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Pathway Informatics Vendors Tout Tox as Open Source Alternatives Gather Steam

SAN FRANCISCO “Toxicology” is the magic word among pathway informatics vendors here at Cambridge Healthtech Institute’s Molecular Medicine Tri-Conference, where both Ingenuity Systems and GeneGo are showcasing the capabilities of their respective platforms to address the molecular toxicology requirements of potential drug-discovery customers.
Outside the exhibit hall, however, there was clear evidence this week that freely available pathway informatics resources are holding their own against commercial databases, and that these tools are quickly becoming more sophisticated.
The leading pathway informatics vendors — Ingenuity, GeneGo, Ariadne Genomics, and Jubilant Biosys — all had a strong presence at a conference that was otherwise relatively light on bioinformatics. As the field gets more competitive, it’s clear that these companies are reacting rapidly to customer requests for new features and functionality.
As an example, Ingenuity was previewing Ingenuity Pathway Analysis 5, which the company plans to launch in April. The new release includes two capabilities expected to be of great interest to drug-discovery researchers: biomarker analysis and molecular toxicology analysis.  
Megan Laurance, product research scientist at Ingenuity Systems, told BioInform that the company’s team of curators carefully screened the scientific literature to add a large amount of new data to the database, particularly in the areas of hepatotoxicity, cardiotoxicity, and nephrotoxicity.
In addition, she said, the company worked with its pharmaceutical customers and the National Institute of Environmental Health Sciences to create a “lexicon” of toxicology terms. “We used basically anything we could get our hands on,” she said.
GeneGo, meanwhile, is in the process of creating a toxicology consortium based on its MetaDrug resource. Julie Bryant, vice president of business development and marketing at GeneGo, told BioInform that the FDA and several pharmaceutical companies have agreed to join the consortium, which will be a collaboration with the goal of adding new toxicology content to MetaDrug.
Bryant said that GeneGo’s drug discovery customers are increasingly asking for new toxicology functionality because they want to take more of a “systems-level” approach to toxicity. While many companies have relied on gene expression signatures to assess the toxicogenomics aspects of their compounds, Bryant said that customers are now looking to map those signatures onto biological pathways in order to gain a better understanding of toxicity mechanisms.
In a bid to attract another segment of the drug-discovery market, GeneGo was also showcasing a new model for its flagship MetaCore database that is targeted to “casual users” of pathway-analysis tools. The so-called “1-2-3 Workflow” is a pay-as-you-go offering that allows researchers to analyze up to eight gene or protein lists of up to 1,000 genes each for $1,000.
The workflow allows users to submit their list, compare the data within the context of biological pathways, and generate a comprehensive Word report with three mouse clicks, Bryant said.
The offering is expected to appeal to end-user biologists who don’t need to access MetaCore very often, Bryant said. She noted that most pathway analysis is still within the domain of bioinformatics groups or expert users, so GeneGo’s goal was to create a user-friendly and low-cost alternative for biologists and therapeutic researchers.
Open-Source Options
While commercial pathway vendors are adjusting their offerings to meet the requirements of industrial drug-discovery teams, academic pathway resources are also developing rapidly to add new functionality.
In a conference track dedicated to open source pathway databases, representatives from GenMAPP, Cytoscape, Reactome, and the Pathway Commons discussed new developments and features that are expected to improve the usability and interoperability of their resources.
Bruce Conklin, associate investigator at the University of California San Francisco’s Gladstone Institute of Cardiovascular Disease and founder of the GenMAPP project, noted that one advantage of the open source model is that it encourages collaboration between different projects.
As an example, he noted that the GenMAPP user community is beginning to develop a suite of tools to improve the functionality of the core resource. One such project, PathVisio, developed by the BiGCaT bioinformatics group at the University of Maastricht in the Netherlands, is a pathway-visualization and -editing tool that implements GenMAPP pathways in XML via a newly developed format called GPML (GenMAPP Pathway Markup Language).
Conklin said that GenMAPP users should be able to benefit from projects like PathVisio, which enable a more user-friendly version of the resource while freeing the GenMAPP team from the burden — and cost — of development. “We had very little involvement” in the development of PathVisio, he said.
Cytoscape is another example of an open-source project with growing development community. The Cytoscape website currently lists 35 “plug-ins” that have been submitted by various development teams. One of those teams is Agilent Laboratories, which developed the Agilent Literature Search plug-in, which automatically queries lists of genes or proteins against PubMed and displays the results within a Cytoscape network.

Agilent’s molecular technologies lab is “a tiny group,” but collaborating with Cytoscape gave Agilent access “to the best minds around.”

Allan Kuchinsky, principal project scientist in Agilent’s molecular technologies lab, said that the company currently has a prototype version of another tool called Agilent Network Builder that scans the scientific literature and other public resources to find all possible interactions with a given set of genes. The level of confidence in each interaction is indicated by the thickness of the line, Kuchinsky said.
Agilent sells the GeneSpring software suite, so it’s no stranger to the commercial bioinformatics market. Kuchinsky said that the company sees several advantages in working with the open source Cytoscape project, however. Network analysis is particularly complicated, he noted, so it made sense for the company to align itself with a project that already had made some headway in that area.
“We’re a tiny group,” he noted, but said that collaborating with Cytoscape gave Agilent access “to the best minds around.”
Another effort is underway to begin integrating the wide range of publicly available pathway databases into a single view. Gary Bader, assistant professor at the Banting and Best department of medical research at the University of Toronto, described the newly launched Pathway Commons project, which eventually aims to provide “a single point of access to all publicly available pathway data,” Bader said.
That’s a tall order, considering that there are currently around 220 different pathway databases, and each of them currently uses different formats, relies on different representation models, and has very different levels of coverage.
Bader noted that the ongoing BioPax standardization effort is an important first step toward interoperability. Around 25 pathway databases currently make their data available in BioPax or the BioPax-compatible PSI-MI format, which enables them to be aggregated into the Pathway Commons website, he said.
The first version of Pathway Commons was launched in January and includes data from the Cancer Cell Map, Reactome, HumanCyc, and the NCI/Nature Pathway Interaction Database. The current version includes 921 pathways and 9,924 interactions for 10 organisms.
These open source efforts are not going unnoticed by commercial groups. Ingenuity’s Laurance told BioInform that while the company believes its database has much more depth of content and a more user-friendly interface than most freely available options, it still considers these non-profit efforts to be “very important” for the field.
She added that while Ingenuity has no formal plans to release its data in BioPax format at this time, the company does recognize the importance of enabling its customers to export pathway data in a community-accepted format. She added that the company anticipates participating on some level with the open source pathway informatics community “at some point.”

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