Ann and John H. Broadbent, Jr. ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering
Professor, Department of Chemistry and Chemical Biology
Professor, Department of Biology
Professor, Department of Chemical and Biological Engineering
Rensselaer Polytechnic Institute

Education:
Ph.D., Organic Chemistry, The Johns Hopkins University, 1979
M.A., Organic Chemistry, The Johns Hopkins University, 1977
B.S., Chemistry, Marquette University, 1975

Career Highlights:
After 21 years on the faculty of the University of Iowa, Linhardt joined Rensselaer in 2003 as a senior constellation professor. During his career in Iowa, he spent eight years as the university’s F. Wendell Miller Distinguished Professor of Chemistry and ten years as a member of the Executive Committee of the Center for Biocatalysis and Bioprocessing. Linhardt began his professional career with a three-year postdoctorate in chemical engineering at Massachusetts Institute of Technology.

Government agencies and numerous foundations and corporations have provided extensive funding for Linhardt’s research. An active contributor to professional publications, Linhardt has served on the editorial board of such top journals as the Journal of Biological Chemistry, Applied Biochemistry and Biotechnology, and the Journal of Carbohydrate Chemistry. He has published more than 400 research papers and holds 35 patents.

Among the many honors Linhardt has received include the Claude S. Hudson Award from the American Chemical Society (2003), the Volweiler Research Achievement Award in Pharmaceutical Sciences (1999), the Horace S. Isbell Award from The Carbohydrate Division of the American Chemical Society (1994), the Iowa Regents Award for Faculty Excellence (1992), and the University of Iowa Excellence in Teaching Award (1989).

Linhardt is a member of many professional societies including American Chemical Society, American Society of Biochemistry and Molecular Biology, American Association for the Advancement of Science (AAAS), Society for Glycobiology, American Association of Colleges of Pharmacy, and American Association of Pharmaceutical Scientists. Linhardt has been a consultant to industry and government for over 20 years.

Research Areas:
Linhardt is internationally known for his research on the study of bioactive carbohydrates, particularly the complex polysaccharide heparin. Heparin is a major clinical anticoagulant with more than 500 million doses used worldwide each year. Heparin and related molecules exhibit a large number of newly discovered biological activities and have great therapeutic potential.

Research in his laboratory focuses on complex carbohydrates. Glycoprotein, proteoglycans, and other glycoconjugates are prepared by fermentation using recombinant technology, extraction from tissues, or by chemical and enzymatic synthesis. After determining the structure of these molecules, his group studies their biological activities. By establishing a structure-activity relationship, these molecules often become lead compounds for new drug development.

Mapping of the mouse glycome is underway with a focus on heparan sulfate proteoglycans. Heparan sulfate is being isolated from tissues obtained from wild type and knock out mice, missing various isoforms of enzymes involved in heparin sulfate biosynthesis. Mouse embryonic stem cell proteoglycan glycomics are also being studied. The structures of these sulfated polysaccharides are being determined, and biochips and microarrays containing heparin sulfate from these tissues are being prepared as a tool for glycomic screening.

Linhardt also is conducting biochemistry and structural biology studies which focus on the preparation, purification, and characterization of carbohydrates and glycoconjugates. His group develops methods to purify these glycoconjugates and determine their structure by microsequencing using mass spectrometry (MS).

Biophysical chemists in his laboratory study the kinetics and thermodynamics of protein-carbohydrate interactions, relying primarily on isothermal titration calorimetry and surface plasmon resonance (SPR) spectrometry. X-ray crystallography and nuclear magnetic resonance (NMR) solution structure analysis are used in conjunction with molecular modeling to determine the molecular contacts in the protein carbohydrate complex.

The Linhardt group has recently begun to study the medical application of nanomaterials.  This research specifically focuses on carbohydrate-containing nanocomposites in medical and power storage devices.  These implantable devices may someday be used in biosensor, therapeutic and nanorobotic applications.   

Linhardt’s synthetic chemistry group relies on chemical and enzymatic synthesis to prepare target carbohydrates for biological evaluation. An artificial Golgi is also being used to study the parameters affecting glycan biosynthesis in the cell.  The group’s current focus is to prepare acidic carbohydrates. Targets include: sialic acid C-glycoside analogues as vaccines and glycosaminoglycan oligosaccharides for therapeutic evaluation by high throughput activity screening.

Selected Publications:
R.J. Linhardt, "Heparin: Structure and Activity, " Journal of Medicinal Chemistry, 46, 2551-2564, (2003). 

J. Chen, F.Y. Avci, E. M. Muñoz, L. M. McDowell, M. Chen, L. C. Pedersen, L. Zhang, R. J. Linhardt, J. Liu, "Enzymatic Redesigning of Biological Active Heparan Sulfate," Journal of Biological Chemistry, 280, 42817-42825, (2005).

S. K. Olsen, J. Y. H. Li, C. Bromleigh, A. V. Eliseenkova, O. A. Ibrahimi, Z. Lao, F. Zhang, R. J. Linhardt, A. L. Joyner, M. Mohammadi, "Structural Basis by which Alternative Splicing Modulates the Organizer Activity of FGF8 in the Brain," Genes and Development, 20, 185-198, (2006).

S. Murugesan, T. Park, H. Yang, S. Mousa and R. J. Linhardt, "Nano-based Neoproteoglycans – Blood Compatible Carbon Nanotubes," Langmuir, 22, 3461-3463, (2006).

J. J. Wolff, L. Chi, R. J. Linhardt, I. J. Amster, "Distinguishing Glucuronic from Iduronic Acid in Glycosaminoglycan Tetrasaccharides by Using Electron Detachment Dissociation," Analytical Chemistry, 79, 2015-2022, (2007).

F. Zhang, J. S. McLellan, A. M. A. Jiménez, D. J. Leahy, R. J. Linhardt, "Kinetic and Structural Studies on Interactions between Heparin/Heparan Sulfate and Proteins of the Hedgehog Signaling Pathway," Biochemistry, 46, 3933-3941, (2007).

X. Yuan, D. K. Ress, R. J. Linhardt, "Synthesis of C-linked Neuraminic Acid Disaccharide: a Versatile Precursor of C-Analogs of Oligosialic Acids and Gangliosides," Journal of Organic Chemistry, 72, 3085-3088, (2007).

V. L Pushparaj, S. M. Manikoth, A. Kumar, S. Murugesan, L. Ci, R. Vajtai, R. J. Linhardt, O. Nalamasu, P. M. Ajayan, "Flexible Nanocomposite Thin Film Energy Storage Devices," Proceedings of the National Academy of Science USA 104, 13574-13577, (2007).

P. Sinnis, A. Coppi, T. Toida, H. Toyoda, A. Kinoshita-Toyoda, J. Xie M.M. Kemp, R. J. Linhardt, "Mosquito Heparan Sulfate and its Potential Role in Malaria Infection and Transmission," Journal of Biological Chemistry, 282, 25376-25384, (2007).

A. V. Nairn, A. Kinoshita-Toyoda, H. Toyoda, J. Xie, K. Harris, S. Dalton, M. Kulik, J. M. Pierce, T. Toida, K. W. Moremen, R. J. Linhardt," Glycomics of Proteoglycan Biosynthesis in Murine Embryonic Stem Cell Differentiation," Journal of Proteome Research, in press, (2007).