{"markup":"\u003C?xml version=\u00221.0\u0022 encoding=\u0022UTF-8\u0022 ?\u003E\n    \u003Chtml version=\u0022HTML+RDFa+MathML 1.1\u0022\n    xmlns:content=\u0022http:\/\/purl.org\/rss\/1.0\/modules\/content\/\u0022\n    xmlns:dc=\u0022http:\/\/purl.org\/dc\/terms\/\u0022\n    xmlns:foaf=\u0022http:\/\/xmlns.com\/foaf\/0.1\/\u0022\n    xmlns:og=\u0022http:\/\/ogp.me\/ns#\u0022\n    xmlns:rdfs=\u0022http:\/\/www.w3.org\/2000\/01\/rdf-schema#\u0022\n    xmlns:sioc=\u0022http:\/\/rdfs.org\/sioc\/ns#\u0022\n    xmlns:sioct=\u0022http:\/\/rdfs.org\/sioc\/types#\u0022\n    xmlns:skos=\u0022http:\/\/www.w3.org\/2004\/02\/skos\/core#\u0022\n    xmlns:xsd=\u0022http:\/\/www.w3.org\/2001\/XMLSchema#\u0022\n    xmlns:mml=\u0022http:\/\/www.w3.org\/1998\/Math\/MathML\u0022\u003E\n  \u003Chead\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_itu2PgFdrjV-docKmLK8Jn5oXe_05RgvQh73eOhI_mE.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_at_symbol.js?nzmv41\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_article_reference_popup.js?nzmv41\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_I8yX6RYPZb7AtMcDUA3QKDZqVkvEn35ED11_1i7vVpc.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\n(function(i,s,o,g,r,a,m){i[\u0022GoogleAnalyticsObject\u0022]=r;i[r]=i[r]||function(){(i[r].q=i[r].q||[]).push(arguments)},i[r].l=1*new Date();a=s.createElement(o),m=s.getElementsByTagName(o)[0];a.async=1;a.src=g;m.parentNode.insertBefore(a,m)})(window,document,\u0022script\u0022,\u0022\/\/www.google-analytics.com\/analytics.js\u0022,\u0022ga\u0022);ga(\u0022create\u0022, \u0022UA-15605596-27\u0022, {\u0022cookieDomain\u0022:\u0022auto\u0022});ga(\u0022set\u0022, \u0022page\u0022, location.pathname + location.search + location.hash);ga(\u0022send\u0022, \u0022pageview\u0022);ga(\u0027create\u0027, \u0027UA-189672-26\u0027, \u0027auto\u0027, {\u0027name\u0027: \u0027hwTracker\u0027});\r\nga(\u0027hwTracker.send\u0027, \u0027pageview\u0027);\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\njQuery.extend(Drupal.settings, {\u0022basePath\u0022:\u0022\\\/\u0022,\u0022pathPrefix\u0022:\u0022\u0022,\u0022highwire\u0022:{\u0022markup\u0022:[{\u0022requested\u0022:\u0022full-text\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;11\\\/15\\\/8\u0022},{\u0022requested\u0022:\u0022long\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;11\\\/15\\\/8\u0022}],\u0022ac\u0022:{\u0022spmdc;11\\\/15\\\/8\u0022:{\u0022access\u0022:{\u0022reprint\u0022:true,\u0022full\u0022:true},\u0022pisa_id\u0022:\u0022spmdc;11\\\/15\\\/8\u0022,\u0022atom_uri\u0022:\u0022\u0022,\u0022jcode\u0022:\u0022spmdc\u0022}}},\u0022googleanalytics\u0022:{\u0022trackOutbound\u0022:1,\u0022trackMailto\u0022:1,\u0022trackDownload\u0022:1,\u0022trackDownloadExtensions\u0022:\u00227z|aac|arc|arj|asf|asx|avi|bin|csv|doc(x|m)?|dot(x|m)?|exe|flv|gif|gz|gzip|hqx|jar|jpe?g|js|mp(2|3|4|e?g)|mov(ie)?|msi|msp|pdf|phps|png|ppt(x|m)?|pot(x|m)?|pps(x|m)?|ppam|sld(x|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip\u0022,\u0022trackUrlFragments\u0022:1},\u0022ajaxPageState\u0022:{\u0022js\u0022:{\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/jquery.cluetip.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.hoverIntent.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.bgiframe.min.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_at_symbol.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_article_reference_popup.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/contrib\\\/google_analytics\\\/googleanalytics.js\u0022:1,\u00220\u0022:1}}});\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EEach year, the American Heart Association presents the Lewis A. Conner Memorial Lecture to honor the memory of one of the founders of the AHA. This year, Joseph Loscalzo, MD, PhD, FAHA, Harvard Medical School, Boston, Massachusetts, USA, delivered a presentation on the potential for a more personal, systems- and network-based approach to drug development.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPrevention \u0026amp; Screening\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EEach year, the American Heart Association (AHA) presents the Lewis A. Conner Memorial Lecture to honor the memory of one of the founders of the AHA. This year, Joseph Loscalzo, MD, PhD, FAHA, Harvard Medical School, Boston, Massachusetts, USA, delivered a presentation on the potential for a more personal, systems- and network-based approach to drug development.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EStanding at the Crossroads\u003C\/h2\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EToday, we stand at a crossroads between a one-size-fits-all drug development paradigm and a systems-based approach that incorporates the developing fields of genomics, proteomics, metabolomics, phenomics, pathophenomics, transcriptomics, epigenomics, and metagenomics (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/15\/8\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Systems Biology and Pathobiology.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-872780037\u0022 data-figure-caption=\u0022Systems Biology and Pathobiology.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/15\/8\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/15\/8\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/15\/8\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11695\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-4\u0022 class=\u0022first-child\u0022\u003ESystems Biology and Pathobiology.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from J. Loscalzo, MD, PhD, FAHA.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EIntegration of systems biology and network analysis is setting the stage for a novel drug development paradigm that is based on the identification of mechanisms that underlie physiological circuits that are corrupted in disease states [Loscalzo J, Barabasi AL. \u003Cem\u003EWiley Interdiscip Rev Syst Biol\u003C\/em\u003E Med 2011; Waldman SA, Terzic \u003Cem\u003EA Clin Transl Sci\u003C\/em\u003E 2011]. Insights into these processes offer unparalleled opportunities for a network-based approach to human illness [Barabasi AL et al. \u003Cem\u003ENat Rev Genet\u003C\/em\u003E 2011] and personalized medicine.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe goal of personalized medicine is to match precisely the right drug at the right dose to the specific biology of the disease in an individual patient and to maximize therapeutic efficiency while minimizing adverse and off-target effects [Waldman SA, Terzic A. \u003Cem\u003EClin Transl Sci\u003C\/em\u003E 2011]. The principle itself is straightforward, but its implementation remains challenging [Hamburg MA, Collins FS. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EMoving Beyond the Silver Bullet\u003C\/h2\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe science of drug discovery has accelerated exponentially; yet, delivery of its benefits to patients and populations has lagged [Waldman SA, Terzic A. \u003Cem\u003EClin Transl Sci\u003C\/em\u003E 2008; Waldman SA, Terzic A. \u003Cem\u003EClin Pharmacol Ther\u003C\/em\u003E 2008]. One reason is that pharmaceutical research and development (R\u0026amp;D) productivity has been in decline since the mid-1990s. This may be due, in part, to an intrinsically flawed reductionist approach to drug development (ie, the need to identify a single drug target or a \u201csilver bullet\u201d).\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003ESince the advent of genomics in the 1990s, potential drugs\u2014typically proteins that appear to have a key role in disease pathogenesis\u2014have been the main focus of discovery efforts. Great advances in the development of new tools to identify targets and compounds that interact with them have taken place. Yet, declines in R\u0026amp;D productivity point to potential limitations in the target-centric approach to drug discovery [Swinney DC, Anthony J. \u003Cem\u003ENat Rev Drug Discov\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EBefore the introduction of these approaches, drug discovery was driven primarily by phenotype, often with limited knowledge of molecular mechanisms of disease. Nonetheless, the pharmaceutical industry was successful in the discovery and development of innovative medicines [Swinney DC, Anthony J. \u003Cem\u003ENat Rev Drug Discov\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003ESome suggest that the more limited use of phenotypic screening in recent years has contributed to the current lack of success in drug R\u0026amp;D [Williams M. \u003Cem\u003EBiochem Pharmacol\u003C\/em\u003E 2005; Flordellis CS et al. \u003Cem\u003ECurr Top Med Chem\u003C\/em\u003E 2006]. Others blame an increasing focus of research activities on the development of selective drugs in complex scientific areas that are characterized by a low probability of success.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EBetween 1998 and 2008, the number of new medical entities (NMEs) that was approved per year declined (although it has been roughly constant since 2005). Conversely, attrition rates, development times, and R\u0026amp;D expenditures have all increased. The growth in attrition rates\u2014the proportion of failures out of the total number of projects that enter any given stage of R\u0026amp;D\u2014has been dramatic [Pammolli F et al. \u003Cem\u003ENat Rev Drug Discov\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThe Imperative for Change\u003C\/h2\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EFrom 2000 to 2008, there were 35 NMEs per year out of 1740 new projects. The probability of success was 2.01% per year. Development time was 13.9 years (up from 9.7 years during the 1990s), and United States clinical trials took 7 years on average to complete [Pammolli F et al. Nat \u003Cem\u003ERev Drug Discov\u003C\/em\u003E 2011]. These statistics represent the status quo\u2014a drug development process that has been in place for the past 50 years [Fishman MC, Porter JA \u003Cem\u003ENature\u003C\/em\u003E 2005; Butcher EC et al. \u003Cem\u003ENat Biotechnol\u003C\/em\u003E 2004].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EIt is widely recognized that major improvements are required in the methods that are now being used to develop new drugs. The time from initial target identification to market can be 10 to 14 years and incur a cost in the hundreds of millions of dollars. Even after substantial investment, only 30% to 40% of the candidate compounds that enter clinical trials are successful [Nordsletten DA et al. \u003Cem\u003EIEEE Trans Biomed Eng\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ESystems Pathobiology and Network Medicine - The Shape of What is to Come\u003C\/h2\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EA contemporary approach to human disease requires that it be viewed from a systems perspective rather than as a simple correlation between clinical syndromes and pathological analysis [Loscalzo et al. \u003Cem\u003EMol Syst Biol\u003C\/em\u003E 2007; Loscalzo J, Barabasi AL. \u003Cem\u003EWiley Interdiscip Rev Syst Biol Med\u003C\/em\u003E 2011]. Network modeling of whole-transcriptome expression data, for example, enables characterization of complex gene-gene interactions that underlie cellular functions [Chu J et al. \u003Cem\u003EBMC Syst Biol\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EDrug-target interactions have been studied in the context of interactome networks or interactions between proteins [Rask-Andersen M et al. \u003Cem\u003ENat Rev Drug Discov\u003C\/em\u003E 2011; Yidirim MA et al. \u003Cem\u003ENature Biotech\u003C\/em\u003E 2007]. The field of interactomics represents a new way to understand the success of drug targets in the context of their functional milieu [Rask-Andersen M et al. \u003Cem\u003ENat Rev Drug Discov\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003ENetwork-based approaches represent a relatively recent trend in drug discovery. However, the fact that drug development is clearly affected by intricate network effects suggests that network pharmacology will become an essential component of drug development strategies [Schadt EE et al. \u003Cem\u003ENat Rev Drug Discov\u003C\/em\u003E 2009; Hopkins AL. \u003Cem\u003ENature\u003C\/em\u003E 2009; Barabasi AL et al. \u003Cem\u003ENat Rev Genet\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EAccording to Dr. Loscalzo, quantitative holistic systems biology that is applied to human disease offers a unique approach for diagnosing established illness, defining disease predilection, and developing individualized (personalized) treatment strategies. These approaches will be able to take full advantage of modern molecular pathobiology and the comprehensive datasets that are rapidly becoming available for populations and individuals, and in so doing, they offer the promise of redefining our approach to disease, its treatment, and the practice of medicine [Loscalzo et al. \u003Cem\u003EMol Syst Biol\u003C\/em\u003E 2007; Loscalzo J, Barabasi AL. \u003Cem\u003EWiley Interdiscip Rev Syst Biol Med\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/11\/15\/8.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmv41\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmv41\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}