Educational Infographic produced by the Human Toxicology Project Consortium

THE FUTURE OF TOXICITY TESTINGHTP_infographic_FINAL_revised

A new infographic produced by the Human Toxicology Project Consortium shows in three sections how the future of toxicity testing promises a steady reduction in testing costs, increases in human relevance and confidence in safety assessments, and the eventual elimination of animal tests.

The first section provides a snapshot comparison of the current and future costs, efficiency and efficacy of toxicity testing, while the mid portion uses pesticide testing as a specific example of now, vs near-future, vs the optimal approach that, given the focus and resources necessary, will be envisioned within the decade.

The near-future and optimal approaches rely increasingly on our understanding of biology and using it to build a predictive systems biology platform that is comprised of an interrelated network of biological pathways. This platform is used to design and interpret tests that provide much more efficient and effective characterization of chemical activity that can be used to predict safe use of chemicals.

Finally, the results of this progression are captured in the summary graphic at the end – decreasing costs, animal use and time while human relevance and our confidence in safety decisions continue to improve.

As explained on our Project page, the Human Toxicology Project Consortium works on three areas critical for the successful, international implementation of a pathways-based approach to chemical safety testing: advancing the science, communicating the purpose and goals of pathway-based toxicology, and lobbying for funding and policy changes that will support pathway-based approaches in the US and around the world.

To advance our communication and education efforts, HTPC member organizations worked together to create this infographic, to quickly and effectively illustrate the differences between traditional animal-based toxicity testing and pathway-based testing in terms of predictive power, cost, and testing capacity.

Details on the numbers used in this comparison are available here (PDF).

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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

3D cell & tissue culture alternative toxicity testing AOPs drug discovery HTPC members in the news pathway-based approaches

Brain-in-a-dish: researchers create “the most complete model of a human brain ever grown in a lab”

Photo courtesy of Ohio State University

Photo courtesy of Ohio State University

Ohio State University researchers Rene Anand and Susan McKay say they have grown a miniaturized human brain from re-programmed adult skin cells. The structure is described in this Washington Post story as “no bigger than a pencil eraser” and is said to contain “all the major structures and 99 percent of the genes present in the brain of a five-week-old fetus.”

“It’s a scalable model that can be engineered to carry the genetic variants that give rise to all these diseases … and it gives us incredible access to things we never have done before,” lead researcher Anand told The Washington Post. “We can screen drugs, we can ask questions, we can follow the development at every stage.”

Because the researchers are patenting their process, they have not released data describing their methods. (They have also formed a commercial startup.) But according to an OSU press release, the team has already used the technique to model autism, Alzheimer’s, and Parkinson’s disease “in-a-dish,” and hopes to receive funding from the Small Business Technology Transfer program to use the model in drug development.

The announcement comes on the heels of another advance in organotypic brain modeling – a 3D bioprinted structure developed by Rodrigo Lozano and colleagues at the University of Wollongong in Australia. A functional brain “organoid” that can be subjected to environmental manipulations, or genetically engineered to reproduce inherited conditions, holds great promise for human-relevant toxicity testing, more efficient drug-candidate screening, and the study of neurodevelopmental and neurodegenerative diseases.

3D bioprinting 3D cell & tissue culture disease-in-a-dish drug discovery stem cells

New non-animal methods for predicting cardiotoxicity

Cardiotoxicity is defined as damage or dysfunction occurring in the heart as a result of exposure to a chemical substance.  Cardiotoxicity is one of the major reasons given when the development of a drug fails or a drug is withdrawn from the market.  With the cost of bringing a new drug to market averaging $2.6 billion USD, there are pressing ethical and economic reasons to find a faster, more accurate way to predict cardiotoxicity.

Developments announced in the last few weeks are encouraging.  UC Berkeley researchers led by Professor Kevin Healy published a study of their functional “heart-on-a-chip:” a 3-dimensional network of adult stem cell-derived heart muscle cells linked together on a microfluidic platform that reproduces blood flow.  The cells beat normally, and responded appropriately to the effects of four well-described heart drugs (isoproterenol, E-4031, verapamil and metoprolol).  According to Healy, “Ultimately, these chips could replace the use of animals to screen drugs for safety and efficacy.” (See the open-access paper here.)

In addition, NC3Rs recently awarded its 2014 3Rs prize to Oliver Britton, a PhD student who created an innovative computational model of cardiac electrophysiology. Because the model incorporates within-species variations in heart properties (which are usually averaged in more simplistic models), it has the potential to more accurately identify potentially toxic drug compounds – allowing them to be pulled from development before animal studies begin.  Quoted in the NC3Rs press release, Professor Ian Kimber said of the model: “Mr Britton’s paper really stood out to the panel because of (its) potential as a replacement for early-stage animal tests in drug safety studies, across a broad range of disciplines. The model has also been developed into a piece of user-friendly software, encouraging uptake and use by industry, which could have an important impact on the reduction of animals in research.”

Human-relevant alternative models such as these have the potential to reduce the cost, time, and numbers of animals expended in drug development, while increasing human safety.

Watch video of the beating UC Berkeley “heart-on-a-chip”:

alternative toxicity testing computational toxicology drug discovery organs-on-chips

Pfizer and HemoShear partner to predict toxicity in early stages of drug discovery

Pfizer Inc. and HemoShear, a privately held biotechnology company, are collaborating to develop methods to predict drug-induced vascular injury (DIVI) – a complication that slows or stops the development of many promising new drug candidates.

As Hemoshear’s press release explains:

Drugs in development may cause DIVI, such as inflammation or vascular lesions, in animals during testing for drug safety and toxicity. When this occurs, significant program delays and additional costs are incurred to investigate and explain the underlying biology and determine whether the compound is safe to move forward to human testing, or to determine if another compound would be safer. In some cases, decisions are made to stop the program altogether in the absence of a clear understanding of the injury and whether an animal response translates to human response.

The collaboration will make use of Hemoshear’s computational models and “translational tissue systems” — species-specific multidimensional tissue structures that replicate circulation and other physiological dynamics. Using these tissue systems, Hemoshear is able to run comparative studies (human tissues versus other animal tissues) that show whether, and how, human and animal responses differ.

The Pfizer/HemoShear collaboration has the potential to prevent unnecessary additional animal testing, and to reduce the cost and time it takes to bring new medications to market.

Source: http://www.prnewswire.com/news-releases/hemoshear-announces-collaboration-with-pfizer-inc-to-help-identify-and-predict-drug-induced-vascular-injury-for-early-stage-compounds-300018567.html

Read more about HemoShear’s translational tissue systems here.

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