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A pragmatic approach to alternatives to animal testing

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Retitled and cross-posted from the June 30, 2015 posting (Testing times: the future of animal alternatives) on the International Innovation blog (a CORDIS-listed project dissemination partner for FP7 and H2020 projects).

Maryse de la Giroday explains how emerging innovations can provide much-needed alternatives to animal testing. She also shares highlights of the 9th World Congress on Alternatives to Animal Testing.

‘Guinea pigging’ is the practice of testing drugs that have passed in vitro and in vivo tests on healthy humans in a Phase I clinical trial. In fact, healthy humans can make quite a bit of money as guinea pigs. The practice is sufficiently well-entrenched that there is a magazine, Guinea Pig Zero, devoted to professionals. While most participants anticipate some unpleasant side effects, guinea pigging can sometimes be a dangerous ‘profession’.

HARMFUL TO HEALTH

One infamous incident highlighting the dangers of guinea pigging occurred in 2006 at Northwick Park Hospital outside London. Volunteers were offered £2,000 to participate in a Phase I clinical trial to test a prospective treatment – a monoclonal antibody designed for rheumatoid arthritis and multiple sclerosis. The drug, called TGN1412, caused catastrophic systemic organ failure in participants. All six individuals receiving the drug required hospital treatment. One participant reportedly underwent amputation of fingers and toes. Another reacted with symptoms comparable to John Merrick, the Elephant Man.

The root of the disaster lay in subtle immune system differences between humans and cynomolgus monkeys – the model animal tested prior to the clinical trial. The drug was designed for the CD28 receptor on T cells. The monkeys’ receptors closely resemble those found in humans. However, unlike these monkeys, humans have other immune cells that carry CD28. The trial participants received a starting dosage that was 0.2 per cent of what the monkeys received in their final tests, but failure to take these additional receptors into account meant a dosage that was supposed to occupy 10 per cent of the available CD28 receptors instead occupied 90 per cent. After the event, a Russian inventor purchased the commercial rights to the drug and renamed it TAB08. It has been further developed by Russian company, TheraMAB, and TAB08 is reportedly in Phase II clinical trials.

HUMAN-ON-A-CHIP AND ORGANOID PROJECTS

While animal testing has been a powerful and useful tool for determining safe usage for pharmaceuticals and other types of chemicals, it is also a cruel and imperfect practice. Moreover, it typically only predicts 30-60 per cent of human responses to new drugs. Nanotechnology and other emerging innovations present possibilities for reducing, and in some cases eliminating, the use of animal models.

People for the Ethical Treatment of Animals (PETA), still better known for its publicity stunts, maintains a webpage outlining a number of alternatives including in silico testing (computer modelling), and, perhaps most interestingly, human-on-a-chip and organoid (tissue engineering) projects.

Organ-on-a-chip projects use stem cells to create human tissues that replicate the functions of human organs. Discussions about human-on-a-chip activities – a phrase used to describe 10 interlinked organ chips – were a highlight of the 9th World Congress on Alternatives to Animal Testing held in Prague, Czech Republic, last year. One project highlighted at the event was a joint US National Institutes of Health (NIH), US Food and Drug Administration (FDA) and US Defense Advanced Research Projects Agency (DARPA) project led by Dan Tagle that claimed it would develop functioning human-on-a-chip by 2017. However, he and his team were surprisingly close-mouthed and provided few details making it difficult to assess how close they are to achieving their goal.

By contrast, Uwe Marx – Leader of the ‘Multi-Organ-Chip’ programme in the Institute of Biotechnology at the Technical University of Berlin and Scientific Founder of TissUse, a human-on-a-chip start-up company – claims to have sold two-organ chips. He also claims to have successfully developed a four-organ chip and that he is on his way to building a human-on-a-chip. Though these chips remain to be seen, if they are, they will integrate microfluidics, cultured cells and materials patterned at the nanoscale to mimic various organs, and will allow chemical testing in an environment that somewhat mirrors a human.

Another interesting alternative for animal testing is organoids – a feature in regenerative medicine that can function as test sites. Engineers based at Cornell University recently published a paper on their functional, synthetic immune organ. Inspired by the lymph node, the organoid is comprised of gelatin-based biomaterials, which are reinforced with silicate nanoparticles (to keep the tissue from melting when reaching body temperature) and seeded with cells allowing it to mimic the anatomical microenvironment of a lymphatic node. It behaves like its inspiration converting B cells to germinal centres which activate, mature and mutate antibody genes when the body is under attack. The engineers claim to be able to control the immune response and to outperform 2D cultures with their 3D organoid. If the results are reproducible, the organoid could be used to develop new therapeutics.

Maryse de la Giroday is a science communications consultant and writer.

Full disclosure: Maryse de la Giroday received transportation and accommodation for the 9th World Congress on Alternatives to Animal Testing from SEURAT-1, a European Union project, making scientific inquiries to facilitate the transition to animal testing alternatives, where possible.

ETA July 1, 2015: I would like to acknowledge more sources for the information in this article,

Sources:

The guinea pigging term, the ‘professional aspect, the Northwick Park story, and the Guinea Pig Zero magazine can be found in Carl Elliot’s excellent 2006 story titled ‘Guinea-Pigging’ for New Yorker magazine.

http://www.newyorker.com/magazine/2008/01/07/guinea-pigging

Information about the drug used in the Northwick Park Hospital disaster, the sale of the rights to a Russian inventor, and the June 2015 date for the current Phase II clinical trials were found in this Wikipedia essay titled, TGN 1412.

http://en.wikipedia.org/wiki/TGN1412

Additional information about the renamed drug, TAB08 and its Phase II clinical trials was found on (a) a US government website for information on clinical trials, (b) in a Dec. 2014 (?) TheraMAB  advertisement in a Nature group magazine and a Jan. 2014 press release,

https://www.clinicaltrials.gov/ct2/show/NCT01990157?term=TAB08_RA01&rank=1

http://www.theramab.ru/TheraMAB_NAture.pdf

http://theramab.ru/en/news/phase_II

An April 2015 article (Experimental drug that injured UK volunteers resumes in human trials) by Owen Dyer for the British Medical Journal also mentioned the 2015 TheraMab Phase II clinical trials and provided information about the information about Macaque (cynomolgus) monkey tests.

http://www.bmj.com.proxy.lib.sfu.ca/content/350/bmj.h1831

BMJ 2015; 350 doi: http://dx.doi.org.proxy.lib.sfu.ca/10.1136/bmj.h1831 (Published 02 April 2015) Cite this as: BMJ 2015;350:h1831

A 2009 study by Christopher Horvath and Mark Milton somewhat contradicts the Dyer article’s contention that a species Macaque monkey was used as an animal model. (As the Dyer article is more recent and the Horvath/Milton analysis is more complex covering TGN 1412 in the context of other MAB drugs and their precursor tests along with specific TGN 1412 tests, I opted for the simple description.)

The TeGenero Incident [another name for the Northwick Park Accident] and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event? by Christopher J. Horvath and Mark N. Milton. Published online before print February 24, 2009, doi: 10.1177/0192623309332986 Toxicol Pathol April 2009 vol. 37 no. 3 372-383

http://tpx.sagepub.com/content/37/3/372.full

Philippa Roxbuy’s May 24, 2013 BBC news online article provided confirmation and an additional detail or two about the Northwick Park Hospital accident. It notes that other models, in addition to animal models, are being developed.

http://www.bbc.com/news/health-22556736

Anne Ju’s excellent June 10,2015 news release about the Cornell University organoid (synthetic immune organ) project was very helpful.

http://www.news.cornell.edu/stories/2015/06/engineers-synthetic-immune-organ-produces-antibodies

There will also be a magazine article in International Innovation, which will differ somewhat from the blog posting, due to editorial style and other requirements.

ETA July 22, 2015: I now have a link to the magazine article.

Deux Seurats: one (was an artist) and one (is an inquiry into scientifically sound alternatives to animal testing)

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It must have been a moment of artistic madness which led to naming one of the European Union’s biggest projects dedicated to finding alternatives to animal testing, SEURAT-1. (Note: [1] All references used for this post are listed at the end. [2] There is a full disclosure statement after the references.)

Georges Seurat, a French post-impressionist painter, left no record that he was ever concerned with animal testing although he could be considered the ‘patron saint of pixels’ due to paintings which consist of dots rather than strokes.

Le Cirque (1891) by Georges Seurat in the Musée d'Orsay [Public domain or Public domain], via Wikimedia Commons; The Yorck Project: 10.000 Meisterwerke der Malerei. DVD-ROM, 2002. ISBN 3936122202. Distributed by DIRECTMEDIA Publishing GmbH; downloaded from https://commons.wikimedia.org/wiki/File:Georges_Seurat_019.jpg

Le Cirque (1891) by Georges Seurat in the Musée d’Orsay [Public domain or Public domain], via Wikimedia Commons; The Yorck Project: 10.000 Meisterwerke der Malerei. DVD-ROM, 2002. ISBN 3936122202. Distributed by DIRECTMEDIA Publishing GmbH; downloaded from https://commons.wikimedia.org/wiki/File:Georges_Seurat_019.jpg

Still, the idea of painstakingly constructing a picture dot by dot seems curiously similar to the scientific process where years of incremental gains in knowledge and understanding lead to new perspectives on the world around us. In this case, the change of perspective concerns the use of animals in testing for toxicological effects of medications, cosmetics, and other chemical goods intended for humans.

Animal testing dates back to back to the third and fourth centuries BCE (before the common era) although the father of vivisection, Galen, a Greek physician, doesn’t make an appearance until 2nd-century CE in Rome. More recently, we have an Arab physician, Avenzoar (Ibn Zuhr), in 12th-century Moorish Spain to thank for introducing animal experimentation as a means of testing surgical procedures.

The millenia-old practice of animal testing, surgical or otherwise, has presented a cruel conundrum. The tests have been our best attempt to save human lives and reduce human misery, albeit, at the cost of the animals used in the tests.

Social discomfort over animal-testing is rising internationally and thankfully, it looks like animal testing is in decline as alternatives and improvements (animal physiology is not perfectly equivalent to human physiology) are adopted. Alternatives and improvements have made possible actions such as the

  • European Union’s (EU) March 2013 ban on the sale of animal-tested cosmetics from anywhere in the world; there was an earlier 2009 ban on the sale of animal-tested cosmetics from anywhere in the EU,
  • China’s July 2014 announcement that animal-testing for cosmetics produced domestically is no longer required,
  • Israel’s 2013 ban on importing and marketing of cosmetics tested on animals,
  • India’s bans on cruel animal testing in India’s laboratories (2013) and on importing animal-tested cosmetics (Oct. 2014)

There are also a number of outstanding (as of December 2014) legislative proposals regarding animal-testing and cosmetics in countries such as Australia, Brazil, Taiwan, New Zealand, and the US.

However, cosmetics are only one product type among many, many chemical products. For example, medications, which rely on animal-testing for safety certification. Despite recent victories, the process of dismantling the animal-testing systems in place is massive, complex, and difficult even with support and encouragement from various government agencies, civil society groups, scientists, and various international organizations.

Well-entrenched national and international regulatory frameworks make animal testing mandatory prior to releasing a product into the marketplace. Careful thought, assurances to policy makers and the general public, and confidence that replacement regimes will be equivalent to the old system to the old system of animal-testing are necessary.

Strangely, assuring even sophisticated thinkers can prove surprisingly difficult, David Ropeik, a former Director of Communications for Harvard University’s Center for Risk Analysis and currently an international consultant and speaker on risk analysis, wrote in a Sept. 2014 post for The Big Think about the EU’s 2013 ban on cosmetics testing on animals,

But people use lotions and toothpastes and deodorants and perfumes repeatedly. We  expose ourselves everyday to hundreds of human-made chemicals, and some of those substances, which also fall under the European ban on animal testing for cosmetics, have the potential to do deeper damage, like cancer, or reproductive damage to the developing fetus. And there are no reliable replacement tests for those serious outcomes.

This now-banned animal testing for the systemic risks from repeated exposure to these everyday products was also a source of important information on the health effects of industrial chemicals generally. Results from cosmetic testing become part of the library of what we know about how industrial chemicals might harm us, no matter what products they’re in.

So the European community has eliminated a way for science to study the risk of industrial chemicals…because it feels right to consider the rights of animals. [emphasis mine] We have done what feels right, but in the process, without realizing it, we have made it harder to figure out how to keep ourselves safe.

Ropeik doesn’t substantiate his comment about the EU community acting from ‘feelings’ or discuss how current alternatives are inferior to animal testing or offer data about how this ban has made the earth a more dangerous place for humans. Meanwhile, more jurisdictions are limiting or eliminating testing of cosmetics on animals while an international competition which has already developed new techniques is underway to find yet more alternatives. SEURAT-1 the main European Union project, designed to carry out a set of scientific inquiries to facilitate the transition to animal testing alternatives where possible. It is organized around seven interlinked projects (or borrowing from Georges, seven dots):

  •  SCR&Tox (Stem Cells for Relevant efficient extended and normalized TOXicology): Stem cell differentiation for providing human-based organ specific target cells to assay toxicity pathways in vitro
  • Hepatic Microfluidic Bioreactor (HeMiBio): Developing a hepatic microfluidic bioreactor to mimick the complex structure and function of the human liver (liver-on-a-chip)
  • Detection of endpoints and biomarkers for repeated dose toxicity using in vitro systems (DETECTIVE): Identifying and investigating human biomarkers in cellular models for repeated dose in vitro testing
  • Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of COSMetics to Optimise Safety’ (COSMOS): Integrating and delivering of a suite of computational tools to predict the effects of long-term exposure to chemicals in humans based on in silico calculations
  • Predicting long term toxic effects using computer models based on systems characterization of organotypic cultures (NOTOX): Developing systems biological tools for organotypic human cell cultures suitable for long term toxicity testing and the identification and analysis of pathways of toxicological relevance
  • Supporting Integrated Data Analysis and Servicing of Alternative Testing Methods in Toxicology (ToxBank): Data management, cell and tissue banking, selection of “reference compounds” and chemical repository
  • Coordination of projects on new approaches to replace current repeated dose systemic toxicity testing of cosmetics and chemicals (COACH): Cluster level coordinating and support action or this could be called, Administration

As SEURAT-1 nears its sunset date in 2015 (it is a five-year, 50M Euro project started in 2011), there are successes to celebrate. For example, Emma Davies in her article titled, Alternative test data publicly available; ToxBank data warehouse (Sept. 4, 2014 for Chemical Watch) notes that ToxBank, includes data from SEURAT-1’s “gold” standard reference compounds which have documented liver, kidney, and cardio toxicity. As well, data sets from a comprehensive 2012 liver toxicity study supplied by the European Commission’s Joint Research Centre (the EU’s research hub and laboratory) have been added. ToxBank has also negotiated with Open TG-Gates, a Japanese toxicogenomics data resource and with ToxCast and Tox21, two US high-throughput screening programmes to add their data to the ToxBank data warehouse. Meanwhile, the warehouse’s data is publicly available on request.

COSMOS, the other data-oriented member of the SEURAT-1 cluster, should provide a good starting point for in silico studies (computer simulations) as it now boasts information on some 19,000 cosmetics-related substances, including toxicity data for more than 12,000 studies according to Davies’ article, Critical toxicity pathways at heart of Seurat-1 follow on (Sept. 11, 2014 for Chemical Watch).

While we can take Ropeik’s point that animal testing has been an important element in ensuring drug and chemical safety, the move to limit or ban animal testing for cosmetics has been over 50 years in the making and this current wave of regulatory changes has been approached cautiously. There may be some unforeseen consequences both good and bad to these bans on animal testing but to remain mired in the procedures and processes of the past is to deny an improved future for humans and the animals we have used for testing.

References

Pointillism

http://en.wikipedia.org/wiki/Pointillism

History of animal testing

http://en.wikipedia.org/wiki/Alternatives_to_animal_testing

2013 EU ban ban on animal testing for cosmetics

http://www.bbc.com/news/world-europe-21740745

http://ec.europa.eu/consumers/archive/sectors/cosmetics/animal-testing/index_en.htm

More legislation on cosmetics testing

http://en.wikipedia.org/wiki/Testing_cosmetics_on_animals

India ban

http://www.hsi.org/news/press_releases/2014/10/animal-tested-cosmetics-import-ban-india-101414.html

China ban

http://www.care2.com/causes/its-official-china-ends-mandatory-animal-testing-for-cosmetics.html

EU 2013 one year later

http://www.huffingtonpost.com/monica-engebretson/celebrating-the-first-ann_b_4994028.html

David Ropeik’s credentials and resistance to eliminating animal-testing

http://en.wikipedia.org/wiki/David_Ropeik

http://utility.prod.bigthink.com/risk-reason-and-reality/the-ban-on-animal-testing-morally-right-emotionally-appealing-but-dangerous

SEURAT-1

http://www.seurat-1.eu/

Cluster projects

http://www.seurat-1.eu/pages/cluster-projects.php

Emma Davies, Sept. 4, 2014 article (not behind a paywall)

http://chemicalwatch.com/21061/alternative-test-data-publicly-available

Emma Davies, Sept. 11, 2014 article  (behind a paywall)

http://chemicalwatch.com/register?o=21147&productID=1

Reference to cosmetics ban being over 50 years in the making

https://www.nc3rs.org.uk/the-3rs

The principles of the 3Rs (Replacement, Reduction and Refinement) were developed over 50 years ago as a framework for humane animal research.

Johns Hopkins Centre for Alternatives to Animal Testing (CAAT)

Resource list (http://caat.jhsph.edu/resources/) includes (and more):

Full disclosure: (1) SEURAT-1 paid for my flight, lodging, and attendance at WC9, the 9th World Congress on Alternatives and Animal Use in the Life Sciences. (2) I have written about alternatives to animal testing prior to any knowledge of SEURAT-1.

University of Toronto, ebola epidemic, and artificial intelligence applied to chemistry

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It’s hard to tell much from the Nov. 5, 2014 University of Toronto news release by Michael Kennedy (also on EurekAlert but dated Nov. 10, 2014) about in silico drug testing focused on finding a treatment for ebola,

The University of Toronto, Chematria and IBM are combining forces in a quest to find new treatments for the Ebola virus.

Using a virtual research technology invented by Chematria, a startup housed at U of T’s Impact Centre, the team will use software that learns and thinks like a human chemist to search for new medicines. Running on Canada’s most powerful supercomputer, the effort will simulate and analyze the effectiveness of millions of hypothetical drugs in just a matter of weeks.

“What we are attempting would have been considered science fiction, until now,” says Abraham Heifets (PhD), a U of T graduate and the chief executive officer of Chematria. “We are going to explore the possible effectiveness of millions of drugs, something that used to take decades of physical research and tens of millions of dollars, in mere days with our technology.”

The news release makes it all sound quite exciting,

Chematria’s technology is a virtual drug discovery platform based on the science of deep learning neural networks and has previously been used for research on malaria, multiple sclerosis, C. difficile, and leukemia. [emphases mine]

Much like the software used to design airplanes and computer chips in simulation, this new system can predict the possible effectiveness of new medicines, without costly and time-consuming physical synthesis and testing. [emphasis mine] The system is driven by a virtual brain that teaches itself by “studying” millions of datapoints about how drugs have worked in the past. With this vast knowledge, the software can apply the patterns it has learned to predict the effectiveness of hypothetical drugs, and suggest surprising uses for existing drugs, transforming the way medicines are discovered.

My understanding is that Chematria’s is not the only “virtual drug discovery platform based on the science of deep learning neural networks” as is acknowledged in the next paragraph. In fact, there’s widespread interest in the medical research community as evidenced by such projects as Seurat-1’s NOTOX* and others. Regarding the research on “malaria, multiple sclerosis, C. difficile, and leukemia,” more details would be welcome, e.g., what happened?

A Nov. 4, 2014 article for Mashable by Anita Li does offer a new detail about the technology,

Now, a team of Canadian researchers are hunting for new Ebola treatments, using “groundbreaking” artificial-intelligence technology that they claim can predict the effectiveness of new medicines 150 times faster than current methods.

With the quotes around the word, groundbreaking, Li suggests a little skepticism about the claim.

Here’s more from Li where she seems to have found some company literature,

Chematria describes its technology as a virtual drug-discovery platform that helps pharmaceutical companies “determine which molecules can become medicines.” Here’s how it works, according to the company:

The system is driven by a virtual brain, modeled on the human visual cortex, that teaches itself by “studying” millions of datapoints about how drugs have worked in the past. With this vast knowledge, Chematria’s brain can apply the patterns it perceives, to predict the effectiveness of hypothetical drugs, and suggest surprising uses for existing drugs, transforming the way medicines are discovered.

I was not able to find a Chematria website or anything much more than this brief description on the University of Toronto website (from the Impact Centre’s Current Companies webpage),

Chematria makes software that helps pharmaceutical companies determine which molecules can become medicines. With Chematria’s proprietary approach to molecular docking simulations, pharmaceutical researchers can confidently predict potent molecules for novel biological targets, thereby enabling faster drug development for a fraction of the price of wet-lab experiments.

Chematria’s Ebola project is focused on drugs already available but could be put to a new use (from Li’s article),

In response to the outbreak, Chematria recently launched an Ebola project, using its algorithm to evaluate molecules that have already gone through clinical trials, and have proven to be safe. “That means we can expedite the process of getting the treatment to the people who need it,” Heifets said. “In a pandemic situation, you’re under serious time pressure.”

He cited Aspirin as an example of proven medicine that has more than one purpose: People take it for headaches, but it’s also helpful for heart disease. Similarly, a drug that’s already out there may also hold the cure for Ebola.

I recommend reading Li’s article in its entirety.

The University of Toronto news release provides more detail about the partners involved in this ebola project,

… The unprecedented speed and scale of this investigation is enabled by the unique strengths of the three partners: Chematria is offering the core artificial intelligence technology that performs the drug research, U of T is contributing biological insights about Ebola that the system will use to search for new treatments and IBM is providing access to Canada’s fastest supercomputer, Blue Gene/Q.

“Our team is focusing on the mechanism Ebola uses to latch on to the cells it infects,” said Dr. Jeffrey Lee of the University of Toronto. “If we can interrupt that process with a new drug, it could prevent the virus from replicating, and potentially work against other viruses like Marburg and HIV that use the same mechanism.”

…

The initiative may also demonstrate an alternative approach to high-speed medical research. While giving drugs to patients will always require thorough clinical testing, zeroing in on the best drug candidates can take years using today’s most common methods. Critics say this slow and prohibitively expensive process is one of the key reasons that finding treatments for rare and emerging diseases is difficult.

“If we can find promising drug candidates for Ebola using computers alone,” said Heifets, “it will be a milestone for how we develop cures.”

I hope this effort along with all the others being made around the world prove helpful with Ebola. it’s good to see research into drugs (chemical formulations) that are familiar to the medical community and can be used for a different purpose than originally intended. Drugs that are ‘repurposed’ should be cheaper than new ones and we already have data about side effects.

As for the “milestone for how we develop cures,” this team’s work along with all the international research on this front and on how we assess toxicity should certainly make that milestone possible.

* Full disclosure: I came across Seurat-1’s NOTOX project when I attended (at Seurat-1’s expense) the 9th World Congress on Alternatives to Animal Testing held in Aug. 2014 in Prague.

FrogHeart goes to the 9th World Congress on alternatives to animal testing

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Also known as ‘Humane Science in the 21st Century’, the 9th World Congress on ‘Alternatives to Animal Testing in the Life Sciences‘ is being held next week (Aug. 24 – 28, 2014) and FrogHeart will be reporting on various aspects of the work. These posts are sponsored. I realize some folks don’t approve of the practice, which seems odd given that all writing, ultimately, is paid for and sponsored in one fashion or another. While direct sponsorship of a piece of writing can make objectivity (such as it is) more of challenge; it is not beyond the realms of possibility. Conversely, salaried writers can also become compromised due to friendships and loyalties built up over the years or, possibly, due to graft.

All of the posts generated as a consequence of the sponsorship will be identified with the sponsoring agency (SEURAT-1).

For anyone who wishes analyze and compare the posts for bias, here are a few pieces written prior to any contact about the congress:

  • Reducing animal testing for nanotoxicity—PETA (People for the Ethical Treatment of Animals) presentation at NanoTox 2014 (April 24, 2014)
  • Nanomaterials, toxicology, and alternatives to animal testing (Aug. 22. 2013)
  • Animal love and nanotechnology (Jan. 12, 2012)
  • Global TV (national edition) and nanotechnology; EPA develops a ‘kinder to animals’ nanomaterials research strategy (Oct. 8, 2009); scroll down 25% of the way)

Should you detect undue bias in any of the sponsored pieces, please do let me know.