Read Animal Aid's scientific Briefing on the Bristol experiments

Genetically modified mouse
experiments at Bristol University –
cruel and without medical benefit
<strong>Briefing</strong> sheet
www.animalaid.org.uk • tel: 01732 364546
<strong>Animal</strong> Aid, during the course of researching its
Science Corrupted report into the suffering endured
by genetically modified (GM) mice, uncovered a longrunning
series of deeply unpleasant animal experiments
conducted at Bristol University. We have rigorously
examined the justifications given for such work, and
the details of exactly what the mice endured. We
conclude that the research, in common with a mass of
other recent and contemporary experiments, is both
extremely cruel and without <strong>scientific</strong> merit.
These continuing experiments are investigating, in
animals, the role of a protein-like substance called
galanin in pain perception. Researchers have created
and bred both knockout and transgenic mice 1 , with
the inevitable mass killing and death from ‘side effects’
that such processes entail. GM mice have then been
subjected to prolonged pain experiments, which
involve nerve damage surgery followed by protracted
suffering in a range of invasive testing regimes.
The first of the papers we cite was published in 1998,
and the most recent in 2012. A continuous flow of
public and charity money has kept the programme
going for the last 15 years. Despite millions of pounds
in funding, it has yet to produce any new treatments
for patients.
Mice are complex, sensitive animals
Mice used in experiments are no less complex or
vulnerable than their wild-living counterparts. The
laboratory environment is completely alien to them, and
already fraught with potential stressors even before
they are subjected to the procedures detailed below.
Mice are a prey species, which means that they are
highly motivated to stay close to safe cover. They
also find routine human contact very stressful unless
they are properly habituated, and are especially upset
by being caught or handled. They have an inherent
tendency to hide signs of pain or distress, and can
become unwell and deteriorate quickly, with often
only subtle signs of suffering, until illness is severe.
<strong>Animal</strong>s in laboratories are often selected on grounds
of convenience and tradition, rather than any predictive
value for human ailments. Mice, for example, breed
prolifically and are relatively cheap to buy and maintain.
Dozens of mice have their nerves
crushed, tied or severed
During the course of the experiments, dozens of mice
were subjected to surgery, which entailed crushing,
severing or tying nerves in their back legs. This left
them with a marked hypersensitivity to painful stimuli,
a kind of neuropathic pain 2 . This is described by the
long-term lead researcher as ‘persistent and incredibly
unpleasant’ when experienced by humans – there is no
reason to assume that it is any less severe in smaller
mammals.
Mouse undergoing nerve damage experiment of the type conducted
at Bristol University
No mention is made of the administration of any
painkilling medications following the surgery. This is in
keeping with studies of laboratory practices that show
rodents receive less consideration than larger animals,
even though they feel pain in the same way as people.

Paws poked with wires, heated up and
injected with corrosives
After enduring nerve damage surgery, mice had their
hypersensitive back paws poked repeatedly with fine
wires, they were heated with thermal beams or they
were injected with formalin (a highly irritant corrosive).
This infliction of pain was performed on repeated
occasions, from shortly after surgery until the end of
the experiments two weeks later.
In other procedures, mice with nerve damage had their
paws dipped in food colouring, and were then made
to walk on white paper, to establish how crippled they
were. Others had their skin injected with substances
that caused violent itching, or had the active ingredient
in chilli pepper injected into their cheeks.
Distressing and lethal ‘side effects’ of
genetic modification
Many animal victims of genetic manipulation suffer
unforeseen and unpredictable ‘side effects’, in addition
to the intended suffering from their designer diseases.
The Bristol researchers report how they generated
knockout mice with the gene for galanin production
disabled, through gene targeting in embryonic stem
cells 3 . The team reported that ‘mutant females fail
to lactate and pups die of starvation/dehydration
unless fostered onto wild-type mothers. This apparent
failure of lactation was absolute during the first two
pregnancies.’ Clearly, many pups were callously
allowed to die, as ‘in subsequent pregnancies, 80 per
cent of pups died but on some occasions one or two
survived to the weaning period’.
Mass destruction of living creatures
The researchers created and bred their own lines
of genetically engineered mice for subsequent
experimentation. These procedures are notable for
the waste of lives and sheer scale of animal killing
required. The initial creation stages, for example, entail
the deaths of hundreds of animals to produce only
one ‘founder’. Mice who are judged to be ‘excess’
or ‘failures’ are generally gassed or have their necks
broken.
Contradictory findings even between
animal studies
On several occasions, the researchers reported
findings that contradicted previous animal experiments
in different species, findings in other GM mice and
other mouse pain ‘models’, as well as the ‘existing
pharmacological data’.
They stated in one case that ‘the most obvious
explanations for the apparent discordance in
nociceptive (pain) behaviours between these two
different GalR2-MUT (mutant) lines are that each
study has used a different model of neuropathic
pain, and the animals have been generated on
differing genetic backgrounds’. In other words, the
results of the experiments are not even verifiable
between different kinds of mice. The absurdity of
their extrapolation to humans, therefore, is glaringly
obvious. The researchers, however, proposed further
pain experiments on more knockout mice to clarify the
problem.
‘An eye fixed firmly on the marketplace’
<strong>Briefing</strong> sheet
www.animalaid.org.uk • tel: 01732 364546
The Bristol papers do not specify how many ‘surplus’
mice were killed prior to the creation of a stable GM
line. Minutes of a Bristol University Ethical Review
Meeting from 2010, however, refer to an experimental
series entitled: ‘The adaptive response of the nervous
system to injury’. This title is identical to that found on
the Bristol University website of the lead researcher,
and to a Home Office public summary that describes
the experimental protocols. It is highly unlikely that
the Ethical Review does not refer to the experiments
detailed in this <strong>Briefing</strong>.
The minutes, released under the Freedom of
Information Act, show that ‘very high numbers of
animals are needed for the maintenance of genetic
lines due to several factors including the size of the
research group and the fact that the use of multiple
crosses means only 1 in 64 animals may be usable.
However, there was concern that the use of 18,000
animals in the renewal application was not justified in
the text. It was noted that large numbers of animals
were also quoted in the original application.’ Despite
these concerns, the Ethical Review Body approved the
renewal of the project licence.
As in many cases of university research, there are
clear links between the researcher’s publicly funded
experiments and their potential for private profit.
A continuous flow of public and charity money
(including a £4.3 million grant in 2010 from the
Wellcome Trust) has sponsored the programme for the
last 15 years. In 2007, its lead researcher was paid out
of public funds (from the Medical Research Council) to
spend six months at GlaxoSmithKline learning about
drug development – having founded his own ‘spinout’
drug company from Bristol University some years
earlier.
In fact, the lead researcher is clearly keen to tap
the ‘billion dollar market’ for drugs for neuropathic
pain. The Bristol University Annual Report from 2004
describes his drug company ‘bounding forward with
its eye fixed firmly on the marketplace’, with its founder
extolling the commercial potential of Bristol’s many
research programmes.
For patients in pain, the wait continues
An article in Nature Medicine (2010) highlights the
‘abysmal track record’ of animal pain experiments
- they ‘have produced an explosion of information

about pain, but this knowledge has failed to yield new
painkillers for humans’. A 2010 meta-analysis of 174
randomised controlled trials (RCTs) of neuropathic pain
treatments found that the majority of patients saw no
benefit, with a high number of early drop-outs because
of adverse drug reactions. A London researcher
commented at that time: ‘The animal models of
neuropathic pain just don’t seem to be that efficient.’
poor mimic of human disease. The damage induced in
young, genetically identical and usually male animals is
fundamentally different from the pain experienced by
patients with chronic diseases, who are often elderly.
The kind of neuropathic pain experienced by patients
with diabetes, post-viral syndromes and cancer, for
example, is not due to injury of their peripheral nerves
such as that inflicted on the Bristol mice.
The Bristol experiments are no exception. Despite
inflicting considerable suffering on animals, they have
so far produced no concrete benefits for patients.
Galanin was discovered in 1978. It belongs to a group
of substances known as neuropeptides, because of
their role in biological communications between nerve
cells. Galanin is found widely in mammalian central
and peripheral nervous systems, and also in hormone
producing organs. The chemical is involved in several
biological processes, including pain perception, eating
and sleep regulation and mood. However, despite
decades of basic research (mainly but not exclusively
using rodents), the roles of galanin in the human
body remain far from clear. Molecules that both block
and stimulate galanin receptors have been tested in
‘animal models’ of pain, epilepsy, Alzheimer’s disease,
morphine addiction, alcoholism, eating disorders,
depression and anxiety. Many of these experiments
involve manifestly cruel physical and psychological
torments.
The disconnect between the preclinical animal studies
and the subsequent human trials is enormous. A 2008
article, authored by animal pain researchers, points out
that ‘of the 123 interventions assessed in the 105 RCTs
included in a recent clinical meta-analysis, 53% were
conducted in patients with peripheral polyneuropathies
and 21% were in post-herpetic neuralgia patients. In
contrast, only 9% of the RCTs studied patients with
peripheral nerve injury.’
Another reason for the systematic failure to help
human patients is the measurement of largely irrelevant
data. These experiments are measuring evoked
hypersensitivity of a mouse paw after a peripheral nerve
injury, via withdrawal from a painful stimulus. However,
the predominant symptom suffered by patients with
neuropathic pain (and therefore the primary measure
of a treatment’s efficacy) is spontaneous pain.
Limb withdrawal in an injured animal is expected
to somehow represent patients’ pain intensity and
character, psychological status, sleep disturbance,
physical function and overall quality of life.
‘A measurable failure of replacement
and reduction’
<strong>Briefing</strong> sheet
www.animalaid.org.uk • tel: 01732 364546
Mouse in nerve damage experiment
However, this continued infliction of suffering has not
resulted, to date, in even one galanin-based drug
being approved for use in any human disease. In
fact, the <strong>scientific</strong> literature is littered with speculative
declarations of therapeutic breakthroughs that date
back at least 25 years. The Home Office summary of
the Bristol experiments makes clear that the primary
purpose of the experiments is not patient care, but the
acquistion of ‘new knowledge’, and that ‘the aim is
to publish the findings in academic journals’. Human
health is only a ‘secondary potential benefit…in so far
as the results may at some later stage be of value in
the development of new pharmaceutical products’.
Pain research on mice does not
translate to humans
The Bristol experiments are basic research, involving
the laboratory destruction of animal physiology and
anatomy in the hope of finding out something clinically
relevant. It has been estimated that this kind of work
has only a 0.004 per cent chance of leading to a new
class of drug.
The pain model used in these experiments is a very
‘Researchers conducting prolonged pain research on
mice are paying little, if any, heed to 3Rs principles in
the planning and execution of their research.’ This was
one of the damning conclusions of a literature review
published in January 2013. The study details how the
total amount of prolonged pain research (defined as
that which subjects mice to a source of pain for at least
14 days), and the number of mice used, has increased
dramatically in the past decade. The use of transgenic
mice has also risen significantly.
The authors discovered that neither the 3Rs concept,
nor any of the 3Rs components - replace, reduce, or
refine - were mentioned in any of 55 randomly selected
recent studies. This ‘suggests that prolonged mouse
pain researchers may be unaware of or indifferent to
the 3Rs framework’, and that ‘adherence to guidelines
and/or animal use committee requirements is not
translating into significant progress from a reduction
or replacement perspective’. This is hardly surprising,
given the highly permissive and non-critical attitude of
most Ethical Reviews.
Science Corrupted
Despite these failings, Bristol University currently
remains committed to animal-based research, much
of which involves GM mice. <strong>Animal</strong> Aid has produced
a fully referenced <strong>scientific</strong> report, Science Corrupted,
which reveals how, every year, millions of these
sensitive and vulnerable animals suffer a chain of
misery. It begins with the invasive procedures needed
to create new genetic lines, and then continues
with the harmful effects of genetic alteration, colony

eeding, experimentation and traumatic death. The
scale of suffering involved is incomparably greater than
any other area of animal experimentation.
Furthermore, using GM mice to mimic human disease
is not delivering meaningful healthcare advances.
This peculiar science continues to lead to ineffective
drugs, disastrous clinical trials, and the dashing of
the elevated hopes of hundreds of thousands of
patients and their carers. Science Corrupted details
the serious misgivings of numerous researchers and
commentators about the value and relevance of this
work.
Humane research and medical progress
In contrast to the assertions made to the Home Office
by the researchers, there are alternative approaches
that can replace animal use in pain experiments.
Studies on cultured human skin cells, minimally
invasive microdialysis testing, and studies of human
nerve tissue have all been used to investigate the role
of galanin. Brain-imaging technologies, like functional
MRI, are a powerful tool for investigating allodynia 4 in
patients. As the 2013 study cited above points out: ‘In
the area of pain research, ethical clinical studies with
human patients have the advantage that humans can
reliably report their experience of pain and pain relief.’
Double helix - the structure of DNA
<strong>Briefing</strong> sheet
www.animalaid.org.uk • tel: 01732 364546
<strong>Animal</strong> Aid, like the general public, is keen to see
research undertaken that is both humane and has
a good prospect of leading to genuine medical
advancement. However, GM mouse experiments are
a betrayal of patients desperate for genuine progress
instead of endless false dawns. Bristol University must
give a clear commitment that it will end all involvement
in irrelevant and cruel animal experiments.
<strong>Read</strong> Science Corrupted and view <strong>Animal</strong> Aid’s short
film about GM mouse experiments at
www.animalaid.org.uk/GMmice
References available on request
1 Transgenic animals have been altered to carry
a foreign gene from another organism within their
natural genome. Knockout animals have certain genes
prevented from working.
2 Neuropathic pain is chronic pain resulting from
damage to or dysfunction of the nervous system
3 For a detailed explanation of this technique, please
see page 13 of <strong>Animal</strong> Aid’s Science Corrupted report
4 Allodynia is pain produced by a stimulus that does
not normally produce pain