We have established two resource initiatives for the scientific community to collaborate on the creation, integration and use of common terminologies, vocabularies and ontologies for application in predictive toxicology (including reuse of existing medical, biological and chemical ontologies):
OpenTox Collaborative Ontology Development (based on Collaborative Protege):
On Sunday May 30 we host an OpenTox Workshop near Berlin in Potsdam that will bring many leading international research program directors and leaders together to discuss how collaboration and the increased linking of resources over the World Wide Web could progress human safety research and safety assessment. By linking resources and data increasingly powerful computer-based models can be built for predicting and avoiding unwanted adverse toxic side effects of drugs, chemicals, ingredients in soaps and cosmetics, pesticides etc. thus enhancing human safety and protecting the environment better. Such methods should also eventually lead to the replacement of many animal experiments.
During the workshop we will apply a variety of design, informatics and modelling methods to predictive toxicology problems guided by workshop leaders with expertise in the approaches used. A case study approach will additionally be followed so that groups can work together throughout the week on their case study problems. The case studies will also be developed virtually before the workshop week with support extended afterwards for further work including experimental testing of interesting results and hypotheses developed. The virtual aspects of the case study work will additionally be supported by the Synergy and OpenTox infrastructures and related Collaboration Pool and pilot collaboration study.
Case studies will focus on the development of innovative integrated testing strategies applied to the problem of predicting the toxicity of a molecule. Such strategies are becoming an increasingly important part of drug design strategies so as to remove toxic liabilities as early as possible in the design processs. REACH legislation is also requiring organisations in coming years to carry out a more extensive safety testing of all chemical ingredients in a variety of products ranging from consumer products to food to agrochemicals. Related to this activity is the relatively unsatisfactory use of animal experiments to predict human toxicity, which are not only complex and expensive, but also often do not predict human effects well, if at all. Hence new approaches combining computational modelling, in vitro assays, systems biology, stem cell technology etc. are required.
We will apply techniques to the study of existing knowledge (e.g., from adverse events, biological literature, pathway models etc.) to help support mechanism-based hypotheses and strategies. Modelling techniques based on data-mining, database searching, and read-across will be applied to chemical categories. Integrated QSAR-based models supported by the new OpenTox infrastructure will be used to build properly validated models including estimation of applicability domain. We will also research ADME and kinetics properties of structures as relevant to their toxicity profiles. We will attempt to predict primary metabolities based on P450 metabolism simulation and model the potential toxicities of metabolites. Population-varied physiologically-based ADME Simulations will be carried out for in vitro-in vivo extrapolation, exposure estimation and to study the variation across individuals and populations. We will also apply workflow techniques to the combination of methods and Bayesian networks to the evolution of weight of evidence based consensus predictions.
The most promising strategies and predictions developed will be used to design experimental human toxicity-oriented in vitro assays which will be run after the workshop as part of the virtual case study extension work. Both computational and experimental work will be documented according to industry best practices in a collaborative electronic laboratory notebook. We will attempt to develop new combined in silico - in vitro strategies superior to existing approaches which should help advance the field and industry testing and regulatory needs.
Through the time spent working and discussing together combined with the availability of a variety of leading software and expert support from workshop leaders, workshop participants should take home ideas and learning to help accelerate their own projects related to safety design and risk assessment. The location and atmosphere in Oxford is also an ideal background for networking, getting to know your peers and joining the ongoing eCheminfo community of practice activities. As is often common with eCheminfo gatherings the workshop usually attracts a variety of backgrounds including industry, academia and government research instititutes and from many different countries. We also welcome the participation of non-modelling specialists from different areas of chemistry, biology and toxicology to participate and bring an interdisciplinary interaction to the collaborative group work.
Neglected diseases such as parasitic infections reek havoc on many communities in different parts of the world. As part of our committment to responsible, sustainable development and a community culture, we will make neglected disease problems, where we evaluate we can make a significant difference, a goal of our collaborative virtual organisations in years to come. Please contact me to discuss your ideas and also consider joining the new Collaboration Pools summarised at bottom of this post. We can also work together on new funding opportunities.
However and also, my experiences in Africa, for example on our conservation trip to the remote Caprivi Delta region of Namibia: http://barryhardy.blogs.com/theferryman/2009/02/experiences-from-expedition-work-in-the-caprivi-delta.html (please keep in mind this post was based on a summary for my younger son for awareness!), was that "small contributions" can make a big difference. One story from that trip was the inability of a local clinic to deal with the torn foot of one of our party, and we ended up stitching him up with a veterinary kit back at base camp. Once that was done, how would he get around we asked, as there were no crutches to be had locally?! Discussing the incident around the camp fire afterwards, we came up with the simple solution of each throwing some money into a "needles and crutches" hat, and that was able to buy needles and crutches for the local clinic to keep them going for a couple of years, and it could be directly organised. So in this reality-focused context something like $200 made a bigger difference on the real problem for the future than a (possibly failed) major $100m program. A bit of a stretched analogy, but you probably get the point.
We intend to continue our support of sustainable development work in the community in Caprivi in community-involved wild life conservation development, and look forward to our next trip, and others in the community who might be interested. Let me know, if this might be for you too.
Here I would like to draw attention to a new local initiative in the area to help support the families affected by a widespread HIV infection epidemic. There is need for education, healthcare, and support of the many orphans left behind by parents who simply die from untreated HIV infection. Consider what you might do by volunteering some simple help and support to the work out there. The new center is called TAG Volunteers (TAG for think-act-grow):
I vouch this is a real legitimate project as Ronel, the woman setting it up, was also very much involved in competently running the important activities at our base camp on our last visit, such as getting something to eat when we got back very tired and hungry from our trips into the bush!
Welcome your feedback. If you do decide to take some time out to volunteering in some way, I suspect you will find it rewarding. And it is also at the same time such a special and beautiful country to experience!
We are establishing an InnovationWell Collaboration Pool of individuals and organisations who have an interest in collaborating together in areas of healthcare and life science innovation. For example, a selection of Pool members could participate in a collaborative life science, systems biology or predictive toxicology project, develop a funding proposal or response to a call opportunity together, or develop an innovation or best practice.
Collaborations will take a virtual organisation approach, i.e., partners can bring contributing knowledge, computational or experimental capabilities to a partnership for the duration of a project or other endeavour.
We will run two such virtual organisation (VO) projects for the first time this year starting later this Spring: A) Drug Design project which will examine the application of a variety of leading modelling and design approaches to novel target kinases, to experimentally test predictions, and to initiate a best practices virtual screening resource. B) Predictive Toxicology project to apply a combination of in silico and in vitro approaches to predict in vivo toxicity including exposure.
Both VOs will be supported by a variety of leading modelling and design software, informatics infrastructure, and collaborative content management and electronic lab notebook systems.
The VOs will be supported by knowledge-oriented collaboration services developed under the FP7 Synergy research project, including a reactive complex event driven engine, collaboration moderator, collaboration pattern services and partner knowledge base.
The Predictive Toxicology VO will be supported by distributed REST-driven web services for data management, model building, validation and reporting, developed under the OpenTox Framework (http://www.opentox.org/)
We will also consider incorporation of Case Studies into the eCheminfo Drug Discovery and Predictive ADME/Tox workshops to be held in Oxford this summer. See http://echeminfo.com/
For those of you in the community interested in closer involvement with OpenTox development and application use cases, joining related new initiatives and proposals, discussing our collaborating more closely with your own project, taking a leadership role etc., please feel free to contact me with your interests and motivations, and we could for example have a chat via Skype, get introduced and discuss your needs or ideas.
Contact Barry Hardy in his role as OpenTox Coordinator at Barry.Hardy !-(at)-* douglasconnect.com
I enclose here an abstract and copy of the presentation for the Plenary Lecture "Collaborative Development of Predictive Toxicology Applications" that I presented in Istanbul on 6 July 2009 at the Fifth International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (CMTPI 2009).
Collaborative Development of Predictive Toxicology Applications
Barry Hardy*a, Christoph Helmab, Nina Jeliazkovac, Romualdo Benignid, Stefan Kramere, Andreas Karwathf, Haralambos Sarimveisg, David Gallagherh, Vladimir Poroikovi, Sunil Chawlaj, Sylvia Escherk
This lecture will provide a perspective on the growing significance of community and collaboration approaches in predictive toxicology. In part these challenges are technical and involve progressing issues related to cross-organisational, enterprise and application interoperability. Additional challenges include the development and application of best practices related to knowledge management, culture, organizational and industry development.
The EC-funded FP7 project “OpenTox” (www.opentox.org) is developing an Open Source-based predictive toxicology framework that provides a unified access to toxicological data and (Quantitative) Structure-Activity Relationship i.e., (Q)SAR models. OpenTox provides tools for the integration of data, for the generation and validation of (Q)SAR models for toxic effects, libraries for the development and integration of (Q)SAR algorithms, and scientifically sound validation routines. OpenTox will support the development of applications for non-computational specialists in addition to interfaces for risk assessors, toxicological experts and model and algorithm developers.
OpenTox is relevant for the implementation of REACH as it allows risk assessors to access experimental data, (Q)SAR models and toxicological information from a unified interface that adheres to European and international regulatory requirements including OECD Guidelines for validation and reporting.The OpenTox framework is being populated initially with data and models for chronic, genotoxic and carcinogenic effects. These are the endpoints where computational methods promise the greatest potential reduction in animal testing required under REACH. Initial research has defined the essential components of the framework architecture, approach to data access, schema and management, use of controlled vocabularies and ontologies, web service and communications protocols, and selection and integration of algorithms for predictive modelling.The initial results of this research and next steps will be discussed.
OpenTox has been initiated as a collaborative project involving a combination of 11 different enterprise, university and government research groups to design and build the initial framework.Additionally numerous organizations with industry, regulatory or expert interests are being included from the start in providing guidance and direction.The goal is to expand OpenTox as a community project enabling additional expert and user participants to be involved in developments in as timely a manner as possible. To this end, our agreed upon intention is to carry out developments in an open and transparent manner from the early days of the project, and to open up discussions and development to the global community at large, who may either participate in developments or provide user perspectives.Cooperation on data standards, data integration, ontologies, integration of algorithm predictions from different methods, and testing and validation all have significant collaboration opportunities and benefits for the community.Additionally, practices for building effective collaborations from the OpenTox community approach will be discussed.
OpenTox - An Open Source Predictive Toxicology Framework, www.opentox.org, is funded under the EU Seventh Framework Program: HEALTH-2007-1.3-3 Promotion, development, validation, acceptance and implementation of QSARs (Quantitative Structure-Activity Relationships) for toxicology, Project Reference Number Health-F5-2008-200787 (2008-2011).
Douglas Connecta, In Silico Toxicologyb, Ideaconsultc, Istituto Superiore di Sanita'd, Technical University of Muniche, Albert Ludwigs University Freiburgf, National Technical University of Athensg, David Gallagherh, Institute of Biomedical Chemistry of the Russian Academy of Medical Sciencesi, Seascape Learningj and the Fraunhofer Institute for Toxicology & Experimental Medicinek
Advisory Board European Centre for the Validation of Alternative Methods, European Chemicals Bureau, U.S Environmental Protection Agency, U.S. Food & Drug Administration, Nestle, Roche, AstraZeneca, LHASA, Leadscope, University of North Carolina, EC Environment Directorate General, Organisation for Economic Co-operation & Development, CADASTER and Bayer Healthcare
*Contact Address: Dr. Barry Hardy, OpenTox Project Coordinator and Director, Community of Practice & Research Activities, Douglas Connect, Baermeggenweg 14, 4314 Zeiningen, Switzerland
Just saw an article I wrote for Future Science has come out as a Perspective:
Growing significance of communities and collaboration in discovery and development Barry Hardy, Future Medicinal Chemistry, June 2009, Vol. 1, No. 3, Pages 435-449. http://www.future-science.com/toc/fmc/1/3
Sorry, but I don't have the budget just right now to take the Open Access option, but there is some other open material available at the above link.
In summarising the drivers for the growing significance of communites and collaboration I introduced:
The benefits of community participation or collaboration should outweigh the costs to support a rational decision to pursue such routes. Lions usually prefer to hunt as a group as the shared food from group kills offers a better return and lower risk than hunting alone; in a similar manner organisations may also choose to collaborate to have greater success in acquiring new resources or income. The current convergence of a number of factors appears to be driving up the R&D collaboration benefit/cost ratio. The drivers include:
1. Scientific research is becoming more complex and multi-disciplinary, requiring researchers to move more away from “working in the expert’s box”.
2. Our work, economy and society are becoming more knowledge-oriented. (I define knowledge here as including understanding gained from experience and involves individual and collective knowledge in addition to explicit knowledge such as intellectual property (IP).)
3. Business models in the chemistry and pharmaceutical industry that worked fine historically, e.g., manufacturing products based predominantly on patents related to chemistry, appear to be increasingly lacking.
4. The goals of translational and personalized medicine have stronger requirements for networked and collaborative approaches over discipline and time than the historically relatively linear drug discovery and development process. Integrated services offer greater future value creation than stand-alone products.
5. Patient Safety has become an issue of growing concern requiring new more integrative approaches to data, knowledge and disciplines.
6. Computational Science continues to grow in importance, fueling overlaps and interactions between scientific disciplines including that of computer science.
7. The maturing of the Internet-based World Wide Web including enhanced usability, services, social software and the semantic web, provide new community and collaboration resource opportunities.
8. Challenging problems we face as a race such as global warming, energy management, population growth, and sustainable development are often linked to healthcare issues and are demonstrating the need and benefit for greater cooperation and at larger scales.
9. Continuing education and learning throughout life has been growing in importance as knowledge workers go through greater numbers of career and job changes than in the industrial age.
10. Work can increasingly be done anywhere on the planet where the best combination of costs and skills are available. As Thomas Friedman discussed in his recent book, the “world is now flat” (1). A work objective can be broken into a workflow of numerous tasks, each of which may be done in different locations or by different organizations or individuals.
And I will add three more uncertain or controversial factors here:
11. There is a growing importance of small and medium size enterprises (SMEs) collaborating in knowledge-oriented activity and growth in the global economy.
12. As our modern life seems increasingly less rewarding beneath the surface, we need, search for and find new happiness from the benefits of taking advantage of new collaboration opportunities through interacting with others more. In addition to needing better conversations for learning, work and self-development, we also simply need them psychologically and to feel good. (Happier workers are also more productive ones.)
13. Enabling international cooperation, collaboration and knowledge transfer in socio-economic areas such as healthcare, including building shared cultural meaning between different countries, races and cultures will significantly progress the security and prosperity of the world we leave to our children, whereas other current flawed political, military and unsustainable economic strategies will not.
Welcome your feedback and additions...
(1) Friedman TL, “The World is Flat”, Picador, (2005).