If wishes were horses...

I've talked about animal experimentation before (e.g. here and here) but I was pointed to this discussion on the Guardian website:

Dr Sebastien Farnaud of the Dr Hadwen Trust and Prof Roger Lemon of UCL debate the ethics and uses of tests on monkeys

The opening piece by Dr Farnaud contained so many anti-vivisection tropes I was moved to repeat it here (with my comments):

"I thank you very much for giving me the opportunity to start this discussion about a very controversial matter, the validity of the use of non-human primates in medical research, a subject in which, as a medical research charity, the Dr Hadwen Trust is particularly interested."

No, the Dr Hadwen Trust was set up specifically to oppose animal research.

"The first thing to consider is the aim of the Bateson report, which has just been published, its standpoint and who wrote it.
This report is an independent review commissioned by all the major research funders in the UK, to assess the quality, outputs and impacts of research carried out on non-human primates, and their benefits to human health. This review follows the publication in 2006 of the Weatherall report by a working group chaired by Sir David Weatherall that recommended that the major funding organisations should undertake a systematic review of the outcome of all their research using non-human primates (NHPs) supported over the last decade.
Interestingly, whereas the Weatherall report was unambiguously in favour of the use of NHP in medical research, the Bateson report adopts a more challenging position. Professor Bateson, who is emeritus professor of ethology at Cambridge University and president of the Zoological Society of London, is very well respected within the scientific community.
It is therefore very important that statements in his report, indicating that almost one in 10 research projects that used monkeys in the UK result in no scientific or medical benefit, are not ignored. He also states that the justification for some projects carried out over a 10-year period from 1996 was "inadequate or insufficient" and that future projects involving non-human primates that could not demonstrate plausible medical or social benefits should not be funded."

I think only 1:10 experiments showing no scientific or medical benefit is a surprisingly high proportion  showing benefit. I'd imagine most scientific research is of minimal use, even medical research, and a figure as high as 90% showing benefit is amazing. Justification for most experiments, when considered outside the narrow question of what people in a particular scientific field think is interesting, is generally poor anyway. So again, I see little to criticise primate experiments over any other area of science.

"The reviewers also reported the unnecessary and unjustified repetition of work published a decade earlier."

To be fair, there are plenty of reasons to repeat experiments done a decade earlier, including replicating a study to show that the effect is robust and repeatable, and verifying that you are performing a particular technique correctly by reproducing a know effect so you can then go on to develop that further.

"These points underline that the issue is not simply an ethical issue but also a scientific one. This simply questions the scientific validity of NHP use in medicine."

No it doesn't. 10% does not equal 100%.

"The report recommends the promotion and development of alternatives to the use of NHP in research."

Well, duh! I imagine 'mom and apple pie' also get a mention.

"Since most diseases studied in NHP are human diseases that do not naturally occur in NHPs, it seems logical to try to develop models which are from the start human-relevant. Here we have to make clear that nobody is proposing we use invasive methods on human subjects. On the other hand, advanced techniques, which were barely mentioned in the Weatherall report, are highlighted in the Bateson report.. These techniques include, for example, magnetoencephalography (MEG) and transcranial magnetic stimulation (TMS), non-invasive imaging techniques that are already in use to help us understand diseases and the needs of patients who suffer from neurological disorders. Organisations such as the Dr Hadwen Trust have promoted and funded these techniques for over a decade."

Yeah, because if fMRI doesn't have the anatomical resolution then MEG or TMS are going to do the trick. If wishes were horses...

"One very important point that the report makes concerns regulation. It emphasises the importance of and the need for a robust system of regulation for animal experiments, at a time when the Home Office is preparing the implementation of the new EU directive for the protection of animals used for scientific purposes."

Good job UK regulation is the tightest in he world (which is not to say it doesn't focus excessively on process and paperwork rather than welfare).

"To conclude I would say that although this report will not please everybody, I like to believe that it is a first step towards major changes, a different attitude that will challenge the use of NHPs in medical research."

Indeed.

Replacing animal experiments

Nick Anthis at the Scientific Activist finds another article about the evils of animal research published in Bioessays. Gill Langley from the "Dr Hadwen Trust for Humane Research" gets some real scientists in on the act:

"Universities are failing to take up the challenge of replacing their animal experiments with non-animal techniques, whilst industry has made significant strides forward, says an article to be published in the September issue of the international peer-reviewed journal BioEssays. Animal experiments conducted by industry in Britain have fallen significantly over several years, but those carried out by universities and medical schools have risen by 52% in the last decade.

The article is authored by eminent professors engaged in academic research in immunology, infection and pain, as well as the Dr Hadwen Trust’s Dr Gill Langley, one of the world’s leading authorities on non-animal replacement techniques...Replacing animal experiments is a well-established concept in industry, especially in the pharmaceutical, chemical and cosmetics sectors. By contrast, in academia, animal use continues to rise and efforts to replace animal experiments are all too often poorly prioritised or focused. In areas where researchers have pioneered replacement efforts, some animal experiments have been successfully replaced, such as in neurological, reproductive and dentistry research. But elsewhere in the university sector progress has been unnecessarily slow.
...
“In recent years industry has started to respond actively to the replacement challenge in a way that we have yet to see within academia. In safety testing, particularly within the cosmetics, chemical and pharmaceutical sectors, non-animal techniques are recognised as advanced methods that are more ethical and also more relevant to humans, as well as being quicker and cheaper solutions. There is a growing acknowledgement of the need to develop non-animal methods, with legislative reform and consumer pressure for cruelty-free choices both playing a key role in speeding up the pace of change. However, universities tend to be less accountable and more isolated from these external factors and as a consequence their animal use has continued to increase unabated.”"

So says the Dr Hadwen Trust about its own article. Not sure why they think that industry large scale toxicity testing has any repercussions for basic scientific research, but what do I know?

The article starts by making the perfectly valid observation that industry has reduced the number of animals used, whilst academia has increased the numbers (likely due in part to increased use of transgenics as Nick points out) and then highlights a couple of examples of where replacement has taken place (toxicity testing, computer models of placental physiology and orthodontics, and transcranial magnetic stimulation in brain research) and then goes on to suggests how replacement may help in other fields, for example in sepsis:

"Animal models have provided a large body of evidence to establish the major pathophysiological mechanisms that operate during sepsis, and as a springboard in the development of new therapies. However, they are imperfect models...The in vitro tools of molecular and cellular biology will still provide much important information in the future...Newer methods of cell culture using three-dimensional supports hold promise as better models of tissue function...and advances in stem cell biology may well allow quite complex tissues to be constructed entirely in vitro. Similarly, progress being made in computer modelling of sepsis may also allow modelling of septic processes without the use of animals...A greater use of human subjects and material in sepsis research could contribute to the reduction of animal experimentation, while providing mechanistic insights into this serious medical problem."

or respiratory disease:

In the case of COPD, epithelial cells at baseline and following exposure to tobacco smoke extract also exhibit markers of injury and repair that occur in vitro in the airway cells of patients, but not in those from normal volunteers...Building upon the in vitro monolayer system, it has been possible to produce a fully differentiated airway epithelium...they can be used to look for novel molecular targets using genomic and proteomic platforms. They can also be used as test systems for novel therapeutics...Computer simulations have also been used to explore mechanisms of asthma pathology and predict the efficacy of potential treatments"

and pain:

"Animal models have provided us with key information about the detailed anatomical connections of nociceptive pathways...and potential physiological mechanisms of pain perception...To achieve a more physiological approach to pain classification, it will be necessary to identify the normal physiological...and pathophysiological mechanisms of pain perception...For example, PET studies have shown a selective reduction in receptors for natural opiates in the brains of patients with severe pain due to stroke...Following identification of mechanisms in humans, targeted drug development should be narrowly based on modulation of those mechanisms. Having identified and measured the pathophysiological mechanisms, proof-of-concept trials will be much more cost-effective. Preferably no drug should be developed without establishing that it reaches the target organ in humans, prior to clinical trials. In many cases, this can be achieved using molecular imaging e.g. PET. In summary, techniques exist to begin to reclassify human pain physiologically and to identify candidate pathophysiological mechanisms in volunteers. By working back from these mechanisms to drug development, some animal experiments maybe replaced."

They go on to conclude that:

"In academia, with an emphasis more on fundamental medical research, change has been slower. There are several reasons: (1) open-ended research questions are perceived as being more difficult to pursue without animal experiments, (2) there are few avenues for consumer pressure to be exerted, and (3) academic research is less shaped by legislative and regulatory initiatives. However, recent systematic reviews of the translation of animal research into clinical benefit may well signal a change."

I'm sure this article will be jumped on by the anti-vivisection crowd but when you analyse it this is all so much smoke and mirrors. To a naive reader this looks like what the anti-vivs have to say is true, that there are all these alternatives to animal research out there and the evil scientists are ignoring them.

It is worth noting that they explicitly don't say that animals are so different to humans that all research on them is meaningless, and that is a rather popular trope among the anti-viv crowd, so it is interesting that they couldn't get the scientists to say that here. If you read the sections written by the scientists they explicitly say that animal research has contributed much knowledge (and notice the caveats about what non-animal methods may add), but what they don't say, and this goes to the heart of it, is that all scientists are well aware of these other techniques and they are already very widely used because they are complementary to other research (they are also relatively, last 20 years say, new, and could never have contributed to biological knowledge in the past because they simply didn't exist).

I mean, seriously, for fuck's sake, what working medical scientist isn't either aware of, or actively involved in in vitro molecular and cellular work? And how do we think these computer models and other assays were developed, how do we know they are accurate reflections of the biology? Oh yes, the animals. And that is not even to think about where half the reagents and tissue comes from (I'll give you a clue, they're fluffy).

When a working scientist reads this they are bemused, 'what is this article trying to tell us?', it simply mentions a few techniques which are already widely known and widely employed, they represent the state of play in a field of research, they are not replacements because they are doing different things. Sure, new techniques might give us new knowledge, quelle fucking surprise! This paper has absolutely nothing to add to the vivisection debate.

For instance, much of the rise in animal research has been in transgenics, animals with genetic manipulations. Let us take an example of a disease Huntington's disease, a neurodegenerative condition where mutations in the Huntingtin gene have been implicated. Now where do we go from here? We might wonder whether we can reverse the effects of this mutation with treatment or is the damage done too early for us to do anything about it? Luckily enough we can engineer an animal model with mutant Huntingtin, and interestingly it turns out that we can't reverse the neuronal damage and behavioural deterioration when it manifests, but we can arrest it by turning off the gene - making gene silencing therapies a promising avenue of research. But this was animal research precipitated by non-animal 'alternatives', oh no - it is like the alternatives aren't alternatives after all, but different modalities for research, complementary but not necessarily replacing animal experiments.

These genetic animal models, in, for example, Alzheimer's are loads better than the models we had before the genetic knowledge was there (for example, anticholinesterase treatment was inspired by previous models based on the degeneration of cholinergic cells in Alzheimer's, but this is merely a downstream consequence of the pathology, so the treatments cannot be curative only relieve symptoms).

This kind of stuff just seriously pisses me off - it isn't that offensive in and of itself, but it is just meaningless platitudinous drivel in pursuit of a wider agenda. It looks all reasonable until you see that it is attempting to provide intellectual cover for the anti-vivs through confusing non-scientists into thinking that there are somehow these magic replacements for animal research.

What they try and imply is that there are all these new techniques that don't (necessarily) require animal vivisection (true), and that animal research in academia has been rising in recent years (also true), but the link is not that scientists are therefore ignoring non-animal techniques because they are stupid, or not subject to 'consumer pressure', but quite possibly because new knowledge spurs on further research, some of which has to be done with animals.

Rant over!


Bizarrely one of the authors has this to say in spiked:

"I should teach the world that higher animals, and specifically humans, function
as complex systems, where the individual inputs produce effects greater than
their sum parts. While reductionist science can help in identifying the parts,
the real difficulty for medical science is how the parts interact in the intact
organism, and how the intact organism is ordered. This must be the challenge of
medical science for the current millennium."

Ethics of animal research

I think the view of the British public is that raising, killing, and eating animals for food and other animal products is perfectly normal, natural even, and nothing to be concerned about. On the other hand, animal research, or vivisection, is a rather distasteful furtive practice that is only tolerated because of the benefits it brings humanity - but must be constantly monitored and regulated to keep it in check.

They're only half right. Their concern for fluffy rabbits and cute monkeys doesn't seem to extend to battery hens or other food animals and this is a rank hypocrisy motivated entirely by a refusal to think about the issues coupled with an irrational sentimentalism. I'm with Peter Singer that animal welfare has to be part of a utilitarian ethic, and based on current farming practices eating meat and animal products fails that cost-benefit analysis.

So why am I in favour of animal research? The reason is pretty simple, on a cost-benefit calculation animal experiments can bring benefits to humans, organisms that weigh very heavily in my moral calculus, at the cost of animals, which weigh somewhat less (depending on species and experiment performed), and these benefits cannot be got through other methods. Contrast this with eating meat which is pretty much unnecessary for me in my rich Western environment, and where rearing and slaughtering methods are far from halcyon.

Most people would probably accept my analysis of the need for animal research, even if they reject my arguments for vegetarian/veganism. And this is the fundamental problem of the anti-vivisection movement, they can put forward a logically consistent, even respectable argument against animal research, often based on a position that essentially rejects privileging humans over other animals (although not necessarily), but most people will never accept their arguments.

So what are they to do? Fortunately for them, there is another line of attack. If the animal suffering end of the equation isn't powerful enough, how about questioning the benefit to humans? Now this isn't entirely an opportunistic strategy, many anti-vivisectionists have convinced themselves of the futility of animal research for benefiting human health because of the cognitive dissonance inherent in the (intellectually respectable) position that whilst animal research may benefit human health, these benefits are outweighed by the suffering of the animals.

Many anti-vivisectionists go further than just asserting that animal research is useless, they want to argue that it is actively harmful to people's health. An additional line of attack is to assert that we don't even need to do animal research, there are in fact a range of super-dooper alternatives that are being ignored by the pharmaceutical companies and evil scientists with their vested interests (these include 'computer models' and 'in vitro' tests, it is never entirely clear how these are supposed to be developed, and how exactly they are meant to work, but the anti-vivisectionists seem quite taken by these mythical beasts).

Now I've spent some time working on researching disease in humans, yet I have, on occasion, carried out animal research in pursuit of this, and constantly rely on the results of studies into animals when interpreting, planning, and evaluating my own work. In fact, if you ask doctors and medical researchers the vast majority will stress the value and relevance of animal studies. Without animal research I wouldn't even know where to begin studying the human brain - it would just be a big squidgy blob of tissue.

Now anti-vivisectionists are not entirely wrong that a whole lot of research goes on that is of, shall we say, questionable relevance to human health (and I've argued before that science could do with a little more direction, in terms of funding). And I can accept that perhaps the existing regulations are not as well enforced as they could be (although I do think the legislative framework is pretty good, and justifiably strict - if unnecessarily bureaucratic). But they go way beyond this. I have a familiarity with the pseudo-academic works of Shanks & LaFollette and Ray & Jean Greek, as well as the continuum from national campaigning to street level demagoguery of the BUAV, SPEAK, Animal Aid, X-CAPE and a host of others.

I feel like I should present some critique here of their overall position, but it is really impossible because they are generally so incoherent, scattergun, and ill-informed that they can only be countered on an argument by argument basis. Not that I would advise actually trying to engage any of the true believers as they are impressively inflexible in their thinking and quite unable to connect with a rational argument. However, there is a loose thread that runs through these arguments, and that is the view that animals are so different from humans that we simply can't infer anything about how humans work from looking at animals - now stop snickering at the back and muttering 'DNA' into your hand these people are serious - they draw a lot of their intellectual strength from Shanks & LaFollette and the Greeks, but the argument is essentially that because humans and animals are not exactly the same you can't extrapolate from one to the other. That is pretty much it, with a variety of anecdotes about how this or that drug works differently in humans than this or that species, oh, and mentioning thalidomide of course (yes, I know that thalidomide was never tested for teratogenicity in animals - but they apparently don't).

To get an idea of the level of argument we're talking about here's an exerpt from a BUAV 'report' on animal research in Parkinson's disease, and compare their claims with the development of deep brain stimulation for Parkinson's disease using animal models:

"From a scientific point of view, animal 'models' of PD should be stable over a long period of time so that the effects of new therapies can be evaluated. However, the fact is that the signs and symptoms in primates vary over time, even between individuals. Additionally, specific signs of illness in individual animals used as indicators of the severity of their condition contradict each other, making data interpretation more difficult. There are serious underlying limitations to the primate 'models' of PD which include:

• Symptoms are caused by toxin injection and appear rapidly in primate 'models'. The causes of human PD are unknown and symptoms are
  slow to develop.
• Because of the artificial causation of the condition in monkeys, little can be learned of the causes and progression of the human disease.
• Compensatory mechanisms in surviving brain regions are likely to be different in lesioned monkeys compared to PD patients.
• If dosing is stopped, neurotoxin-treated primates show partial but variable recovery (and there is variation between old and new world monkeys). However, humans always show a progressive worsening of the symptoms over time.
• PD usually affects older people with comorbidities, while the monkeys used in research are young and otherwise healthy.
• In the affected brain regions of primates, Lewy bodies are either never seen or only very infrequently. Yet in patients, these cellular inclusions are the classic hallmark of PD.
• MPTP-treated primates show limb tremor only sporadically. In PD patients tremor is marked and sustained. The cognitive patterns of impairment also differ between primates and patients.
• In neurotoxin-treated monkeys, specific dopamine-containing brain cells are damaged in one part of the brain. In PD, damage is more widespread and involves other neurotransmitters, in addition to dopamine.

Replacing primates in fundamental PD research
Functional imaging has a key role to play in human studies of Parkinson's disease, thereby avoiding problems of species differences and artificiality of the model. Positron emission tomography (PET) imaging has been used to measure levels of dopaminergic activity in the brains of Parkinson's patients. This sheds light on the pathophysiology of the condition, and permits direct study of disease progression at a biochemical level. PET imaging has revealed disturbances of brain functional interactions and cognitive information..."

If you're familiar at all with neuroscientific research, and Parkinson's research in particular you'll be able to see what crap the BUAV are talking moaning about fairly peripheral issues to do with disease progression, whereas the scientists went into the the brains and found a bit that lesioning or stimulating could actually control the symptoms and then translated that into human patients (take a look here at what it can do for real live human patients). No matter how many PET studies you perform you really can't find this kind of stuff out without getting inside that brain - you are not going to look at a PET scan, say 'oh, that bit looks like it lights up a lot in PD, let's cut it out of some people and see if they get better'.

Of course these animal models are not exatly the same as the human disease, but they're not trying to exactly reproduce the disease, they are simply trying to reproduce the relevant problem (dopamine depletion) and find relevant solutions (deep brain stimulation). I could go on about how the normal physiology of the brain can only be discovered by research in animals, and about how much we've learned from animal studies that we've been able to use to interpret the pathology in human disease, but examples of successful research like this are better than any argument I can produce to show how unfounded this sort of stuff from the BUAV and friends really is.

Animal wrongs

The BUAV have got plenty of publicity for their case against the government in the high court. Yet they only seem to have won on one issue:

The High Court ruled that Buav was correct in stating that the government was failing to correctly determine the severity limits for animal experiments.

Which, judging from the BUAV press release refers to

The BUAV is also questioning why the Home Office assigned a ‘moderate’ suffering banding to experiments which included highly invasive procedures such as removing of the top of marmoset’s heads to induce strokes. The guidelines state that any procedure which ‘may lead to a major departure from the animals’ usual state of health and of well-being’ must be categorised as ‘substantial’, and undergo far stricter assessment to get licensed.

Despite this the general tenor of the media coverage is that (e.g.):

The British Union for the Abolition of Vivisection today won its High Court claim that the Government is failing in its legal duty to ensure animal suffering is kept to a minimum in UK laboratories.

Now I'm not sure of the legal minutiae of this case, but my copy of Wolfensohn & Lloyd lists, for moderate severity procedures:

• Surgical procedures where post-operative care and analgesia are reliably provided
• Toxicity tests with defined humane end points (as opposed to lethality as the end point)

and for substantial severity:

• Major surgery causing post-operative suffering
• Toxicity studies with significant morbidity or death as an end point
• Any procedure which results in significant deviation from the animals' normal state of health

I think this puts some context to that last phrase, "Any procedure which results in significant deviation from the animals' normal state of health", which, if you weren't aware of the definitions, you might think basically applies to any surgical intervention you might make (it seems like it is likely to cause 'deviation' from it's normal state of health), but clearly that is not the case, otherise the moderate category wouldn't exist.

Of course, the BUAV may well be right that in this particular case the procedure (inducing strokes) did warrant inclusion under the significant category, but my experience with animals receiving neurological insult for experimental purposes suggests that they are generally surprisingly unaffected by the whole business - this is partly because the effects of stroke on an animal are less severe due to the way their brains are wired, and partly due to their general lack of awareness of any deficits induced (not being human and thus unable to ruminate on their loss of capacity).