Research


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Biology
Pathogenesis of vasodilatory shock: Every year in the U.S. about 500,000 people go into shock from myriad causes, including massive bacterial infections called sepsis. The condition is fatal for about half of them. We are investigating the mechanistic basis of vasodilatory shock, and in particular are studying the syndrome of vasopressin deficiency as an avenue for treatment of this debilitating condition.

Medical application of artificial enzymes: The ability to construct artificial enzymes de novo, or engineer existing enzymes with improved properties, is fundamentally interesting to basic science and has enormous potential in clinical settings. Our current projects focus on two very well known applications: treatment of cocaine abuse, and the detoxification of nerve agents.

Embryonic death and the creation of human stem cells: In the current US political climate there is a need to find common ground between advocates and opponents of embryonic stem cell research. We are researching alternative methods for the production of human embryonic stem cells, which do not involve destruction of human embryos. Our approach relies on identifying human embryos that have died of natural causes and yet may contain live, normal cells, suitable for stem cell lines.
Vasopressin
Every year in the U.S. about 500,000 people go into shock from myriad causes, including massive bacterial infections called sepsis. The condition is fatal for about half of them. Finding better treatments has been exceptionally difficult, as several lines of research and possible drugs have hit dead ends.

Fortunately an existing drug is proving highly effective. Tradionally used to prevent bleeding in the esophagus, the hormone vasopressin has unexpectedly turned out to be powerful as a treatment for shock.

It is very important to treat the patient on time. Althought vasopressin is proving to be a vey effective drug, it has also some side effects. It can cause suddenn increase in B.P., skin necrosis at the site of drug administration and it has also a very low therapeutics index. The solution for these problems is to develop a similar drug but with no side effects. This purpose can be achived by developing a partial agonist of vasopressin.

Our lab has identified certain possible partal agonist of vasopressin which can be potentially used for the treatment of Vasodilatory shock. We are currently invesigating the effects of these new drugs on different human and animal arteries.
Vasopressin Group Members
     
Columbia University    
Donald W. Landry, M.D. Ph.D
Principal Investigator

  Joanne Macdonald, Ph.D
Associate Research Scientist
     
Faisal Cheema M.D
Associate Research Scientist, Dept. of Surgery
  Imran Khalid, M.D.
Postdoctoral Research Scientist
     
Zhengxiang Zhu, Ph.D
Postdoctoral Research Scientist
  Ana Carolina Guillermo Nieto, B.S.
Senior Technician
Vasopressin Publications
 
  • Oliver JA, Landry DW. Endogenous and exogenous vasopressin in shock. Curr Opin Crit Care. 2007 Aug;13(4):376-82
  • van der Zee S, Thompson A, Zimmerman R, Lin J, Huan Y, Braskett M, Sciacca RR, Landry DW, Oliver JA. Vasopressin administration facilitates fluid removal during hemodialysis. Kidney Int. 2007 Feb;71(4):318-24. Epub 2006 Sep 27.
  • Landry DW, Oliver JA. Vasopressin and relativity: on the matter of deficiency and sensitivity. Crit Care Med. 2006 Apr;34(4):1275-7.
  • Malay MB, Ashton JL, Dahl K, Savage EB, Burchell SA, Ashton RC Jr, Sciacca RR, Oliver JA, Landry DW. Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock. Crit Care Med. 2004 Jun;32(6):1327-31.
  • Holmes CL, Landry DW, Granton JT. Science Review: Vasopressin and the cardiovascular system part 2 – clinical physiology. Crit Care. 2004 Feb;8(1):15-23. Epub 2003 Jun 26.
  • Landry DW, Oliver JA. Insights into shock. Sci Am. 2004 Feb;290(2):36-41.
  • Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiovascular system part 1—receptor physiology. Crit Care. 2003 Dec;7(6):427-34. Epub 2003 Jun 26.
  • Robin JK, Oliver JA, Landry DW. Vasopressin deficiency in the syndrome of irreversible shock. J Trauma. 2003 May;54(5 Suppl):S149-54.
  • Morales DL, Garrido MJ, Madigan JD, Helman DN, Faber J, Williams MR, Landry DW, Oz MC. A double-blind randomized trial: prophylactic vasopressin reduces hypotension after cardiopulmonary bypass. Ann Thorac Surg. 2003 Mar;75(3):926-30.
  • Oliver JA, Landry DW. Patient with a sudden drop in blood pressure. Crit Care Med. 2003 Jan;31(1):326-7.
  • Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588-95.
  • Gold J, Cullinane S, Chen J, Seo S, Oz MC, Oliver JA, Landry DW. Vasopressin in the treatment of milrinone-induced hypotension in severe heart failure. Am J Cardiol. 2000 Feb 15;85(4):506-8, A11.
  • Gold JA, Cullinane S, Chen J, Oz MC, Oliver JA, Landry DW. Vasopressin as an alternative to norepinephrine in the treatment of milrinone-induced hypotension. Crit Care Med. 2000 Jan;28(1):249-52.
  • Morales DL, Gregg D, Helman DN, Williams MR, Naka Y, Landry DW, Oz MC. Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock. Ann Thorac Surg. 2000 Jan;69(1):102-6.
  • Chen JM, Cullinane S, Spanier TB, Artrip JH, John R, Edwards NM, Oz MC, Landry DW. Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors. Circulation. 1999 Nov 9;100(19 Suppl):II244-6.
  • Rosenzweig EB, Starc TJ, Chen JM, Cullinane S, Timchak DM, Gersony WM, Landry DW, Galantowicz ME. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation. 1999 Nov 9;100(19 Suppl):II182-6.
  • Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. 1999 Oct;47(4):699-703; discussion 703-5.
  • Argenziano M, Chen JM, Cullinane S, Choudhri AF, Rose EA, Smith CR, Edwards NM, Landry DW, Oz MC. Arginine vasopressin in the management of vasodilatory hypotension after cardiac transplantation. J Heart Lung Transplant. 1999 Aug;18(8):814-7.
  • Morales D, Madigan J, Cullinane S, Chen J, Heath M, Oz M, Oliver JA, Landry DW. Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock. Circulation. 1999 Jul 20;100(3):226-9.
  • Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E, Weinberg AD, Smith CR Jr, Rose EA, Landry DW, Oz MC. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg. 1998 Dec;116(6):973-80.
  • Mets B, Michler RE, Delphin ED, Oz MC, Landry DW. Refractory vasodilation after cardiopulmonary bypass for heart transplantation in recipients on combined amiodarone and angiotensin-converting enzyme inhibitor therapy: a role for vasopressin administration. J Cardiothorac Vasc Anesth. 1998 Jun;12(3):326-9.
  • Argenziano M, Choudhri AF, Oz MC, Rose EA, Smith CR, Landry DW. A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation. 1997 Nov 4;96(9 Suppl):II-286-90.
  • Landry DW, Levin HR, Gallant EM, Seo S, D'Alessandro D, Oz MC, Oliver JA. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med. 1997 Aug;25(8):1279-82.
  • Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alessandro D, Oz MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997 Mar 4;95(5):1122-5.
Stem Cells
Here will be Stem Cells Group
Stem Cells Group Members
     
Columbia University    
Donald W. Landry, M.D. Ph.D
Principal Investigator

  Gordana Vunjak-Novakovic, Ph.D
Co-Investigator
     
Virginia E. Papaioannou, Pd.D
Co-Investigator
  Angela D. Nelson, MBA
Director for Clinical Research, Nephrology & CPET
     
Joanne Macdonald, Ph.D
Associate Research Scientist
  Darja Marolt, Ph.D
Research Fellow, Dept. of Biomedical Engineering
     
Svetlana Gavrilov
Postdoctoral Research Scientist
  Faisal Cheema, M.D
Associate Research Scientist, Dept. of Surgery
     
Imran Khalid, M.D.
Postdoctoral Research Scientist
  Qi Zhao
Postdoc?
     
Mark V. Sauer
CWRC
  Robert Prosser
Columbia IVF
Stem Cells Publications
 
  • Landry DW, Zucker HA, Sauer MV, Reznik M, Wiebe L. Hypocellularity and absence of compaction as criteria for embryonic death. Regen Med. 2006 May;1(3):367-71.
  • Landry DW, Zucker HA. Embryonic death and the creation of human embryonic stem cells. J Clin Invest. 2004 Nov;114(9):1184-6.
Nerve Agents
Here will be Nerve Agents Group
Nerve Agents Group Members
     
Nerve Agents project - active group members
 
Donald W. Landry, M.D. Ph.D
Principal Investigator

  Shi-Xian Deng
Scientist, Chemistry coordinator
     
Michael Vinogradov
Postdoctoral Research Scientist
  Patricia Tamburi, B.S.
Senior Technician
     
Zhengxiang Zhu, Ph.D
Postdoctoral Research Scientist
   
Nerve Agents Related Publications
 
  • Zhan CG, Deng SX, Skiba JG, Hayes BA, Tschampel SM, Shields GC, Landry DW. First-principle studies of intermolecular and intramolecular catalysis of protonated cocaine. J Comput Chem. 2005 Jul 30;26(10):980-6.
  • Larsen NA, de Prada P, Deng SX, Mittal A, Braskett M, Zhu X, Wilson IA, Landry DW. Crystallographic and biochemical analysis of cocaine-degrading antibody 15A10. Biochemistry. 2004 Jun 29;43(25):8067-76.
  • de Prada P, Landry DW. Production and characterization of anti-cocaine catalytic antibodies. Methods Mol Biol. 2004;248:495-501.
  • Deng S, Bharat N, de Prada P, Landry DW. Substrate-assisted antibody catalysis. Org Biomol Chem. 2004 Feb 7;2(3):288-90.
  • Zhan CG, Zheng F, Landry DW. Fundamental reaction mechanism for cocaine hydrolysis in human butyrylcholinesterase. J Am Chem Soc. 2003 Mar 5;125(9):2462-74.
  • Deng SX, de Prada P, Landry DW. Anticocaine catalytic antibodies. J Immunol Methods. 2002 Nov 1;269(1-2):299-310.
  • Stojanovic MN, de Prada P, Landry DW. Catalytic molecular beacons. Chembiochem. 2001 Jun 1;2(6):411-5.
  • Briscoe RJ, Jeanville PM, Cabrera C, Baird TJ, Woods JH, Landry DW. A catalytic antibody against cocaine attenuates cocaine's cardiovascular effects in mice: a dose and time course analysis. Int Immunopharmacol. 2001 Jun;1(6):1189-98.
  • Kuhar MJ, Carroll FI, Bharat N, Landry DW. Anticocaine catalytic antibodies have no affinity for RTI compounds: implications for treatment. Synapse. 2001 Aug;41(2):176-8.
  • Baird TJ, Deng SX, Landry DW, Winger G, Woods JH. Natural and artificial enzymes against cocaine. I. Monoclonal antibody 15A10 and the reinforcing effects of cocaine in rats. J Pharmacol Exp Ther. 2000 Dec;295(3):1127-34.
  • De Prada P, Winger G, Landry DW. Application of artificial enzymes to the problem of cocaine. Ann N Y Acad Sci. 2000;909:159-69.
  • Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, Zhao K, Briscoe RJ, Almonte R, Woods JH, Landry DW. A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10176-81.
  • Landry DW. Immunotherapy for cocaine addiction. Sci Am. 1997 Feb;276(2):42-5.
  • Landry DW, Yang GX. Anti-cocaine catalytic antibodies--a novel approach to the problem of addiction. J Addict Dis. 1997;16(3):1-17.
  • Landry DW, Zhao K, Yang GX, Glickman M, Georgiadis TM. Antibody-catalyzed degradation of cocaine. Science. 1993 Mar 26;259(5103):1899-901.
Cocaine
Abuse of cocaine is an intractable social and medical problem, and treatment has resisted traditional pharmacological methods. Rather than simply reversing the toxic effects of cocaine, our collaborative cocaine research program is investigating the use of artificial enzymes to quickly degrade circulating cocaine to prevent or reduce toxic effects.

All of our artificial enzymes attack cocaine at the same position, producing two inactive byproducts.

catalytic cleavage of cocaine


Cocaine esterase
Cocaine esterase (CocE) is an enzyme produced by the bacterium Rhodococcus sp., which grows in the rhizosphere of coca plants in South America. The bacterium can use cocaine as its sole source of carbon and nitrogen, with CocE initiating metabolism of the cocaine (Bresler et al., Appl Environ Microbiol. 2000 66:904-8). The enzyme gene has been cloned and crystallized (Larsen et al., Nat Struct Biol. 2002 9:17-21), and our collaborative program (led by James Woods) has been testing the use of CocE for cocaine detoxification in mice and rats (Cooper et al., 2006). We are actively working on catalytic and structural improvements to the protein for enhanced in vivo activity.

Butyrylcholinesterase
Butyrylcholinesterase (hBChE) is a naturally occurring liver enzyme that degrades a variety of substrates, including (-) cocaine with low efficiency. Interestingly, the enzyme degrades the (+) cocaine enantiomer at very high efficiency, and this property was exploited by Chang-Guo Zhan to develop a mutant hBCHE that cleaves naturally occurring (-) cocaine at high efficiency (Zheng & Zhan, 2007). Further design improvements in hBChE are continuing, and we are also investigating in vivo use of this enzyme for cocaine detoxification.

Cocaine catalytic antibodies
By creating antibodies (Mabs) to transition-state analogues of cocaine, Donald Landry created novel Mab 15A10, which not only binds cocaine but acts as an enzyme to detoxify at the same position as CocE and BChE (Landry et al., 1993). Administration of Mab 15A10 dramatically increases the amount of cocaine necessary to produce convulsions and death in rats (Mets et al., 1998), and the antibody is an effective antagonist of the reinforcing effects of cocaine in rats (Mets et al., 1998; Baird et al., 2000). The catalytic antibody was crystallized in order to understand more about its active site, and to provide information for structure-based humanization for therapeutic evaluation (Larsen et al., 2004).
Cocaine Group Members
     
Columbia University    
     
Donald W. Landry, M.D. Ph.D
Principal Investigator (Columbia)
  Joanne Macdonald, Ph.D
Scientist, CU Team coordinator
     
Michael Vinogradov
Postdoctoral Research Scientist
  Patricia Tamburi, B.S.
Senior Technician
     
University of Michigan
     
James H. Woods, Ph.D
Principal Investigator (Animals)
  M. C. Holden Ko, Ph.D
Scientist (Animals)
     
Roger Sunahara, Ph.D
Principal Investigator (Biochemistry)
  Diwa Narasimhan, B.S.
Scientist (Biochemistry)
     
Remy Brim
Graduate Student
   
     
University of Kentucky    
     
Chang-Guo Zhan, Ph.D
Principal Investigator (Kentucky)
   
Cocaine Publications
 
  • Cooper ZD, Narasimhan D, Sunahara RK, Mierzejewski P, Jutkiewicz EM, Larsen NA, Wilson IA, Landry DW, Woods JH. Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase. Mol Pharmacol. 2006 Dec;70(6):1885-91. Epub 2006 Sep 12.
  • Zhan CG, Deng SX, Skiba JG, Hayes BA, Tschampel SM, Shields GC, Landry DW. First-principle studies of intermolecular and intramolecular catalysis of protonated cocaine. J Comput Chem. 2005 Jul 30;26(10):980-6.
  • Larsen NA, de Prada P, Deng SX, Mittal A, Braskett M, Zhu X, Wilson IA, Landry DW. Crystallographic and biochemical analysis of cocaine-degrading antibody 15A10. Biochemistry. 2004 Jun 29;43(25):8067-76.
  • de Prada P, Landry DW. Production and characterization of anti-cocaine catalytic antibodies. Methods Mol Biol. 2004;248:495-501.
  • Deng S, Bharat N, de Prada P, Landry DW. Substrate-assisted antibody catalysis. Org Biomol Chem. 2004 Feb 7;2(3):288-90. Epub 2003 Dec 24.
  • Stojanović MN, Green EG, Semova S, Nikić DB, Landry DW. Cross-reactive arrays based on three-way junctions. J Am Chem Soc. 2003 May 21;125(20):6085-9.
  • Zhan CG, Zheng F, Landry DW. Fundamental reaction mechanism for cocaine hydrolysis in human butyrylcholinesterase. J Am Chem Soc. 2003 Mar 5;125(9):2462-74.
  • Larsen NA, Heine A, de Prada P, Redwan el-R, Yeates TO, Landry DW, Wilson IA. Structure determination of a cocaine hydrolytic antibody from a pseudomerohedrally twinned crystal. Acta Crystallogr D Biol Crystallogr. 2002 Dec;58(Pt 12):2055-9. Epub 2002 Nov 23.
  • Deng SX, de Prada P, Landry DW. Anticocaine catalytic antibodies. J Immunol Methods. 2002 Nov 1;269(1-2):299-310.
  • Stojanovic MN, Landry DW. Aptamer-based colorimetric probe for cocaine. J Am Chem Soc. 2002 Aug 21;124(33):9678-9.
  • Deng SX, Bharat N, Fischman MC, Landry DW. Covalent modification of proteins by cocaine. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3412-6. Epub 2002 Mar 12.
  • Stojanovic MN, de Prada P, Landry DW. Aptamer-based folding fluorescent sensor for cocaine. J Am Chem Soc. 2001 May 30;123(21):4928-31.
  • Briscoe RJ, Jeanville PM, Cabrera C, Baird TJ, Woods JH, Landry DW. A catalytic antibody against cocaine attenuates cocaine's cardiovascular effects in mice: a dose and time course analysis. Int Immunopharmacol. 2001 Jun;1(6):1189-98.
  • Kuhar MJ, Carroll FI, Bharat N, Landry DW. Anticocaine catalytic antibodies have no affinity for RTI compounds: implications for treatment. Synapse. 2001 Aug;41(2):176-8.
  • Koetzner L, Deng S, Sumpter TL, Weisslitz M, Abner RT, Landry DW, Woods JH. Titer-dependent antagonism of cocaine following active immunization in rhesus monkeys. J Pharmacol Exp Ther. 2001 Mar;296(3):789-96.
  • Baird TJ, Deng SX, Landry DW, Winger G, Woods JH. Natural and artificial enzymes against cocaine. I. Monoclonal antibody 15A10 and the reinforcing effects of cocaine in rats. J Pharmacol Exp Ther. 2000 Dec;295(3):1127-34.
  • De Prada P, Winger G, Landry DW. Application of artificial enzymes to the problem of cocaine. Ann N Y Acad Sci. 2000;909:159-69.
  • Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, Zhao K, Briscoe RJ, Almonte R, Woods JH, Landry DW. A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10176-81.
  • Landry DW. Immunotherapy for cocaine addiction. Sci Am. 1997 Feb;276(2):42-5.
  • Landry DW, Yang GX. Anti-cocaine catalytic antibodies--a novel approach to the problem of addiction. J Addict Dis. 1997;16(3):1-17.
  • Landry DW, Zhao K, Yang GX, Glickman M, Georgiadis TM. Antibody-catalyzed degradation of cocaine. Science. 1993 Mar 26;259(5103):1899-901.

Chemistry

Organic Synthesis Collaborative Center

History
Biomedical research requires investigators to acquire new experimental methods. However, when the new method is as broad as “synthetic organic chemistry,” then the obstacles are formidable and, for many investigators, insurmountable. The Division of Clinical Pharmacology and Experimental Therapeutics in the Department of Medicine was founded to bring biologically oriented Ph.D. organic chemists to the Columbia medical campus and facilitate novel, chemical solutions to important biological problems. The founder and chief of this division, Dr. Donald Landry, is a Ph.D. organic chemist and a fully trained physician. Dr. Landry’s own work exemplifies the melding of chemistry and biology in his purification and characterization of epithelial ion channels and later his development of artificial enzymes including anticocaine catalytic antibodies. As part of the mission of his division, Dr. Landry sought to facilitate interactions between the chemists of the Division and the wider community of biologists and thus he organized the Organic Synthesis Collaborative Center.

Contact Information:
 
Landry
Dr. Donald W. Landry
dwl1@columbia.edu
Deng
Dr. Shixian Deng
sd184@columbia.edu

Phone: (212) 305-1152
Address: 650 W.168th St, BB1029, NY, NY10032
Projects & Achievements
     
The Center focuses on “bench to bedside” collaborations and supports biomedical research by providing small molecules (probes) to elucidate physiology and pathophysiology, and to validate targets for drug discovery. The Center is well-equipped with its own major instruments (e.g., NMR, LC/MS, HPLCs, SPR) and it has current staff of 8 Ph.D. organic chemists. Since October 2006, the OCCC has contributed chemists and chemistry leadership to the NIH-funded comprehensive Molecular Libraries Screening Center at Columbia University (CU-MLSC), functioning as its Chemistry Core. Over the past 4 years the OCCC has collaborated with over 20 biomedical research groups and synthesized an extensive array of compounds in support of over 25 projects. These projects cover a wide range of biological research areas and disease states, with the major effort in each project focused on “hit-to-lead” optimization for drug or probe development. Some efforts, excluding MLSC projects, include:
  • Compounds that stabilize the calcium release channel and thereby prevent heart failure;
  • BBB-penetrable PDE-5 inhibitors for Alzheimer’s disease;
  • Isoform-selective PK inhibitors for treatment of chronic pain;
  • Inhibitors of the ABAD-A-beta interaction of Alzheimer’s disease ;
  • Steroid-sugar analogs that are inhibitors of A-beta peptide production to treat Alzheimer’s disease ;
  • Inhibitors of the renal sodium-glucose co-transporter to treat diabetes and obesity; and
  • An agent with a capacity for cytoprotection for myocardial ischemia and reperfusion injury.
In addition to drug discovery, the OCCC has synthesized small molecules as probes for other medicinal chemistry studies, for example: agents for labeling ion channels; agents for photoaffinity; labeling agents for the identification of a novel cholesterol transport protein, a novel target for anti-cholesterol drug development ; agents eliciting protection from nerve agents ; cocaine antibodies to cure overdose and addiction ; and the isolation and structure determination of mammalian siderophores from human tissue.
These collaborations have resulted in publications in top tier journals including Science , Circulation , PNAS , and JBC with manuscripts pending in Cell and Nature Medicine. In addition, 12 patents were filed and the Center has been a pivotal resource for a number of successful NIH grants, including P01, R01, and R21 awards, and Columbia University’s Roadmap Clinical and Translational Science Award (1 of the first 12 awarded) as well as for the CU Molecular Libraries Screening Center itself. Additionally, three startup companies have been formed based on “leads” initially discovered at the OCCC: 1) ARMGO Pharmaceuticals (May 2006) to commercialize compounds stabilizing the calcium release channel for the treatment of heart failure; 2) Nociceptive Pharmaceuticals (2006) to commercialize PKG inhibitors as a novel treatment for chronic pain; and 3) Smart Biosciences (2005) to commercialize a novel small-molecule approach to Alzheimer’s Disease. At ARMGO, the lead compounds synthesized at the OCCC demonstrated both high potency and off-target selectivity as well as high efficacy in rodent models. The lead compound will enter clinical trials both in the E.U. and in the U.S. in early 2008 as a joint effort with the large French pharmaceutical concern Servier. At Nociceptive Pharmaceuticals, the lead compound synthesized at the OCCC showed low nanomolar inhibitory activity for PKG with a >200-fold selectivity over PKA, a structurally very similar kinase. The lead compound also showed efficacy in animal models for pain relief (see the Preliminary Studies section below).

The compounds designed and synthesized in this center was covered twice by Chemical & Engineering News:
April 12 issue of 2004 and Feb 18 issue of 2008
Organic Synthesis Collaborative Center Recent Publications
 
  • Wehrens XT, et. al.; Protection from cardiac arrhythmia through ryanodine receptor- stabilizing protein calstabin2. Science (2004), 304(5668), 292-297.
  • Lehnart SE, et. al.; Sudden Death in Familial Polymorphic Ventricular Tachycardia linked to Calcium Release Channel (Ryanodine Receptor) Leak. Circulation 2004; 29; 109(25), 3208-14.
  • Wehrens XT, et. al.; Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. Proc. Nat. Acad. Sci. (2005); 102(27), 9607-9612.
  • Bao L, et. al.; Sitosterol-Containing Lipoproteins Trigger Free Sterol-induced Cell Death in ACAT-Competent Macrophages: Implications for sitosterol-induced atherosclerotic vascular disease and for sterol structure-dependent mechanisms of cell death. Submitted to JBC Feb 2, 2006 .
  • Xie, Yuli et. al; Identification of N-(quinolin-8-yl)benzenesulfonamides as agents capable of down-regulating NFk B activity within two separate high-throughput screens of NFk B activation. Bioorganic & Medicinal Chemistry Letters (2008), 18(1), 329-335.
  • Bellinger A. M., et al.; Remodeling of ryanodine receptor complex causes "leaky" channels: A molecular mechanism for decreased exercise capacity. Proc. Natl. Acad. Sci. USA 2008, 105, 2198

Molecular Robotics
Molecular Robotics & Computing

Center for Molecular Cybernetics

Detailed explanations about computing and robotics can be found at:
www.thespiderworld.org
www.thespiderworld.com

Why do we study moving molecules?
Really simple: you (the reader) are an assembly of many Avogadro’s numbers of molecules that somehow overcame their natural tendency to diffuse away in separate directions. We can argue that through intricately controlled motions the many molecules that form your body make you somehow understand this text and make you feel excited (hopefully) about what you are reading.

We (Stojanovic’s group with collaborators from Center for Molecular Cybernetics, www.thespiderworld.org) start with simpler systems, in which individual molecules are programmed to perform certain tasks, such as move from point A to point B. Then we look whether such molecules can perform additional tasks on their way, such as pick up load at C and drop it of at D. While these sound as trivial accomplishments for each of individual molecules, their strength is in their numbers. Thus, we also study what happens when two or more molecules influence each other and communicate. From a computer science stand point, we can have one Turing machine moving over an endless tape in infinite time, with well-defined transitions, capable of powerful computing. Or we can have many smaller machines, each performing one simple task with very short and rapid walks, but we have also the ability to couple them together. Thus, in the long run, we are looking to explain the raise of complexity from simple, programmable, systems with moving molecules. Such raise could have happened billions of years ago, but that is less important (we will never know for certain) than that it now gives raise to a new science, the chemistry of molecular robots. We are centered in the Division of Experimental Therapeutics, because one day mixtures of molecules, each performing simple tasks, will repair your tissues, eliminate cancerous cells, or autonomously release insulin upon increase in glucose concentration in blood. Or they will build an electronic device, from invisible scratch, in front of your eyes. What we are trying to do now is just the beginning.
Group Members

Milan's Group
Milan's Group: Steven, Mihela, Dmitry, Aihna and Renjun


Our methods can be applied to many systems, inorganic, organic, or biological. However, we focus mostly on artificial DNA systems, because of the available tools and because we know how to control them well. Our currently most processive molecular movers are spiders. Spiders are polycatalytic assemblies that undergo self-repelling random walk over surfaces covered with substrates. Essentially, if you release a spider on substrates, it will keep moving in the direction of new substrates, without leaving the surface, until it runs out of substrates. The spider will then switch to ordinary random walk (read Paul Krapivsky’s papers on spider theory here LINK). You can also read the initial paper on Spiders called NICKs in (jacs06 Milan). Since that publication, with our collaborators we expanded these systems to 2D surfaces and origami linear landscapes.

We have chemists, computer scientists, biophysicist, physicists, mathematicians, and even people who call themselves nanotechnologists. One can argue that the roots of our projects are closest to chemistry, much of our thinking comes from computer science, while, by an accident of nature, our systems are in the right size to take advantage of nanotechnology.
GRANTS


1) NSF Grant CCF-0621600
Project:EMT: Cell Death by Boolean Calculations with Antibodies


Funding:NSF Grant CCF-0621600

This grant pursues molecular computing paradigms suitable for cell surfaces.

Participants:
Milan Stojanov
Steven Taylor
Payal Pallavi

Collaborators:
Sergei Rudchenko
Maria Rudchenko

High-school students:
Safana Khan

We are also grateful to Lymphoma and Leukemia Society Fellowship (Milan) and NIH/NCI R21 for research with Sergei on flow cytometry studies.


2) NSF Grant CCF-0726585


Project:Enzymatic Networks for Pattern Recognition: Basic Principles and Applications

Funding:NSF Grant CCF-0726585


Goal: To combine cross-reactive arrays and molecular computing into autonomous expert systems.

Contributors:
PI: Milan Stojanovic
Participants: Renjun Pei
Collaborators: Joanne Macdonald, Darko Stefanovic.

If interested in molecular computing https://digamma.cs.unm.edu/wiki/bin/view/McogPublicWeb/WebHome

Publications
Copyright 2013 Columbia University. All Rights Reserved.