Professor of Medicine

M.D., 1976, Columbia University College of Physicians and Surgeons
Ph.D., 1974, University of Pennsylvania

522 Johnson Pavilion
Tel: 215-662-6475
Fax: 215-662-7842
Email:rubinh@mail.med.upenn.edu

The work in the lab is focused in three areas: elucidating the genetic and metabolic regulatory networks that allow tuberculosis to persist in the human host for years, determination of the molecular basis of serine protease inhibition and mathematical modeling of complex biomolecular systems.

Research:
Pathogenesis of dormancy in Mycobacterium tuberculosis. It is widely and believed that oxygen limitation, amino acid starvation and carbon source restriction are involved in establishing and maintaining Mycobacterium tuberculosis in a dormant state. Correspondingly, emergence from dormancy is related to a partial or complete amelioration of these conditions. We have identified and are studying three genetic and enzyme systems that comprise regulatory networks in Mtb that may be invovled in Mtb pathogenesis. These are: 1) ribonucleotide reductase systems that carry out the reduction of ribonucleotides to deoxyribonucleotides--the rate limiting enzymatic step in DNA synthesis, 2) the cytochrome system and, 3) the stringent response system that regulates the expression of a complex network of genes. This work is supported by the NIH.

Selected Publications:

Kana, B.D., Weintstein, E.A., Avarbock, D., Dawes, S.S., Rubin, H., Mizrahi, V. (2001) Characterization of the cydAB-encoded cytochrome bd oxidase from Mycobacterium smegmatis. J. Bacteriol. 183:7076-7086

Mizrahi V., Andersen S. and Rubin H. (2000 ) DNA Replication. Molecular Genetics of Mycobacteria ASM Press

Primm, T.P., Anderson, S.J., Mizrahi, V., Avarbock, D., Rubin, H. and Barry, C.E. (2000) The stringent response of Mycobacterium tuberculosis is required for long-term survival. J. Bacteriol. 182:4889-4898.

Avarbock, D., Avarbock, A. and Rubin, H. (2000) Differential regulation of opposing activities by the amino-acylation state of a tRNA-ribosome-mRNA-Rel_Mtb complex. Biochemistry 39:11640-11648.

Liu, A., Pötsch, S., Davydov. A., Barra, A-L., Rubin, H., and Gräslund, A. (1998) The tyrosyl free radical of recombinant ribonucleotide reductase from Mycobacterium tuberculosis is located in a rigid hydrophobic pocket. Biochemistry 37:16369-16377.

Biomolecular Computation. A new area of investigation known as biomolecular computation where complex computational operations are carried out using biomolecules, in particular using DNA. We showed how macromolecules can be manipulated to carry out fundamental logical operations and can be wired together as reversible logic gates. We are currently collaborating with members of the School of Engineering on modeling complex biological behavior using a hybrid systems approach that combines continuous and stochastic modalities. This work is supported by the NSF and DARPA

Selected Publications:

Alur R., Belta C., Kumar V., Mintz M., Pappas G. J., Rubin H., and Schug J. (2002) Modeling and analyzing biomolecular networks. Computing in Science and Engineering Jan/Feb 2002, pp. 20 - 30.

Alur R., Belta C., Ivancic F., Kumar V., Rubin H., Schug J., Sokolsky O. and Webb J. (2002) Visual programming for modeling and simulation of bioregulatory networks.International Conference on High Performance Computing, Bangalore, India, December 2002

Alur, R., Belta, C., Ivancic, F., Kumar, V., Mintz, M., Pappas, G.J., Rubin, H. and Schug, J. (2001) Hybrid modeling and simulation of biomolecular networks. In hybrid systems: computation and control. LNCS 2034. 19-32

Klein, J.P., Leete, T.H. and Rubin H. (1999) A biomolecular implementation of logically reversible computation with minimal energy dissipation. BioSystems 52:15-23.

Leete T.H., Schwartz M.D., Williams R.M., Wood D.H., Salem J.S. and Rubin H. (1999) Massively parallel DNA computation: expansion of symbolic determinants. DIMACS Series in Discrete Mathematics and Theoretical Computer Science. 44:45-58.

Enzymology and cell biology of serine proteases and serine protease inhibitors. Serine proteases and serine protease inhibitors (serpins) play critical roles in a wide variety of biological processes including inflammation, coagulation and growth and development. We have proposed a general model for the mechanism of inhibition of serine proteases by serine protease inhibitors based on site directed mutagenesis, atomic resolution crystal structures and NMR spectroscopic analyses. We are currently exploring the consequences and extensions of this model. This work is supported by the NIH.

Selected publications:

Plotnick, M.I., Samakur, M., Wang, Z-M., Liu, X., Rubin, H., Schechter, N.M., Selwood, T. (2002) Characterization of the breakdown process of HNE-serpin complexes. Biochemistry 41:334-342.

Plotnick M.I., Rubin H., Schechter N.M. (2002) The effects of reactive site location on the inhibitory properties of the serpin alpha 1-Antichymotrypsin. J Biol Chem. 277:29927-29935.

Estbanez-Perpina, E., Fuentes-Prior, P., Belorgey, D., Braun, M., Kiefersauer, K., Maskos, K., Huber, R., Rubin, H. and Bode, W. (2000) Crystal structure of the caspase activator human granzyme B, a proteinase highly specific for an Asp-P1 residue. Biological Chemistry 381:1203–1214.

Plotnick, M., Schechter, N.M., Wang, Z-M., Liu, X. and Rubin, H. (1997) The role of the P6-P3' region of the serpin reactive loop in the formation and breakdown of the inhibitory complex. Biochemistry 36:14601-14608.

Plotnick, M.I., Mayne, L., Schechter, N.M., and Rubin, H. (1996) Distortion of the active site of chymotrypsin complexed with a serpin. Biochemistry 35:7586-7590.