Category Archives: Alternatives to animal testing and research

Toxicity testing without animals

When I mention that I am against animal experimentation, the reaction is often: “Would you prefer these tests were done on humans?” In the discussion that follows it turns out that most people don’t know that there are better and less cruel ways of doing biomedical research. Some people suggest that these alternatives, such as computer-based methods, can never be as adequate as a living animal.

However, over the last decade science has made much progress in developing non-animal methods and tools to use in basic and applied research, and for regulatory testing such as the testing of new drugs and chemicals. Governments are now encouraging and mandating researchers to use these new methods instead of live animals. For example, earlier this year 16 federal agencies in the US developed a Roadmap to guide progress toward replacing animal use in toxicity testing.

The roadmap was developed to guide the application of new technologies, such as high-throughput screening, tissue chips, and computational models, to toxicity testing of chemicals and medical products.

What exactly are these new technologies? An open access article published last year by Mary T. McBride – Future platforms for toxicity testing – provides a good summary of current and future methods for toxicity testing without animals:

  • In vitro model systems, using cells and cell cultures, such as stem cells, tissue engineering and organs-on-chips, with a human-on-a-chip being under development.


  • In vitro pathway-based assays and quantitative high-throughput screening (HTS). The latter employs liquid robotics handling systems and computerised data processing, to screen a single compound against a large number of assays to identify toxicity pathways or to test a large number of compounds using a single assay.


  • Cell-based imaging technologies and high-content screening, using imaging tools such as innovative microscopy methods, ultrasound, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET).


  • Omics approaches, such as genomics, transcriptomics (a microarray technology to establish human genome-wide gene expression profiles by measuring all of the approximately 100,000 mRNA molecules or ‘transcripts’ produced in a cell or a population of cells), proteomics (the comprehensive study of the entire complement of proteins and their modifications of an organism to understand cellular processes) and metabolomics (the study of metabolites, such as lipids and proteins, and used to identify all of the metabolites present in a given cell or organism at a specific time).


  • Data integration analysis and interpretation: bioinformatics and visualisation tools. This involves combining data from different platforms and assays across multiple experiments.


  • Computational toxicology, which includes the integration of mathematical and computer models to map, model and understand the biological circuitry of toxicity pathways to predict the toxicity of environmental chemicals and pharmaceuticals and their dose-response relationships.


Tissue engineering has made tremendous advancement in the field of tissue-engineered preclinical models. Such models now exist for many whole tissues including skin, muscle, cartilage, blood vessels, bone, bladder, liver, cornea, reproductive tissues, adipose, small intestine, neural tissues, kidney and cardiopulmonary systems.

McBride suggested that “the new approach may significantly reduce costs and time required to conduct chemical safety assessments and could markedly diminish and potentially eliminate animal testing.” She pointed out that this is not an exhaustive list, and that rapid advances in biology and biotechnology are continuously emerging.

Various databases listing resources for non-animal research are available to researchers and the general public, for example ALTBIB (Resources for Alternatives to the Use of Live Vertebrates in Biomedical Research and Testing) and EURL ECVAM (European Union Reference Laboratory for alternatives to animal testing).

So no, the often cruel and painful experiments currently conducted on live animals don’t need to be done on humans. Nor do they need to be done on animals.




UK biotech companies call for more human-relevant research methods to meet patient needs and increase profits


Industry leaders say that the key issue is the low predictive power of existing pre-clinical models, with academic research supporting this hypothesis. We will address this by bringing more patient-derived approaches into the mainstream. These include advances in patient derived targets and biomarkers, and more complex models, such as organoids, for discovery and pre-clinical research. These technologies need to be woven throughout the discovery process to place the patient at the heart of the research process.

A new report from the UK has pointed to a productivity crisis in pharmaceutical research: new drugs have a high failure rate, the number of drugs launched per $1bn of research and development spending has fallen nearly thirty-fold over the last 40 years, leaving the pharmaceutical industry return on capital now at only 3.2%.

Let me briefly recap the phases of development that a new drug undergoes. Preclinical research is the stage of research that occurs before the drug is tested on humans. It usually involves in vitro and in vivo tests. In vitro (Latin: in glass) tests are sometimes called test-tube experiments, for example microorganisms in Petri dishes. More recently developed in vitro methods involve omics, such as genomics, proteomics or metabolomics.  In vivo (Latin: within the living) tests are conducted on living organisms or cells. In biomedical research, in vivo methods generally involve animal experiments.

Preclinical research is followed by three stages of clinical trials on humans. Phase I is usually conducted for safety testing. If the drug is found to be safe, it is tested in Phase II to see whether it works as intended. Phases I and II involve small numbers of humans. If the drug is found to be safe and effective, it proceeds to Phase III, where it is tested on a larger number of people and compared to placebo or other treatments for the condition under study. Sometimes there is a fourth phase: after the drug has been marketed, further information is collected on effectiveness of the drug and side effects, or to investigate the effectiveness of the drug for a different condition or in combination with other drugs.

Three pharmaceutical industry groups collected data on clinical development success rates from 2006-2015 and found the following average rates:

probability of success

NDA – New Drug Application to the FDA (US Food and Drug Administration)
BLA – Biologic License Application to the FDA

After in vitro and/or in vivo testing, on average only 9.6% of new drugs achieved approval from the FDA. Cancer drugs had the lowest approval rate (5.1%), haematology drugs the highest (26.1%). A dismal – and very expensive – failure rate.

Back to the UK report. Based on over 100 in-depth interviews with senior executives of UK drug discovery companies and electronic surveys of 250 experts, the authors summarised the problems as follows:

  • Global R&D productivity is under unprecedented pressure
  • The model of medicines R&D must be radically reshaped to meet patient needs
  • A key problem is reliance on using inadequate models for human diseases
  • Commercialising emerging technology will require new models of collaboration
  • Data science is now indispensable to medicines R&D: research data is now generated in such high volumes that the ability to harness it has become a critical factor in developing new medicines
  • It is imperative for the UK to provide industry with straightforward, well-governed access to consented patient data and human tissue samples – this is an acute problem for SMEs*
*SMEs – small and medium-sized enterprises

The authors of the report observed that too much of the preclinical research is patient-free and relies on animal models of disease and toxicology that are a poor approximation of humans. They wrote that drug discovery must be ‘humanised’:

Our interviews and surveys identified many emerging technologies that can ‘humanise’ the drug discovery process. These technologies make the early stages of research more predictive of how a drug will work in real life. They can generate a wealth of humanised in-vitro data, resulting in better drug candidates entering human trials. The benefit is lower attrition and therefore improved research productivity for industry.

… and pointed to new and emerging technologies that don’t involve animal research:

There are many emerging technologies that can make pre-clinical drug development more humanised. Most are derived from human stem cells and the resultant technologies that allow us to create and sustain human tissue in the laboratory. Just 20 years ago, keeping such tissue alive in the lab was a challenge. Now, thanks to pluripotent stem cells, advanced culture methods, microfluidics and precision gene editing we can manipulate the way such tissue grows and differentiates, even down to the substructures of cells and the stratum of the disease which the model reflects. When linked to large human cohorts, we can develop libraries of disease models that reflect the molecular spectrum of human disease, just as the Sanger Centre has done with their library of cancer cell lines. These complex predictive models, when used appropriately, have the potential to be much more discriminating in their ability to weed out the false positives in drug discovery i.e. those compounds that are too toxic, or insufficiently disease modifying.

The report also called for better collaboration between all stakeholders, the sharing of data and better access to consented patient data and human tissue samples.

Data from failed trials and failed pre-clinical projects could be transformative in reducing rework.

Further, a lack of validation efforts was noted. The experts that were interviewed said that ‘many potentially powerful human in vitro models remain in academia. There they have no obvious commercialisation path in the UK, given they often lack IP and so are hard to spin-out.’ Several people pointed out that validation is not a good fit for grant funding.

Many reasons tied up with their careers hold researchers in academic institutions back from leaving animal experiments behind:

It is important to recognise that researchers can be reluctant to invest time and money in implementing a new technique, or to replace an animal model that has served as the basis of their research for many years. … There may be concerns about a lack of historic data comparability, or invalidating past results. Setting up a new model can require additional technical expertise or development of new infrastructure. Referees are familiar with data from the ‘gold standard’ animal models, and may request additional in vivo data to be generated to support in vitro findings. These factors can delay publication in a highly competitive research environment and result in a lack of motivation to change models. (Jackson and Thomas 2017)

Researchers in the pharmaceutical industry are free of some of these constraints. The animal model research paradigm is truly outdated and better, human-relevant methods and technologies are available and are being further developed. This report by Medicines Discovery Catapult and the UK BioIndustry Association is a welcome guide to a future of biomedical research that serves patients, leaves behind cruel and unnecessary animal experiments, and promises a better return on investment for biomedical companies.


Many thanks to Andrew Tilsley for his permission to use an image of his artwork ‘Cures for Diseases’.

Replacing live animals in research and teaching – Progress in the EU


Source: Flickr/ Alpha Bravo Foxtrot

Earlier this month (8 November 2017), the European Commission published a review of the implementation of the Directive 2010/63/EU on the protection of animals used for scientific purposes (the Directive). All use of live animals in the European Union for research, education or drug testing must comply with the Directive, and it requires member states to assist in the advancement of alternative methods to animal testing and to promote the use of non-animal methods.

While the Directive took effect on 1 January 2013, it took until 2015 for all member states to adopt relevant national legislation. The common standards for animal accommodation and care only entered into force in January 2017. This is the first review of the implementation of the Directive, and it is noted that the “report can only give preliminary indications of progress, problem areas and good practice”.

I was most interested in the section of the report that deals with the uptake of alternatives. In the context of the Directive, “alternative” means any tools or strategies implementing the 3Rs* which:

  • Obtain the required information without the use of live animals.
  • Use fewer animals whilst obtaining the same level of information.
  • Improve the way procedures are carried out so as to cause less pain, distress or suffering, or improve welfare.
* 3Rs: Replace, Reduce and Refine the use and care of animals used for scientific purposes

Unfortunately, the report states that “[a]t this stage of the Directive’s implementation, it is too early to assess its impact on the promotion and uptake of alternatives.” However, four areas hindering a more rapid uptake of alternatives were identified: lack of knowledge; insufficient communication/ spreading of information; acceptability, and cost.

Many stakeholders felt, however, that there is significant scope for the replacement of animals used for educational purposes where many alternatives are already available, but not always taken up.

On a positive note, “[m]any Member States have increased their activities in promoting alternatives, e.g., increasing research funding, voluntary development of Three Rs centres, supporting educational events and other information dissemination efforts. Half of the Member States have submitted voluntary reports detailing the actions taken towards the development, validation and promotion of alternative methods”. I had a look at these reports and compiled the summary below:

Government projects/initiatives to develop and/or validate non-animal methods (does not include projects funded or undertaken by animal charities or the private sector; does not include funding for promoting non-animal methods, training or resource development)

United Kingdom 

  • NC3Rs-funded projects – € 10 million annually
  • Non-animal alternative test for botulinum toxin testing; development and validation – Approx. € 8 million
  • Innovation in developing 3Rs technologies – € 5 million in 2014-15


  • Foundation for the Promotion of Alternate and Complementary Methods to Reduce Animal Testing – Approx. € 500,000 annually
  • Research/ welfare prizes – € 55,000 annually, € 65,000 every 2 years, € 25,000-100,000 every 2-3 years, € 15,000 every 5 years


  • Ministry’s (MAF) programme to promote the development and use of alternative methods established in 2013 – MAF funding €100,000 annually 2013-2015 and € 200,000 in 2016.
  • Finnish Centre for Alternative Methods (FICAM) – € 250,000 annually, € 350,000 in 2014-2015
  • MAF research grants – €15,000-€30,000 per year 2010-2016
  • Adipose in vitro model development for diabetes II – Approx. € 100,000 in 2014-15


  • Development of alternative toxicity tests – Approx. € 1 million
  • Development of an alternative model for hepatotoxicity testing – € 60,000


  • Establishing a Danish 3R-Centre – € 190,000
  • Support for the development of new 3R methods and models – € 200,000
  • 3R prize – € 1,500 in 2014


  • Development of in vitro alternative approaches – € 552,500


  • Swedish Research Council grants – Approx. € 1,380,000 annually
  • Swedish Fund for Research Without Animal Experiments grants – € 100,000-200,000 annually
  • Contribution to participation of Swedish laboratories in validation studies at EU level – Approx. €212,000 annually

Several countries listed their activities, but did not include monetary values.

Welfare organisations expressed frustration at the slow progress towards validation and acceptance of new alternative methods. Validation and regulatory acceptance processes vary between different regulatory areas, which are not directly regulated by this Directive. Nevertheless, there is evidence of investment and activity advancing this field. The Directive contributes towards these objectives through obligations on Member States and the European Commission.

In addition to government funding, funding is also available from industry and charitable organisations. For example, in the UK the Dr Hadwen Trust (now Animal Free Research UK) provided approx. € 1,8 million to develop new research models and methods to replace the use of animals in medical research. The EU also provides funding. A recent example is the ORgan-on-Chip In Development (ORCHID) project with € 520,477.


Zebrafish in the lab. Source: Flickr/ detroitstylz

While countries in the EU are slowly moving towards a future where fewer and fewer live animals are used in biomedical research, testing and training, the Australian Government does not have any policies similar to the Directive, nor does the Government’s main funding body, the NHMRC, provide grants specifically to reduce and/or replace animal experiments.

The 2017 Tenth World Congress on Alternatives and Animal Use in the Life Sciences – 3Rs in Action conference in Seattle featured close to 700 oral and poster presentations. Only one Australian researcher is listed among the presenters, and her presentation did not focus on the development of non-animal research methods. This speaks for itself.



European Commission. (2017). Report from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions in accordance with article 58 of Directive 2010/63/EU on the protection of animals used for scientific purposes. Brussels: European Commission. Available at

European Commission. (2017). Commission Staff Working Document. Accompanying the document Report from the Commission oo the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions. In accordance with Article 58 of Directive 2010/63/EU on the protection of animals used for scientific purposes. Brussels: European Commission. Available at

Faustman, E., Zurlo, J., & Kavlock, R. (2017). ALTEX proceedings. Abstracts of the 10th World Congress, Seattle, 2017. Alternatives and animal use in the life sciences 2017: 3Rs in action. Seattle: ALTEX. Available at


Will you support us?

Are you already a member of Humane Research Australia (HRA)? If so, I invite you to renew your membership. It’s only $30 pa. If you are not a member, would you consider becoming one?

I started this blog 3 ½ years ago. I’m the president of HRA, and while I’ve mentioned HRA in some of my blog posts, I haven’t dedicated a whole post to HRA. So this is what we do and what we want to achieve:

Here in Australia, the use of animals in research is very high for such a small country. Only the USA, Japan and China use more animals. We want to see animal experimentation phased out and replaced by humane and human-relevant methods.

Why do we want this? We can’t be sure that insights gained from experiments with animals will be applicable in humans. Animals are not reliable models for human disease. For example, cancer was cured in mice decades ago, but the results didn’t translate to humans. Sadly, scientists know more about mice than humans. Animal research involves many procedures that would be regarded as animal abuse if carried out on our pets. Even when no painful procedures are carried out, the animals are usually kept captive in artificial environments that do not allow for species-specific behaviours. It is a sad situation, both for the lab animals who suffer stress and pain, and for people who miss out on treatments and cures because the research is not relevant to humans.

Many people still think animal experimentation is a necessary evil. But research articles pointing to the many shortcomings of animal research are accumulating*.

So what does HRA do? Below are some of the activities and achievements over the last 12 months.


The Ban Primate Experiments campaign has highlighted the use of non-human primates in invasive, cruel experiments. The macaques, marmosets and baboons involved in these experiments are bred in three government-funded facilities in Australia. While these sentient animals are genetically and cognitively similar to us, they are sufficiently different for primate experiments to result in research findings of little value to humans.

I and another member of HRA’s committee of management (Dr Eleonora Gullone) were signatories to an open letter asking to stop neuroscience research involving non-human primates. It was signed by 22 scientists, primatologists and animal welfare experts, among them Sir David Attenborough and Dr Jane Goodall.

Following a campaign by People for the Ethical Treatment of Animals (PETA) and HRA, the Royal Australasian College of Surgeons (RACS) announced earlier this year that it will phase out the use of live animals for its Early Management of Severe Trauma (EMST) program by 2018. EMST trains physicians and Australian Defence Force (ADF) medical officers on treating traumatic injuries. To date, the training involves cutting holes into the throats, chests, and limbs of live animals including dogs and pigs. This will be replaced by human-simulation technology.

Earlier this month the Australian Government introduced a bill to ban animal testing of cosmetic products. This is a result of campaigning by animal welfare groups around the country, and including HRA and Humane Society International’s Be Cruelty Free Campaign.

Case studies

It is difficult for the public to find out exactly what experiments are conducted on animals. Universities and other research institutions are reluctant to provide detail. Not all animal research is published in professional journals. When it is published, the articles are often behind a pay wall and written in a way that does not make much sense to the lay person. HRA has summarised some of these studies in plain English.

These scenarios are not only highly unethical; they are unscientific. Data cannot be extrapolated from one species to another with certainty of success.

We need to challenge the researchers and the funding bodies and encourage them to embrace new technologies – non-animal methodologies that are both more humane and scientifically-valid as they relate specifically to human conditions. This is the critical role of HRA. It’s imperative that the community and HRA supporters particularly, are aware of what is happening and what they can do to help stop it.

Over the last year, the Australian media have reported on cruel experiments. Some of these reports have been re-published in other countries. For example, the Sydney Morning Herald reported about cruel greyhound experiments at Monash University and the Alfred Hospital in Melbourne, where the dogs were suffocated and had their hearts removed. Those hearts were then transplanted into other greyhounds who were killed after the procedure.

Animal use statistics

Unlike many other countries, Australia does not have a national collection of animal use data. HRA attempts to make up for this absence of data. The states and territories collect these data, but not all states make them available. HRA collects the available data, publishes them on its website, and provides an estimate of the total number of animals used for research and teaching in Australia. For 2015 this number was close to 10 million animals (this also includes environmental studies where animals were observed rather than experimented on).


HRA writes submissions to government bodies, encourages its members and the public to write submissions, and provides background information to assist with submission writing. At present, the proposed Code of Practice for the Keeping of Racing Greyhounds (in Victoria) is open for public comment until 14 August 2017.

This is not all we do. For example, we also lobby the federal government and funding agencies to redirect funding away from animal experimentation and instead provide financial incentives to researchers to develop alternatives to animals. This lobbying takes considerable time and resources. We need your financial support to continue this work, and your assistance to help us to do this is greatly appreciated.

Follow us on Facebook or Twitter , or subscribe to our e-news to learn more about our work.

Here is a video of me (and my best mate Sheba) asking you to support us in the important work we do to end cruel and unnecessary animal experiments. If you have a look at the video, you’ll see that we don’t waste money on media production. It was done in-house, in the HRA office, with our multi-talented CEO Helen Marston directing, filming and editing.

Unlike many other charities, HRA does not have DGR (Deductible Gift Recipient) status – because our work is not classified as public benevolent, and does not involve “hands on” care of animals. This means that we do not qualify for many philanthropic grants that are available and which many charities depend on for their continued work. It also means that we are unable to take advantage of various other schemes such as workplace giving as these also require DGR status.

Furthermore, we do not receive ANY government funding. We are therefore solely reliant on memberships and donations to fund the important work that we undertake towards ending cruel and unnecessary animal experiments.

Thank you for reading this, and I’m more than happy to respond to any questions and/or suggestions.

* On the HRA website, we have dedicated a page to links to academic papers, conference proceedings and government reports that show animals as bad models for human medicines and treatments. Search for “bias” (without the quotation marks) on this web page.



Australia’s new cosmetics testing bill – a welcome move


Source: Flickr/ Lynette Olanos

During the 2016 election campaign, the Australian Government committed to introduce a ban on animal testing of cosmetic products. The Industrial Chemicals Bill 2017 has been introduced in the House of Representatives on 1 June 2017 to implement this commitment. The following sections of the bill refer to animal testing:

103 Ban on animal test data for determining category for cosmetics

(1) Without limiting paragraph 102(1)(b), if an industrial chemical is to be introduced     for an end use solely in cosmetics, rules made for the purposes of that paragraph may include the requirement mentioned in subsection (2).

(2) The requirement is that, when determining the category of introduction for such an industrial chemical, a person must not use animal test data obtained from tests conducted on or after 1 July 2018 in circumstances prescribed by the rules.

168   Ban on animal test data for applications for cosmetics

(1) Without limiting subsection 167(1), if an industrial chemical is to be introduced for an end use solely in cosmetics, an application under this Act relating to the introduction must meet the requirement in subsection (2).

(2) The requirement is that the application must not include animal test data obtained from tests conducted on or after 1 July 2018 in circumstances prescribed by the rules for the purposes of this subsection.

Government legislation to support the end of cosmetic animal testing and trade in Australia is very welcome. However, the draft legislation offers a loophole which would allow newly animal tested cosmetic ingredients to be introduced to the Australian market after the bill becomes law. This would fail to meet the Coalition’s election promise and the expectations of the Australian public to fully end cosmetics testing in Australia.

The loophole rests on the word solely. Only new animal test data used in introductions which are solely for cosmetics use would be prohibited. If the new chemical ingredient would also be used for other purposes, for example in cleaning products, animal testing would still be allowed.

A joint statement by #BeCrueltyFree Australia and Humane Research Australia observes:

This is very welcome progress; however, as not all substances are used exclusively as cosmetic ingredients, some cosmetic ingredients will still be able to be newly animal tested and introduced into Australia under the current proposed language. This is an important departure from existing bans in the European Union, Norway, Switzerland, Israel, and India, which have all banned the use of newly animal-tested ingredients when introducing or marketing cosmetics.

How many of the new chemicals might be used for multiple purposes? A 2013 report by the European Commission stated that:

… large cosmetics manufacturers estimated that, on average, around 10% or less of the new ingredients used by large cosmetics manufacturers were new to market (i.e. have not previously been used in other product sectors).

Dropping the word solely from the bill might fix this loophole. It would ensure that the ban applies to all cosmetics ingredients, and the use of chemicals for non-cosmetic purposes would not be impacted by the ban.

What would happen if a chemical not previously used in cosmetics has been tested in animals and a human health risk has been assumed? Obviously, such a chemical would not be introduced for use in cosmetics, irrespective of the ban (this case would represent disqualifying a chemical for use in cosmetics, rather than introducing one).

On the whole, while this bill does not change much for companies that manufacture cosmetics, it sends a message that Australia does not support cruel and unnecessary testing on animals – if for cosmetics only.

The bill will not have much impact on the number of animals used in animal experiments in Australia, as – to my knowledge – no cosmetics testing on animals has taken place here for some time. But is it a first step towards phasing out animal experimentation for other purposes, too?


Source: Flickr/ Melody


Other countries have made much more progress in this regard. For example, the Parliament of the Netherlands in 2016 passed a motion to phase out all research on non-human primates, and by 2025 the Netherlands aims to become a world leader in animal-free science. The Netherlands National Committee for the Protection of Animals Used for Scientific Purposes (NCad) has provided a schedule for phasing out animal procedures.

In the EU, the Directive 2010/63/EU on the protection of animals used for scientific purposes requires national governments to assist in the advancement of alternative methods to animal testing and to promote the use of non-animal methods.

Unlike Australia, the European Union keeps track of progress made in developing and using alternatives to animal testing. The European Chemicals Agency has just published its third report on “The use of alternatives to testing on animals for the REACH Regulation”. It looks promising:

Registrants use existing information and alternatives to animal testing. Altogether, 6290 substances were analysed for the report. Out of these, 89 % have at least one data endpoint where an alternative was used instead of a study on animals.

The most common alternative method was using information on similar substances (read-across), used in 63 % of the analysed substances, followed by combining information from different sources (weight of evidence, 43 %) and computer modelling (QSAR prediction, 34 %).

In the US, the Federal Accountability in Chemical Testing (FACT) Act was introduced in Congress earlier this year:

The FACT Act would improve reporting by EPA, FDA, NIH, USDA and other government agencies about their efforts to replace inefficient, multi-million-dollar animal tests with faster, less costly and more effective alternative methods for assessing the safety of chemicals, drugs, foods, cosmetics and other substances.


Source: Flickr/ pumpkincat210


However, it’s anyone’s guess if or when this bill might become law, given that the U.S. Department of Agriculture has removed public access to tens of thousands of reports relevant to animal welfare.

Banning cosmetics testing on animals in Australia has been long overdue and is a welcome contribution towards the global move away from animal experimentation more broadly.



PS – On 6/06/2017 the Humane Cosmetics Act was introduced in the U.S. House of Representatives. See this press release.


The organs-on-chips market

After looking at the animal model market, I wondered about industry predictions for new developments in biomedical research that are human-relevant. Perhaps the field known as organs-on-chips holds the greatest promise for physiologically relevant, precisely controlled, and scalable engineered systems for use in the drug development process.

According to the Wyss Institute for Biologically Inspired Engineering at Harvard University, human organs-on-chips are microchips lined by living human cells that can be used in drug development, disease modelling and personalised medicine.

This is what they look like:

The development and testing of new drugs takes many years and is expensive. Very expensive. The cost of developing a new prescription drug is now around $2.6 billion. Traditionally, animals such as mice and dogs have been used in the development of  drugs. But around 90% of new drugs that have been found to be safe and effective in animals fail in clinical trials with humans.

To understand this high attrition rate between drug development and approvals, it is imperative to consider the drawbacks of the current methods of preclinical testing. Traditional 2D cellculture models can be effective in providing a broad indication of
compound efficacy and toxicity; however, they fail to represent cell function and physiology accurately because these cultures are monolayers as opposed to the 3D structures found in an intact organ and hence important tissue–tissue interactions are absent. Furthermore, upon the ingestion of a drug, it undergoes important transformations that allow it to be absorbed, distributed, metabolized and excreted (ADME). Examining these processes provides important information on the pharmacokinetics (PK) of the drug including dose, concentration and toxicity profiles. These parameters are traditionally tested in animals such as rodents and dogs along with a determination of safety and efficacy. However, a simple extrapolation of the PK and toxicity profiles from animals to humans is inaccurate owing to the vast differences in the genomes between the two species, as in the case of TGN1412. The development of assays that can better predict the safety, pharmacology and toxicity of a drug in humans is of paramount importance. Organs-on-chips is one such system that has the potential to reduce the dependence on animal testing and provide a more accurate readout of the safety and efficacy profile of a drug compared with conventional methods.
Source: Balijepalli, A., & Sivaramakrishan, V. (2017). Organs-on-chips: research and commercial perspectives. Drug Discovery Today, 22(2), 397-403.

In 2010, Donald Ingber at the Wyss Institute developed the first organ-on-a-chip, a lung-on-a-chip. Since then, academic institutions and private companies – sometimes working in partnership – have added miniature models of, for example, the liver, kidney, heart, bone marrow, cornea, brain, spleen and the human gut.

A multidisciplinary team at the Wyss Institute have also developed a chip that smokes cigarettes like a human. So there is no excuse to force mice to inhale cigarette smoke, as researchers at the Hunter Medical Research Institute and The University of Newcastle have done.

An organ-on-a-chip is about the size of a human thumb and “made from a flexible, translucent polymer. Microfluidic tubes, each less than a millimeter in diameter and lined with human cells taken from the organ of interest, run in complex patterns within the chip. When nutrients, blood and test-compounds such as experimental drugs are pumped through the tubes, the cells replicate some of the key functions of a living organ“.

Organs-on-chips can be used to study many biomedical phenomena. Apart from drug development and toxicity testing, other possible uses include, for example, personalised medicine (where stems cells derived from individual patients could be used to identify which therapies might be likely to succeed) or testing responses to biological and chemical  weapons.

As an alternative to conventional cell culture and animal models, human organs-on-chips could transform many areas of basic research and drug development. They could be applied to research on molecular mechanisms of organ development and disease, on organ-organ coupling and on the interactions of the body with stimuli such as drugs, environmental agents, consumer products and medical devices. Fundamental questions that might be addressed include how microenvironmental cues regulate cell differentiation, tissue development and disease progression; how tissues heal and regenerate (e.g., mechanisms of control of angiogenic sprouting and epithelial sheet migration); and how different types of immune cells and cytokines contribute to toxicity, inflammation, infection and multi-organ failure. When combined with patient-specific primary or iPS cells, or with gene editing technologies (e.g., CRISPR) to introduce disease-causing mutations, this technology could be used to develop personalized models of health and disease.
Source: Bhatia, S. N., & Ingber, D. E. (2014). Microfluidic organs-on-chips. Nature Biotechnology, 32(8), 760-772.

A recent article in the journal Drug Discovery Today provided the following examples of investment in organ-on-chip developments:

These are only a few examples of work on organs-on-chips. Worldwide, it is considered a multi-million, or even billion dollar market. For example, Yole Développement estimates that “the market could grow at a compound annual growth rate from 2017-2022 of 38-57% to reach $60M-$117M in 2022.” Another company, Accuracy Research, expects the organs-on-chips market to grow around 69.4% over the next decade to reach approximately $6.13 billion by 2025.

Large pharmaceutical and cosmetics companies are expected to start using organs-on-chips. Some companies have already partnerships with organs-on-chips developers, such as L’Oréal, Pfizer, AstraZeneca, Roche and Sanofi.

Ethical concerns are also at the heart of this new market: more than one hundred million animals are used in laboratory experiments worldwide every year, and could be replaced by pieces of microfluidic technology. Source: Yole Développement

Where does Australia sit in this market?

Some projects at the Australian Institute for Bioengineering and Nanotechnology, University of Queensland involve “the development of tumour-on-a-chip, organs-on-a-chip for rapid preclinical evaluation of potential nanomaterials for targeted therapeutics”. At the International Conference on Biomedical Engineering in December 2016, Professor Justin Cooper-White from this institute presented a keynote address on “Human kidney organogenesis from pluripotent stem cells on a chip”. There were other presentation on organs-on-chips, but none from Australia.

Two PhD Scholarships Bioengineering 3D in vitro model systems were recently advertised by Swinburne University of Technology.

A few academics with affiliations to Australian universities have published articles on organs-on-chips. However, it is unclear whether they are involved in the development of this technology. I could locate three articles in peer-reviewed journals on the topic:

  1. Nauman Khalid, a Postdoctoral Research Fellow at Deakin University has co-authored two articles, titled “Recent lab-on-chip developments for novel drug discovery” and “Industrial lab-on-a-chip: design, applications and scale-up for drug discovery and delivery“. I could not locate any information on the Deakin University website that links him to current work on organs-on-chips.
  2. One of the 14 authors of “Screening out irrelevant cell-based models of disease” lists Queensland University of Technology as an affiliation. In the article, the authors discuss new opportunities for exploiting the latest advances in cell-based assay technologies, of which organs-on-chips are one.
  3. Researchers from RMIT had a review of “Successes and future outlook for microfluidics-based cardiovascular drug discovery” published.


Where is the investment in organs-on-chips?

The published outcomes of the 2016 NHMRC Grant Application Round include two projects that involve work on organs-on-chips. The project descriptions are as follows:

Neurodegenerative diseases such as dementia and motor neuron disease are a major health burden for Australia and new approaches to treatment are urgently required. Essential trace elements such as copper, zinc and iron show major changes in neurodegneration, however, we do not understand how this drives disease processes. This proposal will develop an innovative 3D ‘brain on a chip’ cell model to probe the role of trace elements in brain pathology and identify exciting new treatments options.


New human cell culture models of Alzheimer’s disease are urgently needed to help translate drugs into successful patient outcomes. In this proposal we will develop an Alzheimer’s disease brain-on-a-chip that contains the major human brain cell types and neuropathological features of the Alzheimer’s. We will demonstrate the applicability of the model for identifying new Alzheimer’s disease drugs and diagnostics and show that the model can be readily adopted by Australian Alzheimer’s researchers.

Total grant funding for all 1,056 funded projects adds up to $828 million. The extent of the funding for the two organs-on-chips projects is not obvious from the published data, nor at which university, research institute or hospital the work will be undertaken.

I could not find information about investment on this technology by private companies.

body-on-a-chip Khalid et al 2017

Body-on-a-chip. Source: Khalid, Kobayashi & Nakajima, 2017.

Perhaps there is more work on organs-on-chips occurring in Australia, but I couldn’t find relevant information (I searched Google and PubMed). By and large, in Australia researchers continue to use archaic methods that hurt animals, are costly and ineffective. Despite the development of more human-relevant methods, the use of animals for research and education purposes is not decreasing in Australia.

The latest available statistics have just been published by Humane Research Australia. They “show that approximately 10.27 million animals were used in research and teaching in Australia in 2015, although this high number is largely due to NSW counting 4,123,049 native animals in environmental studies which involved observation only.” This compares to approximately 7 million animals in 2014.

Here we have a potentially multi-billion dollar market, and Australia is fiddling at the edges.




The Netherlands – Not just a pretty country

In December 2016, the Netherlands National Committee for the Protection of Animals Used for Scientific Purposes (NCad) provided an advisory report to the Dutch Minister of Agriculture Martijn van Dam after the Minister had requested a schedule for phasing out animal procedures. The report is titled “Transition to non-animal research – About the possibilities for phasing out animal procedures and stimulating innovation without laboratory animals”.

Earlier in 2016, the Dutch Parliament had already passed a motion to phase out all research on non-human primates. The Government aims now at phasing out animal research methods by 2025 and becoming a world leader in animal-free science.

So what is the NCad’s advice?

Overall, the NCad observes that it is time for a paradigm shift. While the animal model has become the “golden standard” in a number of research areas, it inflicts pain and suffering on animals and is perpetuated, for example, “because the current scientific quality assessment system is generally based on bibliometric criteria”, because journals impose animal data requirements on authors, and because the use of animal procedures is stipulated in many guidelines and laws.

Conversely, alternative approaches are becoming more common and “will increase in number and importance”. But the provision of funding for alternatives and innovation is not enough for a paradigm shift to occur. The parties involved in the field will also need to no longer regard animal research as the golden standard, or animal research is “no longer delivering the necessary results”.

In regard to the latter, I would argue that for some decades animal research has not delivered the necessary results for governments and citizens, although it has delivered profits and careers for the industry.

The report argues for strong government leadership to enable a paradigm shift to animal-free science.

The NCad believes that it is only with a broad-ranging and coordinated effort by the ministries involved and other stakeholders that significant progress can be made in reducing the use of animals in research. The choice of a clear direction, clear objectives and concrete steps is essential in this context, but emotions, social structures and other factors over which less influence can be wielded inevitably play a role, given the nature of transitions.

According to the report, regulatory research and testing can and should be phased out by 2025:

The use of laboratory animals in regulatory safety testing of chemicals, food ingredients, pesticides and (veterinary) medicines can be phased out by 2025, whilst maintaining the existing safety level. The same applies to the use of laboratory animals for the release of biological products, such as vaccines.

This should occur together with an international review of the regulatory risk assessment process.

However, the NCad suggests that regulatory pre-clinical research “cannot be phased out at the same pace”.

In regulatory clinical research, medicines that were successful in animal procedures often fail in clinical trials. For these instances, so-called backward validation studies can be used to investigate or determine the predictive value of pre-clinical animal tests and innovative methods for clinical research on human subjects. On the basis of the insights obtained, pre-clinical research models can be improved. The NCad recommends for the Minister for Agriculture to make funds available for this.

For fundamental scientific research, the NCad recommends the development of a 10-year plan for the different areas of basic research in consultation with the public and the scientific community.

In regard to applied and translational research, the NCad observes that “more rapid progress can be made than is being made at the present time. There is a great deal of innovative potential that could be better exploited.”

For education and training,

NCad recognises that the use of laboratory animals in training professionals involved in the field will continue to be necessary to a certain extent, but believes that, here too, cultivating a mindset that does not rely on laboratory animals will help keep the number of animal procedures to a minimum.

The NCad encourages the Netherlands Government to take leadership at the international level. For example:

Urge the European Commission to define a European strategy that takes an ambitious and integrated approach to non-animal research, one that includes animal welfare and the 3Rs in impact assessments and the development of new legislation and regulations. Also, call for existing legislation and regulations to be critically reviewed in this respect, and for it to be mandatory for accepted alternatives to be included, for funds to be made available for the further development of innovations without laboratory animals and for EU standards to be observed in commercial treaties.

…consider collaborating with the US organisations EPA (for the risk assessment of substances and pesticides) and FDA (for the risk assessment of medicines and food additives), as part of a European alliance or otherwise, on the theme of New Risk Management in approval of substances.

… In collaboration with the ministries of Health, Welfare and Sport and Infrastructure and the Environment, the RIVM and relevant international organisations, endeavour to obtain European agreements that make it easier to depart from regulatory animal procedures where possible through the use of validated alternative methods. Also, aim for transparent communication regarding situations where alternatives to the regulatory animal procedures have been used.

Overall, this is a great initiative towards phasing out animal experiments. It shows that it can be done given the political will. Congratulations to Minister van Dam and his government. Congratulations also to the citizens of the Netherlands who have advocated for this change. I hope that other countries will follow your example.