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Monthly Meeting Tailoring the Analytical Medicinal Chemistry Symposium on Type 2 Diabetes Chemistry Effort By Martin Freier 2005 IUPAC Congress Management of and General Assembly Biological Data Report by Morton Z. Hoffman By Mustaq Ahmed, et al. and Mukund Chorgade Report From China: Call For IUPAC Congress and Nominations International Union of Pure General Assembly and Applied Chemistry Morton Z. Hoffman, IUPAC announces the 2006 IUPAC Boston University, U.S. National Representative to the IUPAC Committee on Prize for Young Chemists. The Chemistry Education, Division of Chemical Education, Liaison to IUPAC IUPAC Prize for Young Chemists has been established to encourage out- The 40th IUPAC World Chemistry standing young research scientists at Congress (Innovation in Chemistry) the beginning of their careers.The prize and the 43rd IUPAC General Assembly will be given for the most outstanding were held concurrently at the Beijing Ph.D. thesis in the general area of the International Convention Center, chemical sciences, as described in a August 14-19, 2005. The Congress, 1000-word essay. Prize is USD $1000 which was organized by the Chinese and travel to the IUPAC Congress in Chemical Society and the Institute of Turino, Italy, August 2007. Each Chemistry, Chinese Academy of Sci- awardee will be invited to present a ences, was a general scientific meet- poster on his/her research and to par- ing, not unlike an ACS meeting, while ticipate in a plenary award session. the General Assembly was the occa- sion for meetings of the governing Call for Nominations: (deadline Feb- Dr. Yu Huang (2004 IUPAC Prize for bodies and committees of the Union ruary 1, 2006) a Young Chemist) such as the Committee on Chemistry For more information, including appli- Education (CCE). cation form, please visit the IUPAC Mukund Chorghade (Associate web site at Member of CCE, President of D&O Pharmachem, 2006 NESACS Chair- www.iupac.org/news/prize.html Elect) and I attended the meetings of or contact the IUPAC Secretariat by CCE, where there was much discussion e-mail at
2 The Nucleus December 2005 The Northeastern Section of the American Chemical Society, Inc. Contents Office: Marilou Cashman, 23 Cottage St., Natick, MA 01760. 1-800-872-2054 (Voice or FAX) or 508-653-6329. IUPAC Congress and General Assembly 2 e-mail: [email protected] ______Any Section business may be conducted A report by Morton Z. Hoffman via the business office above. NESACS Homepage: http://www.NESACS.org Call for Nominations______2 Sathish Rangarajan, Webmaster IUPAC Prize for Young Chemists ACS Hotline, Washington, D.C.: 1-800-227-5558 Officers 2005 Tailoring the Analytical Chemistry Effort ______4 Chair: By Martin Freier Amy Tapper Peptimmune 64 Sidney Street, Suite 380, December Meeting-Jointly with Medicinal Chemistry ______5 Cambridge, MA 02139 A Symposium on Type 2 Diabetes, Part II 617-715-8005; [email protected] Chair-Elect: Patricia Mabrouk Call for Nominations______6 Chemistry Department, Northeastern University James Flack Norris Award and the Philip Levins Memorial Prize Boston, MA 02115 617 373 2845; [email protected] Immediate Past Chair: Integration and Management of Biological Data ______7 Jean A. Fuller-Stanley By Mushtaq Ahmed, et al. and Mukund Chorghade Chemistry Department, Wellesley College Wellesley, MA 02481-8203 781-283-3224; [email protected] Historical Notes ______13 Secretary: Homer F. Priest (1916-2004) Michael Singer Sigma RBI 3 Strathmore Rd. Natick, MA 01760-2447 Calendar ______16 508-651-8151x291 [email protected] Treasurer: James Piper Cover: (l-r) Morton Hoffman (Boston University), Bill Carroll (ACS President), 19 Mill Rd., Harvard, MA 01451 Mukund Chorghade (President of D&O Pharmachem) at the 40th 978-456-3155 [email protected] IUPAC World Chemistry Congress and the 43rd IUPAC General Assem- Auditor: Anthony Rosner bly,Beijing, China, August 14-19, 2005. Archivist: Myron S. Simon Deadlines: February Issue: December 9, 2005 20 Somerset Rd. Newton, MA 02465; 617-332-5273 March Issue: January 13, 2006 [email protected] Trustees: Joseph A. Lima, Esther A.H. Hopkins, Michael E. Strem, Councilors: Alternate Councilors: Term Ends 12/31/2005 Mary T. Burgess Patrick M. Gordon Morton Z. Hoffman Lowell H. Hall The Nucleus is distributed to the members of the Northeastern Section of the American Chemical Doris I. Lewis Donald O. Rickter Society, to the secretaries of the Local Sections, and to editors of all local A.C.S. Section publications. Truman S. Light LawrenceT. Scott Forms close for advertising on the 1st of the month of the preceding issue. Text must be received by the Amy E. Tapper J. Donald Smith editor six weeks before the date of issue. Term Ends 12/31/2006 Editor: Michael P. Filosa, Ph.D., ZINK Imaging Incorporated, 1265 Main Street, Michaeline F. Chen Wallace J. Gleekman Catherine E. Costello Howard R. Mayne Waltham, MA 02451 Email: Michael.Filosa(at)zink.com; Tel: 781-386-8479. Patricia A. Mabrouk Alfred Viola Associate Editors: Myron S. Simon, 20 Somerset Rd., W. Newton, MA 02465, Tel: 617-332-5273 Julia H. Miwa Barbara G. Wood Nancy Simons, Analytical Chemist, Corporate R&D, Boston Scientific Corp., Dorothy J. Phillips Michael Singer 1 Boston Scientific Place A4, Natick, MA 01760-1537. Term Ends 12/31/2007 Email: Nancy.Simons(at)bsci.com; Tel. 508-650-8603; Fax 508-647-2329 Thomas R. Gilbert Arlene W. Light Sheila E Rodman, Malden, MA. Email:serodman(at)hotmail.com Jean A. Fuller-Stanley Pamela M. Nagafuji Michael J. Hearn Timothy B. Frigo Tel: 781-771-4116. Michael Singer Susan Chiri-Buta Board of Publications: Vivian K. Walworth (Chair), Mary Mahaney, Martin Idelson, Business Manager: Karen Piper, 19 Mill Rd., Harvard, MA 01451, Tel: 978-456-8622 All Chairs of standing Advertising Manager: Vincent J. Gale, P.O. Box 1150, Marshfield, MA 02050, Committees, the editor Tel: 781-837-0424; FAX: 781-837-1453 of THE NUCLEUS, and Contributing Editors: Morton Hoffman, Feature Editor; Dennis Sardella, Book Reviews; the Trustees of Section Calendar Coordinator: Donald O. Rickter, e-mail: rickter(at)rcn.com Funds are members of the Writers: Martin Freier, Sheila Cusolito Board of Directors. Any Councilor of the American Chemical Society Proofreaders: Donald O. Rickter, Myron S. Simon, Vivian K. Walworth residing within the section area is an ex officio Webpage: Webmaster: Sathish Rangarajan, sathish.rangan2(at)gmail.com member of the Board of Directors. Copyright 2005, Northeastern Section of the American Chemical Society, Inc. The Nucleus December 2005 3 Tailoring the Analytical Golf Tournament - Osmium Level Donor Chemistry Effort IRIX By Martin Freier Corporate Patrons and Golf Platinum Analytical chemists gather information FLP, a Massachusetts based laboratory AstraZeneca R&D Boston regarding compounds, using a host of (Bellingham), has been in the analyti- Cardinal Health sophisticated tools; analyze that infor- cal chemistry field for more than 25 DSM mation; and report their findings. In a years and believes that each of the Genzyme Drug Discovery & Dev. sense, they serve as the auditors in the strategies used to implement analytical Hovione chemical industry by identifying any chemistry should be considered. He is IBM Lyophilization Service of New Eng- deviations from standards. Unlike the a proponent of tailoring the analytical land auditors, however, analytical chemists chemistry work to the specific prob- Phasex Corporation also provide the chemical industry lem. Each chemical problem is unique, Strem Chemicals Inc. with insight into newly synthesized and the analytical chemistry needs Zone Enterprises compounds and thus allow company must be separately assessed and a managers to make some major strate- determination made as to how best to Corporate Sponsors and Golf gic business decisions regarding the address that problem before proceed- Gold production, distribution, and applica- ing. But ultimately, the decisions on Aerodyne Research Inc. tion of such compounds. At the same how much analytical chemistry must Cambridge Isotope Laboratories time, they also help government regu- be authorized has to be made by the New England BioLabs, Inc. latory agencies to implement appropri- chemists and the regulatory agencies Pfizer ate measures required for assuring who have the unique expertise and the Rhodia Pharma Solutions safety and quality to the public. full responsibility. Sigma-RBI Since it is crucial that the informa- When Jordi was pursuing his Ph.D. Teledyne ISCO tion gathered be as accurate and as studies at the Northern Illinois Univer - Donors and Golf Silver timely as possible, in some cases sity’s biochemistry laboratory, his doc- Consulting Resources Corp. robotic real-time instrumentation is toral thesis was enzyme kinetics. In Dishman Pharmaceuticals and Chem- now used to assure quality and safety those days, he considered himself a icals Limited of certain processes and is thus replac - biochemist who loved to synthesize Houghton Chemical Company ing analytical chemists. Oddly enough, chemical compounds. After spending Organix Inc. these instruments and their application several years at the Walter Reed Med- Peptimmune are designed by the analytical chemists ical Center Research facility and Vertex being replaced in the process. They are Waters’ Associates Laboratory, he real- aware that the required sophisticated ized that he enjoyed analytical chem- Some of the many creative tasks tools and qualified scientists who are istry. Indeed, Jordi is a biochemist who analytical chemists perform these days able to use them are in many cases not at a point in his career decided to spe - include designing the processes and as widely available as dictated by cialize in analytical chemistry. Many the instrumentation and computer pro- established schedules, budgets, and scientists have made similar choices. grams required. What is amazing is the safety concerns (areas where it would Given his successful career in syn- complexity of some of the instruments be hazardous to use human operators thesizing compounds, why did Jordi and computer programs the analytical for real-time quality control). Analyti- choose analytical chemistry? chemists are involved in. Nowadays cal chemists often resort to sampling “First, believe it or not, I just some of them are spending a great deal and statistical methods to reduce costs enjoyed analytical chemistry’s highly of time in designing the sensors and and schedules, where possible. Other structured methodology, which still instrumentation for detecting explo- effective means, such as outsourcing of allows the chemist a great deal of cre- sives and radioactive materials as a the work to qualified sources outside ativity, especially with analyzing the means for dealing with potential terror- the company, are now among the effec- new complex compounds being synthe- ist threats. Other applications include tive strategies being implemented. In sized; besides, there is a great deal of closed-loop automation systems based short, one of the major challenges synthesis going on in analytical chem- on spectroscopy that use in-line fiber- chemists face daily is how best to istry.” optic probes to gather information and implement the analytical chemistry What Jordi was alluding to was the facilitate quick comparisons with exist- effort of the project in a timely and fact that there is quite a bit of synthetic ing spectrum profiles and thus assess cost-effective manner. chemistry involved in the columns used deviations from acceptable standards Howard Jordi, PhD, CEO of Jordi in chromatography. Continued on page 12
4 The Nucleus December 2005 Monthly Meeting Abstract: th The Story of Vildagliptin The 865 Meeting of the Northeastern Section of the American (LAF237): A DPP4 Inhibitor Chemical Society for the Treatment of Type 2 Jointly with the Medicinal Chemistry Group Diabetes Symposium: Diabetes II, part II. Thursday – December 8, 2005 Dipeptidyl peptidase IV (DPP4) inhi- Holiday Inn Select – Woburn, MA - 15 Middlesex Canal Park Road bition has the potential to become a valuable therapy for type 2 diabetes. 3.00 pm Refreshments The synthesis and structure activity 3:15 pm Welcome, Raj (SB) Rajur, Program Chair relationship of a new DPP4 inhibitor class, N-substituted-glycyl-2-cyano- 3.20 pm Introductiory Remarks, Norton Peet, North Andover, MA pyrrolidines, are described as well as 3:30 pm Applying RNAi and Structure-Bbased Medicinal Chemistry for the path that led from clinical develop - Treatment of Obesity and Type II Diabetes ment compound 1-[2-[5-cyanopyridin- Mark Tepper, CytRxCorporation, Worcester, MA 2-yl)amino]-ethyl-amino]acetyl-2-cyan o-(S)-pyrrolidine (DPP728) to its fol- 4:30 pm Development of DPPIV Inhibitors Using High Throughput Crystal- low-up, 1-[[(3-hydroxy-1-adamantyl) lography, G. Sridhar Prasad, Merck & Co., Inc., West Point, PA amino]acetyl]-2-cyano-(S)-pyrrolidine 5:30 pm TBA Subramanyah Hosahalli, Aurigene Discovery Technologies, (Vildagliptin, LAF237).The pharmaco- Bangalore India logical profile of Vildagliptin in obese Zucker fa/fa rats along with pharmaco - 6:30 pm Social Hour kinetic pro-file comparison of DPP728 6:45 pm Dinner and Vildigliptin in normal cynomolgus 7:45 pm The Story of Vildagliptin (LAF237): A DPP4 Inhibitor for the Treat- monkeys and humans is discussed. ment of Type 2 Diabetes. Edwin B. Villhauer, Novartis Pharmaceuti- The results suggest that Vildagliptin is cals, East Hanover, NJ a potent, stable, selective DPP4 inhibitor possessing excellent oral Dinner reservations should be made no later than 12:00 noon on Thursday, bioavailability and potent antihyper- December 1, 2005. If you prefer to pay at the door, please contact Marilou glycemic activity with potential for Cashman at (800) 872-2054 or (508) 653-6329 or [email protected]. Reser- once-a-day administration. The results vations not canceled at least 24 hours in advance must be paid. Members, from recent clinical studies will be dis - $28.00; Non-members, $30.00; Retirees, $15.00; Students, $10.00. Anyone cussed during the meeting. who needs handicapped services/transportation, please call a few days in advance so that suitable arrangements can be made. [1] Villhauer, E.B.; Brinkman, J.A.; Naderi, G.B.; Burkey, B.F.; Dun- Directions to Holiday Inn Hotel - http://www.radisson.com/woburnma ning, B.E.; Kapa, P.; Mangold, B.L.; From Boston - Cambridge - Points Nor th: Take Route I-93 to Route 95/128 Russell, M.E.; Hughes, T.E. 1-[[(3- West. After 1 mile, take Exit 35 South to Route 38 (Main Street). Hydroxy-1-adamantyl)amino] *After about 500 feet at the traffic light, turn right into Middlesex Canal acetyl]-2-cyano-(S)-pyrrolidine: A Street to the hotel entrance. Potent, Selective, and Orally From the West: Take Route 95/128 North to Exit 35 South (Route 38 - Main Bioavailable Dipeptidyl Peptidase Street. Follow directions from * above. IV inhibitor with Antihyper- THE PUBLIC IS INVITED glycemic Properties. J Med. Chem. 2003; 46, 2774-2789. ◆ vascular, obesity and diabetes pro- Biography: grams at Sandoz and then Novartis in New Jersey as well as Basel, Switzer- Currently Dr. Villhauer is a Principal land. He has led, and championed its successor, LAF237), he was recently Fellow in Process Research at Novartis numerous diabetes and obesity pro- awarded the title of Novartis Leading Pharmaceuticals in East Hanover, New grams while specializing in protease Scientist. He is the author of over two Jersey. Until the move of Novartis inhibition and combinatorial chemistry. dozen publications and inventor of 9 Research to Boston in 2003, he worked Due to his inventions of Novartis’s two issued US patents. Dr. Villhauer for over 17 years as a medicinal diabetes development compounds in received his B.S., M.S., and Ph.D. chemist in preclinical asthma, cardio- the DPP4 inhibitor field (DPP728 and from the University of Rochester. ◆
The Nucleus December 2005 5 Call for Nominations James Flack Norris Award for Outstanding Achievement in the Teaching of Chemistry Nominations are invited for the 2006 important part of a nominating packet. NESACS, 23 Cottage St., Natick, MA, James Flack Norris Award for Out- These may show the impact of the 01760. email: mcash0953 (at)aol.com. standing Achievement in the Teaching nominee’s teaching in inspiring col- The deadline for nominations is of Chemistry. The Norris Award, one leagues and students toward an active April 15, 2006. ◆ of the oldest awards given by a Section life in chemistry and/or related sci- of the American Chemical Society, is ences, or may attest to the influence of presented annually by the Northeastern the nominee’s other activities in chem- Section. The Award consists of a cer- ical education, such as textbooks, jour - tificate and an honorarium of $3,000. nal articles, or other professional Call for Nominees must have served with activity at the local or national level. special distinction as teachers of chem- Materials should be of 81/2 by 11 istry at any level: secondary school, inch size. The nomination packet Nominations college, and/or graduate school. Since should not exceed thirty pages and Philip L. Levins Memorial 1951, awardees have included eminent should not include books or reprints or Prize and less widely-known but equally software. effective teachers at all levels. Please direct questions about the Nominations for the Philip L. Levins The awardee for 2005 was Profes- content of a nomination to Professor Memorial Prize for outstanding per- sor Morton Z. Hoffman of the Depart- Marietta Schwartz, Univesity of Mass- formance by a graduate student on the ment of Chemistry of Boston achusetts, Boston, e-mail: Marietta way to a career in chemical science University. Schwartz(at)umb.edu. For more infor- should be sent to the Executive Secre - Nominations should focus on the mation about the Norris Award, see tary, NESACS, 23 Cottage St., Natick, candidate’s contributions to and effec- www.nesacs.org. MA 01760 by March 1, 2006. tiveness in teaching chemistry. The Send nomination packets (as hard The graduate student’s research nominee’s curriculum vitae should be copy, or electronically in Adobe PDF should be in the area of organic analyt- included. Seconding letters are also an format) to Ms. Marilou Cashman, ical chemistry, and may include other areas of organic analytical chemistry such as environmental analysis, bio- chemical analysis, or polymer analysis. Nominations may be made by a faculty member or the student may submit an application. A biographical sketch, transcripts of graduate and undergraduate grades, a description of present research activity, and three ref- erences must be included. The nomina- tion should be specific concerning the contribution the student has made to the research and publications (if any) with multiple authors. The award will be presented at the May 2006 Section Meeting. ◆
6 The Nucleus December 2005 Integration and Management of Biological Data for Clinical and Functional Inference; Persistent’s Solutions Mushtaq Ahmed*, Saurabha Daniel*, Armaity Davierwala, Prashant Lele, Ghana Pendse, Aditya Phatak and Prabhakar Ranjekar, Persistent Systems, Pvt. Ltd., Bhageerath, 402, Senapati Bapat Road, Pune 411016, India. www.persistent.co.in and Mukund S. Chorghade, Chorghade Enterprises, 14 Carlson Circle, Natick, MA 01760-4205, USA [email protected]
Introduction companies are faced with a growing Indexed data sources or Linked The pharmaceutical sector has tra- need to integrate proprietary biological Integration ditionally been a vibrant, innovation- data with public data sources across all Linked Integration enables re- driven and highly successful life science domains. The biggest chal- searchers to begin their query search component of industry at large. In lenge today is not just to maintain, but with one data source and then follow recent years, a confluence of spectacu - semantically integrate genomic and hypertext links to related information lar advances in chemistry, molecular clinical data, enabling researchers to on other data sources, facilitating inter- biology, genomic and chemical tech- discover relationships and decipher active browsing. This approach is espe- nology and the cognate fields of spec- patho-physiological process for better cially well suited to explore the data troscopy, chromatography and understanding of disease mechanisms landscape when an investigator has not crystallography have led to the discov - and more accurate decision-making for yet formulated a specific question. ery and development of numerous selecting drugs and targets. Indexed data sources are a varia- novel therapeutic agents for the treat- The most striking feature of life tion of linked integration. In this ment of a wide spectrum of diseases. sciences data is not its volume, but its approach multiple data sources are Multi-disciplinary and multi-functional diversity. Each data source contains a indexed and then linked to support teams focusing on lead generation and different subset of biological knowl- quick queries for customized querying. optimization have replaced the tradi- edge. There are many integration chal- This approach is embodied in a tional specialized research groups. To lenges, as the data sources are dynamic popular tool, Sequences Retrieval Sys- develop a drug, from conception to and the data are heterogeneous. The tem [SRS] (Etzold and Argos 1993). It commercialization, the biotechnology / technical challenge is increased with was originally developed by an EBML biopharmaceutical industry (which has different databases using different scientist, and exclusive license rights been highly entrepreneurial) has DBMS’s and ways of data access. were later acquired by Lion Bio - reached out to establish global strategic Even more challenging is the task of sciences. It is a key word index and partnerships with numerous compa- keeping pace with the continual searching system for biological data- nies. changes and updates of biological data bases and supports flat file, relational Biological research, particularly sources, making integration an ongo- databases and object-oriented data- the genome-sequencing projects allied ing task. Finally, intensive research of bases also. SRS uses specialized pars- to drug development is continually data content and formats and integra- ing language for generating database producing voluminous data that need tion of data sources is a time consum - wrappers and another specializedlan- to be organized, analyzed and queried ing and tedious effort. guage for formulating queries. to generate useful scientific knowl- Integration Approaches Federated Databases edge. There has been an unprecedented There is no single product that Federated databases provide view explosion in the number and size of addresses the issue of data integration integration. Data federation does not public data resources, and variety and in totality. Typically, groups have uti- modify the primary data source and volume of laboratory data. lized three different approaches to does not permit replication or migra- Challenges solve biological data integration prob- tion to a central source. The primary As biological research is being lems in biology. These include Indexed data source remains autonomous, but transformed from purely experimental Data Sources (Linked Integration), builds an environment around the data- to information-driven discovery sci- Federated databases (View Integra- bases that makes them all seem to be ence, academia, pharmaceutical, bio- tion), and Data Warehouses / Data part of one large system. The middle- pharmaceutical and biotechnology Marts. Continued on page 8
The Nucleus December 2005 7 Management of Data data that is modeled through a multidi - ment and integration solutions for mensional approach. An indexing sys- functional genomics (proteomics and Continued from page 7 tem is used for integration and micro array) at The School of Medi- ware creates a logical view of the fed - navigation. It is a relational database cine, Washington University in St. erated databases. Applications inter- optimized for pre-defined types of Louis and data integration solutions for acting with the middleware are searches. Data marts are smaller , the sequencing pipeline at MIT-Broad presented with a unified schema even focused data warehouses designed for Institute for Genome Research. though the actual schema is distributed specific search requirements. Data Data Warehousing Solutions for across the data sources. Middleware warehouses are populated from pri- Functional Genomics leverages the native data management mary data sources, using a three-step At Washington University, School and search capabilities; at the same process: (a) The data are extracted of Medicine, the requirement was to time the wrapper encapsulates the from primary data source and cleaned, integrate data located at four different specificity of each database. Searches (b) transformed, and (c) loaded into the cores and stored in different forms: submitted to the federated middleware database and indexes are built to are partitioned into sub-queries that achieve optimum query performance. • Microarray core can be executed by individual data- Data warehouses offer the advantage • Sequencing core bases. Examples of federated systems of mature and widely accepted • Tissue Procurement core include complex-relational systems RDBMS technology and a high-level • Proteomics core. like BioKleisli/ K2 (S. Davidson, el standard query language (SQL). These al.1996), GeneticsXchange’s K1, systems have been successfully imple- The major design considerations object- relational systems (OPM/ mented in commercial health care include: TINet) and IBM’s relational system enterprises. • Fast querying of data from multiple DiscoveryLink (Haas, Schwarz et al. Persistent’s Solutions sources. 2001). The interplay of all the challenges • Efficient handling of large amounts Data Warehouses and Data Marts in data integration necessitates careful of data, allowing users to upload and The data warehouse approach problem definition, requirement gath- analyze it. assembles data in a centralized system ering and analysis to select the most • Provide access to data via a campus- with a global data schema. A data optimum integration model. Persistent wide intranet for approximately 200 warehouse stores highly redundant Systems has developed data manage- concurrent users. • In addition, while the experimental data generated within the core facili - ties is required to be accessed in almost real time, the annotation data coming from publicly available data- bases needs to be up to date only within the past few weeks. We chose to use the data warehousing model to store the experimental and annotation data sets. This model allows investigators to collect, download and manipulate large amounts of microar- ray, gene annotation, gene sequence, reference sequence and 2-D gel data from the University core facilities and integrate it with publicly available data sources providing real-time annotation to expression data in context of gene annotation including Gene Ontology categories, tissue specificity, metabolic and signal transduction pathways, pub- lished literature and orthologous sequences through web-based and desktop client applications. The analysis tools we have developed and deployed help in capturing, inte-
8 The Nucleus December 2005 Management of Data format suitable for import into down- tation server addresses these issues by stream analysis tools like GeneSpring/ combining management and integra- Continued from page 8 Spotfire. tion of complex microarray data and grating, sharing, and visualizing post- distinct biological and clinical data Function Express Gene Annotation genomic microarray, proteomics, gene types. It provides an enriched collec- Server annotation and clinical data. All these tion of functional information about The gene annotation server anno- solutions provide an integrated query selected genes drawn from various tates probes on microarrays, using pub- environment. public domain databases for facilitat- licly available biomedical databases, Our data warehouse runs on Ora- ing microarray data interpretation. The and automatically updates these anno- cle 9i (version 9.2.0.4- 64 bit) database, analysis tools integrated in Function tations on a regular basis. which is hosted on a Sun Enterprise Express facilitate analysis and visuali- Microarray technology allows 420R consisting of 4 X 450 Mhz Ultra simultaneous study of expression of zation of the various data sets to expe - Sparc-II processors, 4 GB of internal thousands of genes, generating large dite discovery of biomarkers. RAM memory, 36 GB of mirrored amount of complex data. While ana- The Function Express also internal drive space, and two Sun Stor lyzing the microarray data, knowledge includes Gene Literature Network, Edge A1000 RAID boxes, containing of highly selective gene expression, as which generates network of genes 654 GB of total disk space set up to well as sequence homology to known based on co-citation in Pubmed operate in RAID 5 mode. The ware- gene families can provide convenient abstracts. It is tightly integrated with house currently has about 150 GB of short cuts for better understanding of Function Express to enabling correla- data. disease and unravel new information tions with Gene Ontology, etc. LIMS for Microarray about pathways and cellular functions. Function Express is a two-tiered LIMS for Microarray is used at The genome wide data analysis client-server Graphical User Interface (GUI)-driven application. The plat- the Bioinformatics core at Washington typically requires semantic integration form-independent (UNIX, Windows, University. It is designed to realisti- and constant updating of diverse types etc.) server brings gene annotation data cally capture every step in a typical of annotation data, as these databases from various public databases and microarray facility and provide a com - are not only in different formats but are uploads it into the warehouse. Client plete solution for the management of also rapidly evolving, leading to signif- machines running Windows (95, 98, microarray experiments within a icant informatics efforts. NT, 2000, XP) connect to, communi- secure environment. LIMS for The Function Express gene anno- microarray facilitates organization, Continued on page 10 storage, archiving and retrieval of all experiment-related information. Investigators can submit samples GATEWAY CHEMICAL on line using a web-based sample sub- TECHNOLOGY mission form. Once the samples are received, the curator can create and enter metadata about new experiments, CUSTOM SYNTHESIS investigators, samples and chips. Using • Pharmaceuticals LIMS graphical interface, the curator • Agrichemicals can also view, edit or update existing • Combinatorial Platforms information. • Competitor's Products The samples can be tracked by • Intermediates assigning auto-generated unique sam- • Analytical Standards ple IDs. Barcode labels can be printed • Metabolites for samples to facilitate sample track- ing. On completion of an experiment, PROCESS DEVELOPMENT data files can be uploaded to the data - • Process Evaluation base after which an intimation mail • New Route Development will automatically be sent to the inves - tigator notifying him/her that the data SPECTROSCOPIC SERVICES have been successfully uploaded/ • LCMS (APCI and API-ES) archived on server. The investigators • NMR (300 MHz) can retrieve the results through a web • GCMS (EI) interface. The results can be analyzed 11810 Borman Dr • Saint Louis, Missouri 63146 using Function Express gene annota- 314.220.2691 (office) • 314.991.2834 (fax) tion tool or exported in a simple text www.gatewaychemical.com • [email protected]
The Nucleus December 2005 9 Management of Data in the central database. generate protocols and workflows. The The Mutation Analysis Pipeline bar-coding capability simplifies track- Continued from page 9 facilitates localizing mutations on the ing and processing of multiple samples cate with, and transfer data to and gene sequences from the clinical sam- for multiple projects. Tracking of from the server. ples by comparison with reference experiments is simplified through the Web-based Portal for Microarrays sequence and verification with dbSNP hierarchical relationship between sam- We have also developed and database. The application pipeline ples, gels, and spots. deployed web-based tools at the Wash- helps the investigator right from primer Laboratory resources can be man- ington University server, which allow design to the visual comparison of aged effectively through LIMS inter- investigators to download chip data same genes from multiple samples or face by assigning multiple roles to one along with selected annotations. multiple genes from the same sample. user or one role to multiple users with The investigator can also use this LIMS for Proteomics secure access to all or part of the sys - interface to query the database, and Success of a Proteomics labora- tem. Auto forwarding of completed publish chips. The sophisticated tory depends on rapid analysis by opti - task, auto initiation of new task and authorization and authentication meth- mizing throughput, managing data and visual indicators for incomplete tasks ods that are implemented allow the improving quality. automate workflow. investigator to selectively share their Our LIMS for Proteomics is a The most powerful feature of data with colleagues. complete system that integrates and LIMS for Proteomics is its ability to automates sample handling, sample interface with third party tools that Mutation Analysis Pipeline-Inte- analysis, role and resource manage- enables it to capture information from grating the Sequence and Mutation ment and integration of third-party gel reader and display results in a gel Data tools for gel image and protein expres - viewer. For instance, it maps Cartesian The goal of a Microarray experi- sion analyses. coordinates of the significant spots ment is to screen interesting genes in LIMS for Proteomics integrates selected in 2-D Gel electrophoresis patients’ clinical samples by studying the workflow from initial sample char - image (image1) generated by Ettan™ the genome-wide expression levels. DIGE system (Amersham Biosciences) These interesting genes are then actu- acterization through gel analysis to protein identification. From a single with the corresponding spots in the ally sequenced using the same samples scanned image (image2) of the fixed that were used for microarray experi- central screen, the investigator can design experiments, set parameters, gel generated by the ProPic ™ soft- ments. These sequences are then stored ware (Genomic Solutions), which is in a different orientation. The spot-list generated from image1 is transformed so that the coordinates reflect the same spots in image2. This transformed list is used by a robotic arm for precise cutting and picking of the spot material for further analysis (MS). To maximize the opportunity for discovery, the built-in protein identifi- cation viewer integrates spots on the gel image with the Mascot search results. Clicking on the spot generates a consolidated, succinct report from multiple MS jobs on the spot; dif ferent color labels are used for each job. This allows protein identifications to be related to the experimental workflow. All the data are viewed in one fully integrated system. Reports can be gen - erated at any stage to track progress of experiments or review final results. Advantage of Approach The data warehousing based solu- tion has the advantage of having all the data in one place, which is trans- formed to match the desired queries.
10 The Nucleus December 2005 Management of Data Data Marts. the intricacy of biological and biophar- The Initiative Management Data maceutical R & D data needs to be Continued from page 10 Mart efficiently integrates the data carefully considered in order to devise The queries are fast, and there is no related to the sequencing process (a the correct integration solution. dependence on individual data sources. small part of the production database), For selecting the most optimum Data Integration Solutions for and is optimized for generating project data integration methodology, we at Sequencing Pipeline at MIT-Broad management reports. Persistent Systems have thoroughly Institute The Lab Quality Data Mart examined the requirements and com- The MIT-Broad Institute for addresses the complex problem of plexity of data, in the case of both Genome Research is one of the lar gest associating the lab workflow informa- Washington University and Broad genome centers in the world and has tion with the quality of the sequencing Institute. served as one of the flagship centers of process. The lab workflow involves While implementing solutions for the Human Genome Project. Today, the various phases, such as addition of the School of Medicine, Washington center houses a broad range of thriving reagents to the samples (DNA frag- University in St Louis, the highly spe - research programs combining struc- ments) that are to be sequenced, trans - cific scientific questions of relation- tural genomics, medical, population ferring the samples from one plate to ships between the expressions values genetics, and clinical medicine. another, and processing of the samples for genes and the experiment and the The sequencing laboratory at the at several decks (machines). Any biological context were taken into con- center produces over 50 billion high- defect or shortcoming in a workflow sideration. Solutions were devised quality nucleotide base calls per year, phase can lead to deterioration of the such that the data model created each of which has multiple pieces of quality of sequenced samples. The data explicit representation of the relation- information associated with it. The mart links the quality of samples to ships in the system, allowing formula- amounts of data produced by sequenc- various factors of lab workflow such as tion of queries that answered the ing raise significant challenges for materials, plates and decks involved in researchers’ questions. A complete informatics resources. The existing the sequencing process, and tempera- research workflow often requires that operational OLTP (Online Transaction ture/humidity of various phases of the the computational tools be able to Processing) system (Production Data- workflow. The main purpose of the process and display the integrated data base), which hosts the data generated data mart is to allow users to identify in a succinct manner. The computa- by genome sequencing process, is a and analyze the factor(s) that lead to tional tools developed and deployed huge system with thousands of tables drop/rise in the sequencing quality. for Washington University help cap- and terabytes of data. The production The data marts are built on Oracle ture, disseminate, share, query and database is continuously updated and 10g, and Cognos-Cubes are used for visualize post-genomic data. Similarly, hence heavily loaded, as the sequenc- reporting and analysis. Oracle Streams while implementing data marts for ing center runs 24/7. The report gener- is used in the extraction phase to iden - MIT-Broad Institute sequencing ation and analysis queries put extra tify the changes made in the OLTP pipeline, issues of huge volume of burden on the production database. databases and to copy the changes to a data, intricate workflow and complex To resolve the reporting and inte- staging area. Oracle Streams can read query report requirements were taken gration issues at the sequencing center archive logs of the OLTP database into consideration. The value added by at the Broad Institute, we are building without affecting normal processing of our solution provides a compelling a data warehousing solution that will the OLTP system, to efficiently detect argument in terms of the time and take the analysis load off the produc- the relevant inserts, updates and effort saved in accessing multiple dis- tion database and facilitate complex schema changes made to the tables in parate data sources and aiding decision analytical queries. The major chal- the OLTP system. Oracle Warehouse support system. lenges involved in implementing the Builder (OWB) is used as the ETL Dr. Raghunath A. Mashelkar, desired solution were acquiring requi- (Extract-Transform-Load) tool to Director General of the Council of Sci- site domain knowledge, understanding transform and load the staging produc - entific and Industrial Research has the schema of the production database, tion data to the data marts. stated “Rapid paradigm shifts that are taking place in the world, as it moves understanding the reporting and analy- Conclusion from super-power bipolarity to multi- sis needs of the Institute, designing the The widespread adoption of high polarity, as industrial capitalism gives warehouse schema and summaries for throughput technologies and exponen- way to green capitalism and digital optimizing report generation, design- tial increase in the volume of available capitalism, as information technology ing the ETL transformations, and data are challenges often cited in the creates netizens out of citizens, as the designing the physical database. The integration of biological and clinical nations move from ‘independence’ to Warehouse developed and deployed at data. Although, modern data manage- ‘interdependence’, as national bound- the sequencing center includes Initia- ment technologies provide solutions tive Management and Lab Quality that address data scale-up problems, Continued on page 16
The Nucleus December 2005 11 Tailoring Chemistry (method development), Gas Chro- staffed than those of most of his matography (GC) (most standard clients, but it is also independent. After Continued from page 4 methods), Differential Scanning all, an outside laboratory such as in a matter of seconds. Calorimetry (DSC), Titimetry, Infrared Jordi’s has no vested interest in the ana- I did not ask Jordi about the chal - Spectroscopy (IR), Attenuated Total lytical findings. Some clients value an lenges he faced in synthesizing the Reflectance Spectroscopy (ATR), independent analysis in the case of a large number of chromatographic Ultra-Violet - Visible - Spectroscopy new compound, particularly where the (GPC) columns his company now mar- (UV/Vis), Thermogravimetric Analysis client has to deal with investors, gov- kets to major pharmaceutical and bio- (TGA), and Thermal Mechanical ernment agencies, and entrepreneurs. chemical companies. Jordi makes GPC Analysis (TMA), as well as LCMS, Jordi added, “There is also the packings from 100% polydivinyl ben- GC/MS and desorption GC/MS testing. issue of reproducibility. In science, data zene (DVB) to assure compatibility Jordi is aware that costs could be a should be reproducible by more than with high temperatures, high pressures limitation and could discourage his one individual. When our laboratory and the widest range of solvents. A sin- client when he sees the price tag. can duplicate the results from another gle Jordi GPC column replaces several Therefore, in general, he encourages organization, we then have confirma- fragile PS-DVB columns and expands his clients to do their own analysis in tion of the overall data accuracy.” the range of solvents available for house and use the outsourcing option In production, in particular, the solving several polymer analysis prob- when it is more cost-effective. And in relatively stable variability of the data lems. The analytical chemist is thus fact, his staff works with the clients to from one batch of the product to able to use one single Jordi GPC col- do just that. another shows how reliable the manu- umn with toluene, THF, methanol, Typically, Jordi’s clients know that facturing process is, as well as how hexane, HFIP, acetone, Freon, or 5% a subset of the total analytical work stable the product is under various con- water in THF. they need requires sophisticated equip- ditions. Many of Jordi’s clients in the ment, software, and manpower they do Another group of clients are the pharmaceutical and biotech industry not have at their disposal. Especially law firms who would like to base their synthesize or use a great number of during the research phase of the proj- cases on findings that are made through polymer-based products or additives. ect, they would not try to justify any independent analysis. For example, When it comes to analytical methods major capital outlays for extensive independent laboratories identified the for polymers, Jordi and his staff spe- analytical work rather than for the syn - increasing nicotine levels in cigarettes cialize in dealing with these kinds of thetic work. Besides, the qualified and over the years. Other cases include an polymer-related problems. That is pri- experienced manpower for compli- identification of foreign poisonous marily due to Jordi’s, and his staff’s, cated analysis is just not available. contaminants (in minute quantities) extensive chemical background in Those clients know the type of analysis contained in foods, drinks, or drugs polymer chemistry; and in particular, they want conducted and, therefore, sold to consumers. their synthesis work. On his company’s they are able to define the analytical Where does the FDA or the EPA website, (www.jordiassoc.com), Jordi task they want (in collaboration with come in? Both agencies are interested provides a complete database of all the Jordi’s staff as needed). Why would a in independent reproducibility, and procedures his laboratory uses in its chemist who has just developed a com- expect companies to use an independ- analytical work. pound let an outside expert do an ent laboratory, such as Jordi’s, that is I was wondering whether that analysis rather than do it in his own open for inspection and audit, as well means Jordi has a carte blanche from laboratory? as the analysis be conducted in accor- his clients in what analysis his com- “They would like to know all the dance with recognized standards, such pany should do, so I asked him compounds and by-products of a as the ASTM. Jordi’s laboratory is cer- whether that is the situation. newly synthesized compound. There tified by the FDA or EPA to perform “This is not the case,” Jordi are bound to be surprises, both positive certain analyses. responded. “In Polymeric Analytical and negative, that could be revealed in In reality, Jordi himself acknowl- Chemistry, analysis could get to be a more sophisticated laboratory such as edged that his staff chooses to out- expensive. Therefore, knowledgeable Jordi’s,” Jordi commented. As for secu- source part of the effort to various clients have to be selective.” Jordi’s rity concerns, Jordi signs non-compete sources with whom he has established laboratory provides the following serv- agreements to protect the client. Continued on page 13 ices: Gel Permeation Chromatography According to Jordi, his company’s (GPC), High Temperature Gel Perme- analysis is more accurate and compre- ation Chromatography, Polymer De- hensive than that provided by a formulation, Liquid Chromatography chemist who has just synthesized a (LC) (method development), Liquid new compound and has to conserve his Chromatography (LC) (most standard cash for other purposes. Not only is methods), Gas Chromatography (GC) Jordi’s laboratory better equipped and
12 The Nucleus December 2005 Tailoring Chemistry materials field. From 1951-1954 Priest Historical served as Assistant Group leader, Solid Continued from page 12 State Transistor Group, Lincoln Labo- some working relationships rather than ratory, Massachusetts Institute of Tech- try to duplicate the expertise acquired Notes nology. While at Lincoln Laboratory by some of the laboratories. In fact, he held a concurrent position as Execu- Homer F. Priest tive Assistant to the President, High Jordi does provide the following serv- Homer F. Priest retired former ices through outside affiliates: Voltage Engineering Corporation, from Director of the Materials Research 1950-1951. He then left Lincoln Labo - a. Elemental X-Ray Analysis includ- Laboratory, U.S. Army Materials ratory to join the Solid State Research ing: Elemental Spectroscopy for Research Agency, Watertown Arsenal, Group at Baird Associates and Chemical Analysis (ESCA), Energy died March 12, 2004 at the age of 88. remained there until 1957. Dispersive Spectroscopy (EDS) Born June 14, 1916 in Nelson, NH, Priest served as a Supervisory Scanning Electron Microscopy Priest received his bachelor’s degree in Physical Chemist, Materials Research (SEM) Fluorescence SP ARK chemistry from the University of New Laboratory, Ordnance Materials Source Mass Spectroscopy, Induc- Hampshire in 1938 and his master’s Research Office, U.S. Army Water- tively Coupled Plasma Emission degree from Williams College in 1940. town Arsenal from 1957-1963. In 1963 Spectroscopy (ICP), Atomic On November 28, 1941, he married Priest was appointed Director, Materi- Absorption Spectroscopy (AA). Grace L. Ernst, also a chemist. He was als Research Laboratory, U.S. Army b. Organic Structural Characterization: an instructor in chemistry at Columbia Materials Research Agency, Water- Nuclear Magnetic Resonance Spec- University from 1940-1941 while town, Massachusetts. Priest’s last posi- troscopy (NMR), including proton working on his doctorate with Profes- tion was Chief, Materials Science and carbon 13. sor Harold Urey. While at Columbia he Division, U.S. Army Materials and and his wife were enlisted to work on Mechanics Research Center, Water- In those cases where Jordi’s labo- the Manhattan project. From 1941-44 town, Massachusetts. He retired form ratory chooses to outsource, Jordi’s he was head of the Chemistry Division this position in 1980. staff is involved in supervising the and a Section leader at the K-25 Dr. Priest received an Honorary total process, which includes the prepa- Gaseous Diffusion Plant, Oak Ridge, Doctor of Science Degree from the ration of a report. Tennessee, where he and his wife stud - University of New Hampshire in May In most applications each client ied uranium hexafluoride chemistry of 1968 in honor of his contributions to who decides to outsource the analytical and performed materials research to the Manhattan Project and the develop- chemistry effort to Jordi’s laboratory develop barriers for the separation of ment of techniques for growing single has a unique problem. It is the client’s uranium isotopes in the gaseous diffu- crystals of semiconductor materials. responsibility to define the problem. In sion process. He was an avid birder and bird response, Jordi’s staff proposes a spe- From 1944-1946, he was photographer and spent most of his cific analytical solution to the client in employed as a chemist by Carbide and winter vacations in Florida observing terms of priorities, timelines, costs, and Carbon Chemical Corporation, at Oak and photographing in the everglades. expectations, thus giving the client a Ridge, Tennessee. In 1946, he was He enjoyed working outdoors in his choice on how to proceed with the named Director of Research. From garden and yard. He was a lifelong overall analytical effort. At some point, 1948-1950, Priest was appointed as member of the Massachusetts Aubudon there is a meeting of the minds on what Technical Advisor to the Chief of the Society, the National Aubudon Society, analytical tasks will be performed by Technical Command, Decontamination and the National Wildlife Federation. which laboratory and on which time- Branch, Radiological Warfare Divi- He is survived by his wife of 63 line. Tailoring the analytical chemistry sion, U.S. Army Chemical Center, years, Grace Priest. He was an emeri- effort to deal with the specific chem- Edgewood Arsenal, Maryland. tus member of the American Chemical istry problem will ultimately assure the He received his Ph.D. in Inorganic Society with 65 years of membership. client that the information needed will Chemistry from Massachusetts Insti- be acquired and made available at the tute of Technology in 1948 under Pro- Submitted by Dr. John R. Hobbs appropriate time of the project and at fessor W. C. Schumb. After receiving Historical Notes is an ongoing series of optimum costs. ◆ his Ph. D., he was a consultant in the short biographies of recently deceased chemists and chemical engineers whose Have you looked for it on the NESACS website? deaths have been reported to us during Updated frequently • Late-breaking news, position postings the past year. We thank members of the Back issues of the Nucleus archived in .pdf format Northeastern Section who have sent us obituary notices appearing in commu- WWW.NESACS.org nity newspapers we do not see. ◆
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The Nucleus December 2005 15 estheimer Prize Medal.) W alt (Dept. of Chem., Tufts Univ.) Tufts alt (Dept. of Chem., W ufts Univ. Chemical and Biological ufts Univ. and Biological Chemical ufts Univ. Notices for the Nucleus Calendar should be sent to: 88 Hemlock St., Donald O. Rickter, Dr. Arlington, MA 02474-2157 e-mail: [email protected] T Engineering Seminar Series, Room 136, Center, Technology Science and 4 Colby St., Medford, 12:00 m Dec 5 of Illinois) Prof. Jonathan Sweedler (Univ. Time" "Measuring Neurochemistry a Cell at a Lecks Bldg., Edison Brandeis Univ., Gerstenzang 122, 3:30 pm (UCLA) Prof. David Eisenberg (The Frank H. Pfizer Lecture Hall, Harvard Univ., 12 Oxford St., 4:15 pm Prof. David "Array-based Biosensing: DNAArrays" to Cell T Engineering Seminar Series, Room 136, Center, Technology Science and 4 Colby St., Medford, 12:00 m Dec 8 Prof. Clemens Richert (Universität Karlsruhe) “Chemical Primer Extension” Chemistry Building, Pearson Univ., Tufts Medford, Ave., Talbot 62 Room P-106, 4:30 pm Dec 12 Prof. Joanne Stubbe (MIT) "Ribonucleotide Reductases: Something for Everyone" Edison Lecks Bldg., Brandeis Univ., Gerstenzang 122, 3:30 pm .html imescales." (Woodward Lecture imescales." (Woodward T Dec 2 Prof. John Chen (Lehigh Univ.) Their Influence on "Surface Contacts: “ Transfer Multiphase Heat Dec 1 (Stanford Univ.) Wender Prof. Paul “Breaching Biological Barriers: New Drug and Imaging” ; Vivo Probe Delivery Systems and in 2005-2006 University Lectures in Chemistry; Aldrich Chemical Sponsored by Boston College, Merkert 130, 4:00 pm Prof. Charles B. Harris (UC Berkeley) "The Dynamics of Electrons at Interfaces on Ultrafast Series in the Chemical Sciences/Harvard-MIT Phys. Chem. Seminar) Pfizer Lecture Hall, Harvard Univ., 12 Oxford St., 5:00 pm Check the NESACS Homepage for late additions: http://www.NESACS.org Note also the Chemistry Department web pages for and updates. travel directions These include: http://chemserv.bc.edu/seminar http://www.bu.edu/chemistry/events/ http://www.chem.brandeis.edu/colloquium.shtml http://www-chem.harvard.edu/events/ http://web.mit.edu/chemistry/ www.chem.neu.edu/web/calendar/index.html http://chem.tufts.edu/seminars.html http://ase.tufts.edu/chemical/seminar.htm http://www.chem.umb.edu/ www.umassd.edu/cas/chemistry/seminars.cfm www.uml.edu/Dept/Chemistry/speakers.html http://www.unh.edu/chemistry/seminars.html Calendar - NONPROFIT ORG. U.S. POSTAGE PAID NORTHEASTERN SECTION AMERICAN CHEMICAL SOCIETY Applications 19 Mill Road Harvard, MA 01451 ◆◆ The Indian pharmaceutical and sectors, in particular, the contract R tentsys.com an indexing and retrieval tool for flat file data libraries.” Computer in the Biosciences 9: 49-57. A “Biokleisli: L. Wong, Digital Library for Biomedical Researchers,” Journal of Digital Libraries 1, No. 1, 36–53 (1996). Journal of Functional Pro- System,” gramming 10, No. 1, 19–56 (2000). A(2001). “DiscoveryLink: system for access to life sciences data integrated sources.” IBM Systems Journal 40(2): 489-511 1. Persistent Systems website: www.persis- 2. Argos (1993). “SRS— and P. Etzold, T. 3. and Tannen, S. Davidson, C. Overton, V. 4. “Kleisli, a Functional Query Wong, L. 5. Haas, L. M., P. M. Schwarz, et al. & D organizations have seen a dra- D organizations & matic change in their capabilities and sophistication. pharma International ceutical companies should now be ide - seek collaborations to poised to ally innovative drugs to the con- bring price.” sumers at an affordable References: IT aries notional, and as the conbecome - cept of global citizenship gets evolved, will see a world full of new paradigms and new paradoxes. There is no doubt that of science and the rapid advance technology will directly fuel many of these. Management of Data page 11 Continued from