesis that such sequences are logical intermediates in the evolution of the genetic code, i.e., that a small number of primordial amino acids were once coupled to a simplified genetic code.

D.S. Maillet, B. Schmidt and J.T. Drummond.  A hypothesis for the extrachromosomal origin of coding sequences, in preparation (2007).

D.S. Maillet and J.T. Drummond.  Synthesis and characterization of libraries of open reading frames and proteins comprising severely limited and patterned alphabets, in preparation (2006/2007). 

D.S. Maillet and J.T. Drummond.  Combinatorial synthesis of novel open reading frames from limited codon sets reveals, in revision (2006). 

Larson, E. D., Iams K., and Drummond, J.T. (2003) DNA Repair, 2(11): 1199-210.   Strand-specific processing of 8-oxoguanine by the human mismatch repair pathway: inefficient removal of 8-oxoguanine paired with adenine or cytosine.

Wang, H., Yang, Y., Schofield, M.J., Du, C., Fridman, Y., Lee, D., Larson, E.D., Drummond, J.T., Alani, E., Hsieh, P., and Erie, D.A. (2003) Proceedings of the National Academy of Sciences , 100(25): 14822-7. DNA bending and unbending by MutS govern mismatch recognition and specificity.

Larson, E. D. Nickens, D., and Drummond, J.T. (2002) Nucleic Acids Research , 30(3): E14.   Construction and characterization of mismatch-containing circular DNA molecules competent for assessment of nick-directed human mismatch repair in vitro .

Iams, K., Larson, E.D., and Drummond, J.T. (2002) Journal of Biological Chemistry , 277(34): 30805-14. DNA template requirements for the human mismatch repair pathway in vitro .

Larson, E. D. and Drummond, J.T. (2001) Journal of Biological Chemistry , 276(13), 9775-9783.   Human mismatch repair and G*T mismatch binding by hMutS a in vitro is inhibited by adriamycin, actinomycin D and nogalamycin.

Drummond J.T. and Bellacosa A. (2001) Nucleic Acids Research , 29(11) 2234-2243.   Human DNA mismatch repair in vitro operates independently of methylation status at CpG sites.