Each year, billions of dollars worth of drugs, from insulin for diabetics to the stroke drug tPA, are made in huge vats full of microbes engineered to produce human proteins. The process is both inefficient and enormously expensive. Matthew DeLisa, an assistant professor of chemical and biomolecular engineering at Cornell University,  was the first scientist to use a twin arginine translocation (Tat) pathway to produce human proteins.

This should mean cleaner proteins and longer-lived cultures. DeLisa is also modifying bacteria to improve each step in protein production. His focus, he says, is "the engineering of biological machines to tackle problems that nature itself cant do." Until recently, the biotech industry focused on changing the growth environment for bacteria to boost protein productivity, but DeLisa is supercharging production by going inside the cell itself. For example, hes replacing key parts of the bacterias protein-making machinery with components from higher organisms to produce finely tuned miniature drug factories.

Research Focus

Dr. Delisa’s research integrates engineering design principles with protein biochemistry, microbiology and modern biotechnology to create microorganisms with new or improved protein machinery for solving problems in human health that cannot be solved using natural systems. In particular, while nature’s molecular machines possess highly desirable attributes such as specificity and high catalytic activity, it can be difficult (or impossible) to identify protein machines whose natural function is tailored for practical problems. To address this challenge, Dr. Delisa’s group employs protein engineering, the science of redesigning natural biomolecular scaffolds, to engineer new activities or non-natural characteristics into protein frameworks that comprise cellular machinery.

Dr. Delisa group’s long-term goal is to engineer protein machinery that plays a central role in folding and post-translational modification of complex, next generation immunotherapeutic proteins from the Immunoglobulin Supergene Family. These molecules are significant as they show great clinical promise in treating a range of human disorders including Alzheimer’s disease and human autoimmune disease. In addition to the applied nature of the research, an equally important goal is to understand how the structure and function of cellular machines affects the behavior of microorganisms in order to provide a basis from which a protein machine’s functionality can be enhanced or even reprogrammed. The two interrelated areas of Dr. Delisa’s research are: 1) the functional analysis of existing protein machinery; and 2) the design and engineering of entirely new protein machinery.
 

Awards and Honors

NYSTAR James D. Watson Young Investigator Award (2004)

Publicatios

38. Haitjema C and DeLisa MP (2009) Chemical genetic control of protein function in three bacterial compartments (in preparation).

37. Waraho D, Kostecki JS, Lee LL and DeLisa MP (2009) Engineering antibody fragments to fold and function in the cytoplasm of Escherichia coli using FLI-TRAP selection (in preparation).
36. Conrado RJ and DeLisa MP (2009) Rewiring the spatial proximity of metabolic enzymes in living cells for improved catalytic efficiency (in preparation).
35. Perez-Rodriguez R, Huang Q, Ke A and DeLisa MP (2009) CRISPR-associated proteins mediate DNA silencing in prokaryotes (in preparation).
34. Lim H-K and DeLisa MP (2009) Functional display of correctly folded proteins on the inner membrane of Escherichia coli (in preparation).
33. Lim H-K, Mansell TJ, Linderman S, Dyson MR and DeLisa MP (2009) A universal strategy for identifying protein features that correlate with folding and solubility in different bacterial compartments (in preparation).
32. Contreras Martinez L, O’Brien S and DeLisa MP (2009) Protein tethering to engineered ribosomes enables efficient isolation of recombinant proteins from Escherichia coli (in preparation).
31. Kostecki JS, Li H, Turner RJ and DeLisa MP (2009) Visualizing interactions along the Escherichia coli twin-arginine translocation pathway using protein fragment complementation (submitted).
30. Mansell TJ, FIsher AC and DeLisa MP (2009) A genetic selection for protein folding and solubility in the bacterial periplasm (submitted).
29. Fisher AC and DeLisa MP (2009) Identifying signal peptides by eye: bacterial secretomes are enriched with signal peptides bearing twin-lysine motifs (submitted).
28. Rocco MA, Kim J-Y, Burns A, Kostecki JS, Doody A, Wiesner U and DeLisa MP (2009) Site-specific labeling of surface proteins on living cells using genetically encoded peptides that bind fluorescent nanoparticles. Bioconjug Chem (in revision).
27. Contreras Martinez L, Kostecki JS and DeLisa MP (2009) Ribosomal protein L29 is required for efficient synthesis of highly expressed proteins in Escherichia coli. Microb Cell Fact (in revision).
26. Chen D, Metzger S, Osterrieder N, DeLisa MP and Putnam D (2009) Delivery of foreign antigens by engineered outer membrane vesicles. Proc Natl Acad Sci USA (in revision).
25. Fisher AC and DeLisa MP (2009) Genetic selection of stability-enhanced protein sequences using the twin-arginine translocation system. Methods Mol Biol (in press).
24. Waraho D and DeLisa MP (2009) Versatile selection technology for intracellular protein-protein interactions mediated by a unique bacterial hitchhiker transport mechanism. Proc Natl Acad Sci USA 106: 3692-7 [PubMed].
23. Lee LL, Ha H, Chang Y-T and DeLisa MP (2009) Discovery of amyloid-beta aggregation inhibitors using an engineered assay for protein folding and solubility. Protein Sci 18: 277-286. [PubMed]
22. Fisher AC and DeLisa MP (2009) Efficient isolation of soluble intracellular single-chain antibodies using the twin-arginine translocation machinery. J Mol Biol 385: 299-311 [PubMed].
21. Panahandeh S, Moser M, Maurer C, DeLisa MP and Müller M (2008) Following the path of a twin-arginine precursor along the TatABC translocase of Escherichia coli. J Biol Chem 283: 33267-75 [PubMed]
20. Marrichi MJ, Camacho L, Russell DG and DeLisa MP (2008) Genetic toggling of alkaline phosphatase folding reveals signal peptides for all major modes across the inner membrane of bacteria. J Biol Chem 283: 35223-35 [PubMed]
19. Conrado R, Varner JD and DeLisa MP (2008) Engineering the spatial organization of metabolic enzymes: mimicking nature's synergy. Curr Opin Biotechnol 19: 492-9 [PubMed]
18. Fisher AC, Kim J-Y, Perez-Rodriguez R, Tullman-Ercek D, Fish W, Henderson LA and DeLisa MP (2008) Exploration of twin-arginine translocation for the expression and purification of correctly folded proteins in Escherichia coli. Microbial Biotechnol 1: 403-15 [Abstract]
17. Fisher AC and DeLisa MP (2008) Laboratory evolution of fast-folding green fluorescent protein using secretory pathway quality control. PLoS ONE 3: e2351 [PubMed]
16. Kim J-Y, Doody A, Chen DJ, Cremona GH, Shuler ML, Putnam DA and DeLisa MP (2008) Engineered bacterial outer membrane vesicles with enhanced functionality. J Mol Biol 380: 51-66 [PubMed]
15. DeLisa MP and Haugh J (2008) First international conference on biomolecular engineering. Biotechnol Prog 24: 1 (Editorial in special issue covering First ICBE Meeting) [PubMed]
14. Mansell TJ, Fisher AC and DeLisa MP (2008) Engineering the protein folding landscape in Gram-negative bacteria. Curr Protein Pept Sci 9: 138-149 [PubMed]
13. Contreras Martinez L, Borrero EE, Escobedo F and DeLisa MP (2008) In silico protein fragmentation reveals the importance of critical nuclei in domain reassembly. Biophys J 94: 1575-88 [PubMed]
12. Contreras Martinez L and DeLisa MP (2007) Intracellular ribosome display via SecM translation arrest as a selection for antibodies with enhanced cytosolic stability. J Mol Biol 372: 513-24 [PubMed]
11. Conrado RJ, Mansell TJ, Varner JD and DeLisa MP (2007) Stochastic reaction-diffusion simulation of enzyme compartmentalization reveals improved catalytic efficiency for a synthetic metabolic pathway. Metab Eng 9: 355-63 [PubMed]
10. Liao Q, Subramanian G, DeLisa MP, Koch DL and Wu M (2007) Pair velocity correlations among swimming bacteria are determined by force-quadrupole hydrodynamic interactions. Phys Fluids 19: 061701 [Abstract]
9. Perez-Rodriguez R, Fisher AC, Perlmutter JD, Hicks MG, Chanal A, Santini C-L, Wu L-F, Palmer T and DeLisa MP (2007) An essential role for the DnaK molecular chaperone in stabilizing overexpressed substrate proteins of the bacterial twin-arginine translocation pathway. J Mol Biol 367: 715-30 [PubMed]
8. Wu M, Roberts JW, Kim S, Koch DL and DeLisa MP (2006) Collective bacterial dynamics revealed using a three-dimensional population-scale defocused particle tracking technique. Appl Environ Microbiol 72: 4987-94 [PubMed]
7. Diao J, Young L, Kim S, Fogarty EA, Heilman SM, Zhou P, Shuler ML, Wu M and DeLisa MP (2006) A three-channel microfluidic device for generating static linear gradients and its application to the quantitative analysis of bacterial chemotaxis. Lab Chip 6: 381-388 [PubMed]
6. Contreras Martinez L, Martinez-Veracoechea F, Pohkarel P, Stroock AD, Escobedo F and DeLisa MP (2006) Protein translocation through a tunnel induces changes in folding kinetics: a lattice model study. Biotechnol Bioeng 94: 105-117 [PubMed]
5. Fisher AC, Kim W and DeLisa MP (2006) Genetic selection for protein solubility enabled by the folding quality control feature of the twin-arginine translocation pathway. Protein Sci 15: 449-458 [PubMed] [Selected as a “Must Read” paper by Faculty of 1000]
4. Kim J-Y, Fogarty EA, Lu FJ, Zhu H, Wheelock GD, Henderson LA and DeLisa MP (2005) Twin-arginine translocation of active human tissue plasminogen activator in Escherichia coli. Appl Environ Microbiol 71: 8451-8459 [PubMed]
3. Bronstein PA, Marrichi MJ, Cartinhour S, Schneider DJ and DeLisa MP (2005) Identification of a twin-arginine translocation system in Pseudomonas syringae pv. tomato DC3000 and its contribution to pathogenicity and fitness. J Bacteriol 187: 8450-8461 [PubMed] [Supplemental Data.pdf]
2. Bronstein PA, Marrichi MJ and DeLisa MP (2004) Dissecting the twin-arginine translocation pathway using genome-wide analysis. Res Microbiol 155: 803-810 [PubMed]
1. Fisher AC and DeLisa MP (2004) A little help from my friends: quality control of presecretory proteins in bacteria. J Bacteriol 186: 7467-7473 [PubMed]