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A new paper applies pathway biology to disease research and drug discovery

“Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research,” a new paper by a team of international experts including authors from Human Toxicology Project Consortium partners Humane Society International, The Humane Society of the United States, and Unilever, calls for a systems-biology approach to biomedical research and drug discovery. The approach borrows insights from toxicology, where adverse outcome pathways (AOPs) – a framework for documenting the physiological path between chemical exposure and “adverse outcomes” such as illness, injury, or environmental harm – are being used to integrate data from a variety of new scientific technologies. The authors propose that this same framework can be expanded to disease research, and can greatly improve our ability to identify effective drugs and therapeutics.

“…[M]any human illnesses such as cancers, diabetes, immune system and neurodegenerative disorders, and respiratory and cardiovascular diseases are caused by a complicated interplay between multiple genetic and environmental factors,” the authors write. Technology developments over the last two decades have made it possible to measure how genes determine our susceptibility to diseases, as well as how genes, proteins, cells, and tissues react to various environmental exposures. Application of such developments to drug discovery “require(s) a new research paradigm to unlock their full potential.” Just as AOPs integrate these new types of information to help reveal toxicity mechanisms and protect people and the environment from potential effects of chemical exposure, disease pathways can be used to understand risk and disease mechanisms, leading to more effective cures. According to the authors, “The disease AOP approach would better exploit advanced experimental and computational platforms for knowledge discovery, since the emergence of AOP networks will identify knowledge gaps and steer investigations accordingly.”

Progress in disease research and drug discovery has been slow, the authors say, because of continued reliance on inappropriate and unproductive animal models. The AOP framework encourages the use of emerging human-specific cell- and tissue-based models – such as 3D tissue constructs and organs-on-chips – combined with increasingly advanced computational models. The powerful combination can accelerate our understanding of disease, while reducing the use of animals.

The paper was published in the open access journal, Environmental Health Perspectives: http://ehp.niehs.nih.gov/wp-content/uploads/123/11/ehp.1510345.alt.pdf

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artistic rendering of kidney xray

A non-animal method for predicting kidney toxicity

Scientists at Singapore’s Institute of Bioengineering and Nanotechnology have created a non-animal drug screening method that uses stem cell-derived human kidney cells to predict the toxicity of drugs and other chemicals. The method improves on the reliability and availability of earlier stem cell models, promises to reduce the costs and time it takes to test and develop new drugs, and could eventually eliminate certain animal tests.

iStock_kidney-larger-cropBecause of their role in filtering blood, the kidneys are especially vulnerable to any toxic effects of drugs and other substances that pass through them, but predicting the renal toxicity of such substances has been difficult. As the authors write in their article in Scientific Reports, “Typically, compound nephrotoxicity is only detected during late stages of drug development, which is associated with high costs for the pharmaceutical industry. Animal models have limited predictivity and the development of renal in vitro models with high predictivity has been challenging.”

Using primary human kidney cells in toxicity tests is difficult, as well, due to high variability between donors, and difficulties keeping the cells fully functional during tests. For these reasons, generating a reliable supply of kidney cells from stem cells is preferable. Previous human kidney cell models (including one published by the authors) were produced from human embryonic stems cells (hESCs), which are difficult to access and which raise ethical concerns. This new method instead uses induced pluripotent stem cells (iPSCs) created from more readily available cells, such as human skin cells. iPSCs are genetically “reprogrammed” to an early developmental state, from which they can be coaxed into other kinds of cells. The team’s method produces usable kidney cells within 8 days – much faster than previous stem cell models, as well.

To learn more about using stem cells in toxicity testing, read the “primer” on AltTox.org.

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Organovo's Novogen 3D bioprinter (photo credit: Organovo)

Reading round-up

A few good links to share…

A UCLA scientist is using tiny worms – C. elegans – in a high-throughput, automated format, to screen chemicals for reproductive toxicity.

Patrick-Allard-Lab-0841_mid_credit-UCLA Fielding SPH

Patrick Allard (photo credit: UCLA Fielding School of Public Health)

“With this approach we can now simultaneously screen hundreds of compounds for their toxicity to the reproductive process, which can help to prioritize the chemicals that need further analysis,” Allard said. “Beyond that, once we find compounds that are repro-toxic, we can look further into the stages of reproduction that are affected, and how they are affected.”

Organovo's Novogen 3D bioprinter (photo credit: Organovo)

Organovo’s Novogen 3D bioprinter (photo credit: Organovo)

Chemistry World has a good overview of the growing skin 3D-bioprinting industry, noting that while the initial push is coming from cosmetics companies, “The expertise gained could feed into pharmaceutical research, and even help enable patients’ own cells to be made into almost perfectly compatible skin grafts and eventually replacement organs.”

And in the NIH Director’s Blog, Francis Collins describes NIH-funded efforts to develop neural tissue chips that predict neurotoxicity:

Cultivated neural tissue (photo credit: Michael Schwartz, University of Wisconsin-Madison

Cultivated neural tissue (photo credit: Michael Schwartz, University of Wisconsin-Madison

Each cultured 3D “organoid”—which sits comfortably in the bottom of a pea-sized well on a standard laboratory plate—comes complete with its very own neurons, support cells, blood vessels, and immune cells! As described in Proceedings of the National Academy of Sciences [2], this new tool is poised to predict earlier, faster, and less expensively which new or untested compounds—be they drug candidates or even ingredients in cosmetics and pesticides—might harm the brain, particularly at the earliest stages of development.

Collins also co-authored a Nature commentary summarizing six important lessons learned from Human Genome Project, on its 25th anniversary: embrace partnerships, maximize data-sharing, plan for data analysis, prioritize technology development, address the societal implications of advances, be audacious yet flexible… Read the details here.

3D bioprinting 3D cell & tissue culture alternative toxicity testing organs-on-chips stem cells
DNA molecule

China developing a roadmap to twenty-first century toxicity testing

At a special symposium last month in Xi’an, China, participants began to map China’s regulatory steps toward twenty-first century toxicology and away from animal testing.

The symposium, “TT21C/AOP China Roadmap,” was part of a conference on alternatives to animal tests in toxicology that was hosted by the Chinese Society of Toxicology’s Committee on Toxicological Alternatives and Translational Toxicology and the Chinese Environment Mutagen Society’s Committee on Toxicity Testing and Alternative Methods, and co-sponsored by the Humane Society International (HSI), Unilever, L’Oreal, and Shell. The symposium was convened “to address the need to increase Chinese regulatory uptake of currently available alternatives and the AOP paradigm.” Human Toxicology Project Consortium coordinator Dr. Catherine Willett was an invited speaker (a PDF of her presentation, “Use of Adverse Outcome Pathways (AOPs) to Reduce Uncertainty and Animal Use in Chemical Hazard and Risk Assessment,” is available).

During the symposium, a working team comprised of members from the host societies and representatives from Unilever, L’Oreal, HSI, and others was established to begin working on the twenty-first century toxicology “roadmap.” Asked about the team’s next steps in a Chemical Watch article (subscription required) about the symposium, Dr. Carl Westmoreland (Director of Science and Technology at Unilever’s Safety and Environmental Assurance Centre, and a member of the working team) said the host committees will prepare a summary of the proceedings and circulate it to participants for review.

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HTPC member Unilever partners with the EPA to develop non-animal approaches to safety testing

Human Toxicology Project Consortium member Unilever announced Tuesday that it will be collaborating with the US Environmental Protection Agency on a project that will improve and advance human-relevant chemical safety assessment while phasing out the use of animals.

The project will create case studies around chemicals of mutual interest, using existing data from the Toxcast and Tox21 programs combined with Unilever’s data and methods for estimating consumer exposures, and testing new high-throughput screening methods that account for metabolism and more completely assess human biological pathways.

Quoted in the joint press release, Russell Thomas, Director of EPA’s National Center for Computational Toxicology, said that if the project is successful, “research from this collaboration will result in better ways to evaluate the potential human health effects of new ingredients and chemicals we currently know little about. …These methods could be used by both industry and governmental agencies to reduce the costs associated with safety testing and accelerate the pace of chemical risk assessment.” And Julia Fentem, Vice President of Unilever’s Safety and Environmental Assurance Centre, said, “This research collaboration is strategically very important for Unilever’s long-held ambition to eliminate the need for any animal testing while also continuing to ensure the safety of consumers and our environment. If we had robust scientific tools to accurately and rapidly predict exposures to chemicals at the cellular and molecular levels within the human body, this would be a huge step forward in being able to conduct safety risk assessments without using animal data.”

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Free article: ‘Building on a Solid Foundation: SAR and QSAR as a Fundamental Strategy to Reduce Animal Tests’

Last year, HTPC coordinator Dr. Kate Willett co-authored a publication on using QSARs to reduce animal tests.

Now, for one month only, publisher Taylor & Francis is making that article (along with others published in its computer science journals in 2014) freely available to read when you access it through Twitter! Here’s the link to use to reach the article: https://twitter.com/htpconsortium/status/631191189094400000

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mattek epiderm assay

A potential replacement for animal-based medical device tests

Among the tests performed before bringing medical devices to market, the devices must be tested for their potential to cause an allergic reaction when they come in contact with skin.  There are now several in vitro options for testing skin sensitization, but none of them have been validated for medical devices, which typically involve less concentrated exposures to potential sensitizers.  However, a recent article in Applied In Vitro Toxicology describes research demonstrating that a 3D human skin tissue model can reliably detect even very low levels of known skin sensitizers in medical devices. The research is encouraging because the approach – which uses EpiDerm™ reconstructed human skin, along with the SenCeeTox® assay – could eventually replace animal models for certain medical device testing procedures, especially the widely used Guinea Pig Maximization Test.image of a guinea pig

According to the study’s authors, their primary aim was to “address is whether or not the SenCeeTox assay, which has been proven accurate and effective at identifying many types of compounds and materials, can accurately detect low levels of sensitizing chemicals of varying potencies in dilute medical device extracts that may contain monomers, oligomers, plasticizers, antioxidants, colorants, manufacturing process aids, mold release agents, sterilant residues, and the like.”  The authors conclude that “the SenCeeTox assay combined with 3D EpiDerm tissues may be a useful in vitro model for accurately predicting the dermal sensitization potential of medical device extracts.”

The publishers of Applied In Vitro Toxicology, Mary Ann Liebert, Inc., are making the article freely available on the journal website until August 29, 2015.

Full citation: Coleman Kelly P., McNamara Lori R., Grailer Thomas P., Willoughby Jamin A. Sr., Keller Donald J., Patel Prakash, Thomas Simon, and Dilworth Clive. (2015). “Evaluation of an In Vitro Human Dermal Sensitization Test for Use with Medical Device Extracts.” Applied In Vitro Toxicology. June 2015, 1(2): 118-130. doi:10.1089/aivt.2015.0007.

3D cell & tissue culture alternative toxicity testing