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Post details: Recent press reports on the "3 Rs" and rising number of animal experiments


Permalink 08:24:00 pm, by admin Email , 2373 words, 1836 views   English (UK)
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Recent press reports on the "3 Rs" and rising number of animal experiments

The 3 Rs

There has been some interesting press coverage recently of the so-called "3 Rs", three principles that govern the use of scientific research using animals, namely, replace, refine and reduce. Despite the claims of anti-science campaign groups that these are regulations developed as a result of their campaigning, these principles were actually developed by scientists themselves and are fully consistent with the most basic standards one would expect of any scientific research. They are also enshrined in the Animal Procedures Act of 1986.

Because our humanity compels us not to waste animal life senselessly, we should replace the use of animals in research wherever possible, wherever some other method can yield equally useful results. Scientists have been doing this for many decades and alternative methods of testing have always coexisted alongside the use of animals, such as computer modelling of proteins, the use of cell cultures, etc.

Refinement is a central principle of all scientific experimentation: all scientists aim to refine the methods they use in order to get more accurate results from fewer experiments - it's about efficiency. Be it the number of test tubes put in an incubator or the number of mice used to test a substance, scientists want to get accurate results as quickly and cost-effectively as possible, always seeking to build better, more accurate models as they do so.

Reduction flows from the principle of refinement: the better our understanding of our testing models becomes, the fewer test subjects we need. This does not refer to a reduction in the overall number of animals used per year, say, but a reduction in the number of animals used in a given experiment or for a given procedure. Again, it's scientific common sense: if you don't need to use 3 mice, don't use 3 mice, just use what's required to get the results - maybe one mouse, maybe none at all. As science evolves and revolutionises its understanding of the world, we are frequently able to do just this.

The 3Rs are, then, good practice, whether you are using animals, or some other method. They arose from what scientists naturally do. There is even a National Centre for the 3Rs to help share knowledge and expertise across research communities.

The BBC recently ran an excellent feature on the 3Rs, interviewing scientists who work on developing non-animal models: computer modelling, in vitro and imaging techniques. It's worth a full read. Below, I'll just highlight a few key points to help put the 3Rs in context and to help explain these scientists' remarks about why 'alternative' methods cannot at present replace animal research. (See also the BBC report on the development of alternatives towards an 'animal free' laboratory, which accurately reveals how far off we are from that vision.)

Computer Modelling

Professor Dennis Noble and his team work here in Oxford and developed the first "virtual heart" using computers. Prof Noble has been working on this project for 46 years and now has a working model using highly sophisticated computer technology. But, he says:

"Because hundreds of millions of differential equations are simultaneously being solved, it may take 30 hours just to do a few beats of the heart."

Even with today's technology, it's (perhaps surprisingly) slow. Why? Because the human heart, like any organ, is incredibly complex, and even the most powerful number-crunching machine has hundreds of millions of sums to do every second just to model that one organ. Imagine how many calculations would be required to model the whole body! And we'd have to develop the technology first, which is many, many years away.

"I would say the real benefit of the model is that it can do a preliminary filter of your compounds, and that can replace some of the very early stages in animal experimentation."

This is the crucial part: Prof Noble states that the computer models can not replace animal models outright. They can only substitute in the very early stages of research. So procedures that once required an animal can now be done on a computer: animal models have been replaced for this procedure. But of course there will come a stage when we need to, first, check to see if the model got it right for the heart; and second (and most crucially), see how a compound like a drug affects the whole organism.

When you swallow a drug, your stomach has to digest it, and the drug has to be absorbed into your bloodstream, processed by your liver, and distributed around your body. Even if it's injected, it must still be metabolised by the liver. Because we just don't have the technology to model an entire human body, we simply don't know what will happen when we inject or ingest a drug. It could be destroyed by stomach acid, or it could become fatally toxic when metabolised in the liver, or simply lose the properties that made it apparently effective on the computer model. So, as Prof Noble says, computer models are a great way to reduce the use of animals in the early stages of research, and they are extensively used for just this purpose, but we still need animals to complement this method. The alternative would be to introduce drugs straight into human beings, which could often be disastrous, given that we don't know what the effects would be on an entire organism.

In Vitro

The next method discussed in the feature is in vitro testing - testing things in a test tube, on the micro level. Dr Phil Stephens has pioneered an in vitro test for ulcer treatments based on genetic manipulation. He says:

"There are a number of different animal models out there, but they are not really good models for these wounds. So, we began developing an in vitro system."

This is a great example of refinement. Scientists always want a better model for their experiments so as to get better (more accurate) results. If a non-animal method can work better than an animal method, great! Not only does it yield better results, it's a hell of a lot cheaper, too (animal breeding, purchasing, transportation, care, feeding, housing, monitoring, etc, costs an enormous amount of money). But, Dr Stephens also notes:

"The in vitro system is not going to replace the animal models, but it will enable a vast number of pre-screens to be undertaken, hopefully vastly reducing the number of animal experiments that go on."

Again, although the aim is to refine the models and reduce the number of animal experiments, Stephens notes that in vitro testing cannot replace animal testing altogether. The reasons for this are fairly similar to the above: a drug might work fine on a cell in a test tube, but how will it work in a body? A test tube has no blood circulatory system, no liver, no brain, no nervous system at all, and so on. We just don't know whether it would work for sure until we try it on a living creature. And again, it's either animals, or us, that we have to trial the drugs on next.


Finally, Professor Chris Higgins of the Medical Research Council discusses his use of MRI imaging to reduce the need for animal experiments:

"One area we are looking at is what controls appetite and satiety. To do this in the traditional way, we would have to dissect the animal brain, but to avoid this we use in vivo imaging to look at the areas of the brain related to hunger and satiety."

Rapid advances in technology have allowed us to get to the stage where scientists can use scanning to see how certain parts of the brain "light up" under certain conditions, giving us clues about what parts of the brain control different aspects of our bodies, thoughts, cravings, and so on, and clues about how the brain works. However, Prof Higgins goes on:

"the one thing that is difficult to do is to understand the genetic and the underlying molecular basis of obesity, and for this we need to use animals, mainly mice, if we are going to develop more effective therapies."

So again, although this 'alternative' can fulfil a useful role and help reduce the number of animals used, it can not replace animal testing altogether. This is because there is no single cause to the problem under investigation - in this case, obesity (though it is true of many conditions). Watching how the brain works can help us understand part of the problem, but it also occurs on the genetic and molecular level, which MRI scans cannot show us. We need a more invasive technique - and again, the choice is between using those techniques on animals, or on humans.

Reducing and Increasing: What's wrong with the 3Rs?

All this talk of replacing, refinement and replacement as scientific common sense sounds fine, but then people were perhaps shocked to learn in recent press reports that the total number of animals used in experiments has risen this year, reversing a 14-year-long decline. How can scientists be "reducing" and "replacing" animals, if the numbers of animals used is going up?

Well, as we said earlier, the reduce part of the 3 Rs relates to reducing the number of animals used in a given procedure to make it more efficient -- not reducing the number of animals used in total across medical science. The call to "reduce" flows from the basic scientific principle of using the lowest numbers of experiments possible to get the data needed to understand something, not from a political/moral principle that the use of animals should be abolished -- and rightly so. Science takes place within a tightly-regulated ethical framework, but its procedures are guided by scientific rationality.

So, why is the number of animals used going up? There's a range of reasons. The most exciting and positive reason is that we are living in a "golden age" of medical science. Within the last few decades we have developed our understanding of humans and animals in their diseased and normal states very quickly. The mapping of the human genome was a remarkable step forward in understanding how the human body works, and it has opened the door to refining animal models even further. Mice are the most commonly-used animals for research purposes, because, surprisingly for many non-scientists, they have many genetic similarities to human beings, so they make good models for predicting what will happen when things are tried out on humans. With new genetic technology, we are now able to work on developing a "transgenic mouse": a genetically-modified breed of mouse that has even more genetic similarity to human beings, which makes it an even better model for humans. Once this project is completed, we will have an excellent model that will ultimately reduce the numbers of mice needed for research. But the development of the transgenic mouse will require the use of many more mice in the short term. This is a major reason for the number of animals being used in research going up.

There are other reasons, too. One is shifting epidemiology, i.e., changes in the patterns of what conditions/ diseases humans are suffering from. Humans (at least in affluent societies) are living a lot longer than they used to, because, thanks in large part to animal research, people are no longer dying from the old killers like TB, polio, measles, etc. As a result, people increasingly suffer from other sorts of medical problems as they age, such as Parkinson's and Alzheimers, which are predominantly conditions of old age. The development of treatments and cures for these conditions require both the use of more animals for research purposes, and specifically the use of primates. This is because they are diseases of the brain. The complexity of the human brain is staggering, and only primate brains offer a reasonable model with which to understand what is happening as a result of these conditions, and how to stop them. Pro-Test advisor Prof Tipu Aziz pioneered a treatment for Parkinson's as a result of experiments on monkeys based on "deep brain stimulation".

Other reasons are more political than medical. The EU Commission recently announced its intention to order toxicity testing on 30,000 chemicals which have never been subject to testing before, with a total of 140,000 identified for potential testing to date. Toxicity testing always involves animal testing at some stage.

So the issues around the 3 Rs are very complex. A crucial task for groups like Pro-Test who want to make the case for animal research will be to explain why, despite all the talk of "reducing", the use of animals in research has begun to increase and will continue to do so in the short-term. This must involve being totally honest about what the 3 Rs actually are. They are scientific good practice and common sense. They are not, in and of themselves, a justification for animal research. The 3 Rs are often invoked in a purely defensive way by scientists who are challenged by anti-vivisectionists opposed to their work: "Oh, but we use the 3 Rs! We try to replace, refine and reduce!" Animal research is not positively justified by implying that you try to do it as little as possible and hope to phase it out in due course. It might wash in the short term while the numbers of animals used is declining - as it has for the last 14 years - but it looks suddenly very thin and vulnerable when the numbers start to go up, making people wonder what the "reduce" claim is really all about.

The challenge for scientists and their supporters, then, is to explain what the 3 Rs really mean, and to go beyond them. The 3 Rs are sound scientific practice; but so is calculating to three decimal places or rounding to zero from 0.4. They're not a justification for the practice itself. The rising numbers of animals being used in research should be a wake-up call to scientists to start making arguments that genuinely and proudly support animal research as a necessary and integral part of the "golden age" of medical science: that it is an essential and irreplaceable model for understanding the human body, and that it has contributed and will continue to contribute massively to the development of treatments and cures for human ailments.

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