Replacing animal tests with technology

The EU has enacted regulations that will ban the sale of certain cosmetic goods tested on animals in the near future. As a result, the impetus to use non-animal methods has grown in the EU, where animal use and welfare laws already far out pace the US. A news article on one of the non-animal methods that may be key to compliance with the EU regs suggests are are many applications in the US, too. Entelos, Inc. is an important player in this technology.


The article explains the growing demand for Entelos' products:

"Entelos Inc., which has been working for the past decade on computer models that create virtual patients, has supplied Unilever -- maker of products like Dove soap and Pond's lotion -- with a computer model that simulates skin sensitization. Unilever will use the technology in an effort to comply with an EU mandate that by Mar. 11, 2009, cosmetic ingredients sold there cannot be tested on animals.

Entelos president and CEO James Karis anticipates more business might come the company's way as other consumer products companies selling in the EU look at ways to comply with the ban.

"We have a lot of discussions going on [with other companies]. Clearly this announcement was noticed," he says. "This is our first involvement outside of the pharmaceuticals."

...

To date Entelos has been building computer models of various diseases such as cardiovascular disease, asthma, obesity, diabetes and rheumatoid arthritis.

"What we're building here are mathematical representations of human biology," Karis says.

Some text from the article is available online, but a subscription is required to view it in its entirety: Entelos president and CEO James Karis says the life sciences company is creating a virtual test subject that may reduce the use of test animals.

See related stories in the 3Rs topic listed at left.

Sneak peek: Human metabolism recreated in lab

BBC NEWS Health Human metabolism recreated in lab

Following from monkey-on-a-chip and brain-on-a-chip technology, scientists now claim they have captured a comprehensive closed-system model of human physiology. This tool could be very important for replacing some animal experiments.

"Study leader Professor Bernhard Palsson said the network could be used to see what would happen if a drug was used to target a specific metabolic reaction, such as the synthesis of cholesterol.

Or it could be used to predict what would happen if you interfere with a metabolic reaction in a specific type of cell, such as a blood or heart cell.

And eventually it could even be used to create an individual network for a person.

The announcement continues:

'The new tool we've created allows scientists to tinker with a virtual metabolic system in ways that were, until now, impossible, and to test the modelling predictions in real cells,' said Mr Palsson, who is professor of bioengineering and medicine. Study leader Professor Bernhard Palsson said the network could be used to see what would happen if a drug was used to target a specific metabolic reaction, such as the synthesis of cholesterol.

Or it could be used to predict what would happen if you interfere with a metabolic reaction in a specific type of cell, such as a blood or heart cell.

And eventually it could even be used to create an individual network for a person.
'The new tool we've created allows scientists to tinker with a virtual metabolic system in ways that were, until now, impossible, and to test the modelling predictions in real cells,' said Mr Palsson, who is professor of bioengineering and medicine. "

Bound and gagged: the ambivalent vivisector

This week's issue of Nature includes a variety of content on animal experimentation, including the results of an anonymous poll of biologists (80% claimed to conduct animal experiments), editorial content in favor of animal testing on the one hand and more openness on the other, along with interviews with vivisectors aimed at revealing their "nuanced" views.

The editorial piece on the poll is predictable in its endorsement of vivisection, but does acknowledge that there are issues with the way it is communicated.

Animal research saves lives. That is the mantra often used to counter verbal and physical attacks on animal researchers and their institutions by animal-rights activists. And it is unquestionably true: animal research has made many valuable contributions to medical science.

However, the simplicity of the slogan barely does justice to the complexity of the issue. From a scientific point of view, for example, it is clear that certain animal models are useful: the neural prosthetics that promise to restore some independence to paraplegics, for example, arose from curiosity-driven studies of the primate brain (see Nature 443, 122; 2006). But others are imperfect: certain mouse models of cancer, for example, do not accurately mimic the disease in humans, and may even have hampered the development of some drugs (see Nature 442, 739–741; 2006).

May have hampered some drugs? Well that's the understatement of the year, don't you think? 90% of drugs are abandoned without going to human clinical trials. And of those that prove "safe and effective" in animal models, 92% (even more for cancer drugs) don't make it through clinical trials and on to the production line. Some 40% of drugs that do go to market ultimately undergo major relabeling for risks and side effects or are withdrawn entirely. Given all of that, all the Nature editors can muster is that animal models may have hampered the development of some drugs? At least they acknowledge there are some faults.

Onward.

The responses of anonymous invididuals show that there are indeed barriers in the "system" to expressing concerns about welfare, adopting the 3Rs, etc. One participant implies that she is forced to do unnecessary tests and/or tests that she apprently wishes she did not have to do in order to move vaccine candidates through the pipeline:

"As a researcher in the field of HIV vaccine development, I am placed in a very awkward position regarding the use of non-human primates," said one immunologist. "I personally feel uncomfortable with primate research yet I realize that without primate data, vaccine candidates are rarely forwarded to human trial."

Another investigator who uses human data where others continue to rely on animal experiments reports being eschewed and criticized by peers:

It can even be hard, some said, to express nuanced opinions (such as the idea that most, but not all, animal research is strictly essential) within the community of researchers, let alone with the public.

"I am more concerned that the scientific community, rather than the animal-rights movement, makes it difficult to voice a nuanced opinion on animal research," said one neuroscientist, whose research involves using imaging to study the brains of human patients.

It seems that even those who want to move towards epidemiological animal studies over "models" per se encounter resistance. One woman who is trying to use this approach because epidemilogical studies will provide better science and allow her to help individual animals in the context of clinical practice, told her story:

"Naturally occurring diseases might be a better reflection of what is going on in a human than inducing something in a mouse or a rat. People's pets that spontaneously develop these overwhelming infections need the treatment, and we would be more responsible because we are not actually creating diseases in animals."

Otto says she's had a hard time getting a hearing for her proposal from researchers resistant to change.

Another article in Nature's series also addresses the code of silence:

In some labs, at least, scientists feel pressured to keep quiet about the grey areas of debate, lest they undermine the official mantra

Heaven forbid that they offend NABR or some other industry front group. One respondent who spoke about the mantra brought up the issues of transparency and deception:

"I have heard animal-research advocates say that you have to say everything as nicely as possible, and that edges towards fabrication. They say that everything heads towards a cure for something and that all the experiments work."

This was also echoed in near the end of the editorial summary on the findings of the poll:

Many noted that a main difficulty in discussing animal research is in dealing with the fact that some animal models aren't perfect. "We have not addressed legitimate issues that animal rights groups have raised, ...a mouse is not a human and the question to be tested will not be fully answered," said one neuroscientist, who works on animals. "We need to admit this but point out that it is more complex than that."

What does and does not get said is a serious matter. So is how the issues are framed - and how people talk about vivisection. I will further explore the HOW in a separate entry - sequel if you will. :) Watch for it.

Call to ban primate experiments in the EU

Animal Defenders International announced that legislators from the EU are proposing a change to the regulations that govern animal testing in the EU - Directive 86/609 - that would end all primate experimentation.

Dr Caroline Lucas, Green Party MEP for South-East England and Vice-President of the European Parliament’s Animal Welfare Intergroup, said: “Medical and commercial experiments on primates are cruel, unnecessary and, according to increasing numbers of doctors themselves, unhelpful and often misleading. This Written Declaration seeks to ban them in line with the European Commission’s aspiration to make the EU a world leader in animal welfare standards, and I urge my fellow MEPs to sign up and demand legislative proposals to make outdated and outmoded tests on living primates a thing of the past.” Dr Caroline Lucas has recently drafted a set of proposals to end the requirement for industrial toxicity tests on animals.

A new report, called ‘Primate Nations’ has highlighted the suffering of Europe’s 10,000 laboratory primates and describes how these tests can be replaced with advanced techniques based upon human data. Dr Michael Coleman, Senior Lecturer in Toxicology of Department of Pharmacy, Aston University, commented: “As well as the ethical considerations, scientifically primates are simply not close enough to us to act as good experimental models and we should be promoting replacement of animal work with human cellular systems. We must leave behind the intellectual laziness of relying on animal models and invest in human-cellular based alternatives for the future.”

There is a complementary campaign in the US where ADI, an animal advocacy group, is lobbying members of the House of Representatives. Last Friday, HSUS ran a full-page ad in the New York Times calling for the retirement of the chimpanzees now used in experiments (there are about 1300). There is no exact count for all primates in the US, but estimates are between 50 and 80 thousand for labs and breeding centers combined.

See: MEPs lead call to end experiments on primates in the EU

3Rs: Reduction / Replacement: New test could weed out dangerous drug trials

The makers of a new test think that their approach might have provided a warning of risks to the six volunteers in the TGN1412 trial who nearly lost their lives. The utility of the lethal experiments in macaques - or lack thereof - wasn't a major theme here, but it was mentioned.

If there is, in fact, a test that can help predict the safety of anitbodies and other high-risk drug candidates, I'd say this question isn't whether it should be used, but when. Done in advance of experiments that kill countless animals, we wouldn't just save lives, we'd save millions invested in drug candidates that aren't fit for use.

http://www.nature.com/news/2006/061204/full/061204-13.html:

"The victims of the TGN1412 disaster suffered a 'cytokine storm', featuring massive release of inflammatory molecules called cytokines, and overproliferation of immune cells known as CD4 cells. In Inglis's studies, this effect could only be reproduced when the TGN1412 antibodies were dried onto the surface of an experimental vessel before being presented with human immune cells, rather than floating in solution as in usual preclinical toxicity tests. Antibodies that are dried and stuck to a surface are often more active.

It is not entirely clear why the drug produced such devastating effects in humans but not in macaques, which possess an almost identical receptor protein for the antibody. But using antibody-immobilization tests such as the one developed by Inglis could help to identify potential dangers not flagged up by animal tests.

'If I were developing a drug of this kind in the future, I would take these tests seriously,' Inglis said at the unveiling of the expert group's report. 'I would hope they become standard in future.' He and his colleagues are preparing to publish details of the test in a scientific journal."
[Emphasis added]

Prior posts on TGN1412:
Drug rules should change
Drug trial victim has cancer
What the hell happened?

3Rs: Replacement: Heart Valves Grown From Womb Fluid Cells

Heart valves used in replacement surgeries often involve the killing of animals, e.g. pigs, who are used as involuntary donors. This new technology - which has now been used to grow heart valves, bladders and other tissues, would obviate the cruel practices and ethical objections to using animals for xenotransplantation.

Heart Valves Grown From Womb Fluid Cells

3 Rs: Replacement: Animal testing alternative has ticks trembling at the knees

Animal testing alternative has ticks trembling at the knees

3 Rs - Reduction: New Research To Cut Animal Testing, UK

New Research To Cut Animal Testing, UK

"The current pre-animal tests that are used are highly sensitive and so most carcinogens are identified," said Dr Walmsley, who is based in the Faculty of Life Sciences. "Unfortunately, such tests have poor specificity and a lot of safe compounds are also wrongly identified as potential carcinogens. This means that animal testing is still carried out, in case such compounds turn out to be safe.

"The testing process developed at Gentronix has proven very reliable at telling us whether a drug will cause cancer but some chemicals, called promutagens, only become carcinogenic once they have passed through the body's liver.

"This grant will help us develop new non-animal experiments to identify these other toxic compounds and so reduce the need for animal testing."

The funding - awarded by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) - will help the scientists establish new genotoxicity tests using cultured human liver cells. It is hoped the new test will not only reduce the number of compounds that are tested on animals but also ensure harmless chemicals that could prove to be useful new drugs are not falsely labelled as carcinogens.

3 Rs - the difference between theory and practice

Replacing animal experiments with non-animal methods, and reducing the numbers of animals used in authorized experiments are supposed to be embraced by governments and scientists. In theory at least. A new report out of the UK shows this is not happening in practice.

Replacement and reduction are de-incentivized for people who make thier living from government grants to conduct animal experiments. The more experiments, the more money, and thus we see more proposals rather than fewer.

Commentary on non-human primate experimentation under 86/609 will be reviewed in the near future. The public comment period is open until Aug. 19th.

BBC NEWS Science/Nature Continued rise for animal tests

3 Rs: Reduction (maybe) Brain on chip

Scientists have developed a special "brain on a chip" technology which allows scientists to measure precisely the activity of certain brain cells and to potentially measure the effects of drugs. Problem is, the chip is made from rat brains. What we really need is a chip of human brain cells. My guess is that folks aren't busy worrying about rat medicine.

The availability of the chips might reduce the number of live rats needed for experiments in the future, but the rats remain the source of the chip's material. And the brain cells mounted on the chip may require in vivo manipulations before they can be used.

Why, I wonder, aren't human brains from people who have donated their bodies to science being place on these chips if the goal is to study human brain function and medicines?


Brain on chip

3 Rs: reduction and replacement

The FDA announced new guidelines for drug testing today.

"Concerned about a system in which more than nine out of 10 experimental drugs fail when tested in humans, the Food and Drug Administration issued suggestions Thursday on how researchers can more efficiently evaluate the promise of new laboratory discoveries.

The vast majority of drug candidates fail once they're tested on humans, invariably for safety or efficacy reasons difficult to predict based on initial experiments done in test tubes and on animals. That can waste significant amounts of time and money, slowing the process of developing new drugs."

There are provisions for reducing the amount of animal testing done before human testing can begin and for an expanded roll for earlier invetigational trials in small groups of human subjects. One such approach is microdosing, where people are given very small doeses of a drug to study how the human body deals with the chemicals.

3 Rs: Reduction

FDA needs to get with the picture: Bayesian statistical methods could bring clinical (and preclinical) trials into the 21st century.

The authors of this study suggest that a different way of looking at trial design would reduce the number of subjects needed for trials and reduce the risk for those who are used as subjects.

Bayesian statistics overview
Bayesian statistics for the statistically inclined

Non-animal methods

Microdosing and "monkey on a chip" technologies may replace live animal testing

Several "chips" have been introduced lately that allow testing of specific organs or gene activations in specific tissues in response to experimental drugs. Giving tiny, tiny doses of drugs to humans is another non-animal testing technique that many consider useful or at least promising.

This article reviews the general development of non-animal testing methods (from a UK perspective).