Sense about science - making sense of crime

Booklet 'Making Sense of Crime' published by registered charity 'Sense About Science'There’s always heated debate about crime in the media and a lot of political argument about how we should respond to it. But these arguments rarely provide insight into what actually causes crime, what lies behind trends over time and in different places, and how best to go about reducing it. Values inform how a society decides to deal with crime. We may decide that rehabilitation is a better principle than punishment, and this will influence how we decide what is most effective. However, we also expect these choices to be disciplined by sound evidence, because if crime policy ignores what works and what doesn’t, there are likely to be bad social consequences. And with over £10bn spent annually on tackling crime through the police, prisons, probation and courts, unless we look at evidence we can’t see how effective any of it is. Crime policy usually has twin aims – to prevent crime, and to seek justice by punishing those who commit offences. Research shows there’s only a loose link, if any, between the way offenders are punished and the number of offences committed. There is no reliable evidence for example, that capital punishment reduces serious crimes as its supporters claim. Yet politicians and commentators regularly claim that more punishments are a way to cut crime. Academic, government and community organisations have all said crime policies need to be based more on evidence, but much of the evidence available at the moment is poor or unclear. Debates about crime rarely reflect how strong the evidence behind opposing policies is, and even when politicians honestly believe they’re following the evidence, they tend to select evidence that supports their political views. This guide looks at some of the key things we do know and why it has been so difficult to make sense of crime policy. An important point throughout is that policymakers sometimes have to make decisions when things are not clear-cut. They have a better chance of making effective policies if they admit to this uncertainty – and conduct robust research to find out more. In the following pages we have shared insights from experts in violent crime, policing, crime science, psychology and the media’s influence on the crime debate. They don’t have all the answers, but we hope they leave you better-placed to hold policymakers and commentators to account and promote a more useful discussion about crime

Long-Term Preservation of Cones and Improvement in Visual Function Following Gene Therapy in a Mouse Model of Leber Congenital Amaurosis Caused by Guanylate Cyclase-1 Deficiency

Leber congenital amaurosis (LCA) is a severe retinal dystrophy manifesting from early infancy as poor vision or blindness. Loss-of-function mutations in GUCY2D cause LCA1 and are one of the most common causes of LCA, accounting for 20% of all cases. Human GUCY2D and mouse Gucy2e genes encode guanylate cyclase-1 (GC), which is responsible for restoring the dark state in photoreceptors after light exposure. The Glicy2e(-/-) mouse shows partially diminished rod function, but an absence of cone function before degeneration. Although the cones appear morphologically normal, they exhibit mislocalization of proteins involved in phototransduction. In this study we tested the efficacy of an rAAV2/8 vector containing the human rhodopsin kinase promoter and the human GUCY2D gene. Following subretinal delivery of the vector in Glicy2e(-/-) mice, GC1 protein was detected in the rod and cone outer segments, and in transduced areas of retina cone transducin was appropriately localized to cone outer segments. Moreover, we observed a dose-dependent restoration of rod and cone function and an improvement in visual behavior of the treated mice. Most importantly, cone preservation was observed in transduced areas up to 6 months post injection. To date, this is the most effective rescue of the Glicy2e(-/-) mouse model of LCA and we propose that a vector, similar to the one used in this study, could be suitable for use in a clinical trial of gene therapy for LCA1

Dominant Cone-Rod Dystrophy: A Mouse Model Generated by Gene Targeting of the GCAP1/Guca1a Gene

Cone dystrophy 3 (COD3) is a severe dominantly inherited retinal degeneration caused by missense mutations in GUCA1A, the gene encoding Guanylate Cyclase Activating Protein 1 (GCAP1). The role of GCAP1 in controlling cyclic nucleotide levels in photoreceptors has largely been elucidated using knock-out mice, but the disease pathology in these mice cannot be extrapolated directly to COD3 as this involves altered, rather than loss of, GCAP1 function. Therefore, in order to evaluate the pathology of this dominant disorder, we have introduced a point mutation into the murine Guca1a gene that causes an E155G amino acid substitution; this is one of the disease-causing mutations found in COD3 patients. Disease progression in this novel mouse model of cone dystrophy was determined by a variety of techniques including electroretinography (ERG), retinal histology, immunohistochemistry and measurement of cGMP levels. It was established that although retinal development was normal up to 3 months of age, there was a subsequent progressive decline in retinal function, with a far greater alteration in cone than rod responses, associated with a corresponding loss of photoreceptors. In addition, we have demonstrated that accumulation of cyclic GMP precedes the observed retinal degeneration and is likely to contribute to the disease mechanism. Importantly, this knock-in mutant mouse has many features in common with the human disease, thereby making it an excellent model to further probe disease pathogenesis and investigate therapeutic interventions

Photopigment expression in ‘<i>Guca1a</i>^COD3 ‘knock-in’ mice.

<p>Representative cryosections from five month-old mice stained with DAPI and (<b>a</b>) a combined anti-L/M- and S-cone opsin antibody (red) and PNA (green), and (<b>b</b>) an anti-rhodopsin (rod opsin) antibody (red). For both, upper panels show fluorescent light micrographs, and lower panels show single slices from confocal microscopy. The expression of both cone and rod opsin appears similar in both <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice compared with wild-type littermates, although the rod opsin staining indicates a shortening of rod outer segments. PNA staining (green) in (<b>a</b>) indicates a reduced number of cones in the mutant retinae which is more pronounced in homozygous than in heterozygous mutant mice. INL inner nuclear layer, ONL outer nuclear layer, IS/OS inner segment/outer segment.</p

Electroretinography of <i>Guca1a</i>^COD3 ‘knock-in’ mice.

<p>(<b>a</b>) Representative ERG traces recorded at five months of age. Light-adapted, cone-mediated ERG (upper trace, right eye, lower trace, left eye) is reduced in <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice compared to wild-type littermates, as is the cone-mediated flicker response to 10- and 15-Hz stimuli (* and # respectively). (<b>b</b>) Representative ERG traces recorded at 12 months of age. There is a greater reduction in cone function in mutant mice, with light-adapted flash responses further attenuated and flicker responses almost extinguished. (<b>c</b>) Averaged photopic, cone-mediated b-wave amplitudes from wild-type, <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice recorded over a twelve month period from birth. There is a progressive loss of cone function over time in both heterozygous and homozygous mutant mice compared to wild-type littermates (<i>n = 8</i> per genotype). (<b>d</b>) ERG b-wave amplitudes from <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice plotted as a percentage of wild-type amplitudes over a twelve month period from birth.</p

E155G mutation in GCAP1 causes photoreceptor degeneration.

<p>Photomicrographs of resin-embedded sections from (<b>a</b>) wild-type (<b>b</b>) <i>Guca1a</i>^+/COD3, and (<b>c</b>) <i>Guca1a</i>^COD3/COD3 mice at five months of age. There is a marked thinning of the outer nuclear layer (ONL) in mutant eyes as shown by the loss of photoreceptor nuclei. There is also an apparent shortening of outer segment length, particularly in the <i>Guca1a</i>^COD3/COD3 homozygous mice. Photoreceptor loss in <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice was quantified by counting photoreceptor nuclei in photomicrographs of sections from paraffin-embedded eyes taken at fixed positions around the optic nerve. At five months of age (<b>d</b>), there is 30% loss in <i>Guca1a</i>^+/COD3 and a 46% loss in <i>Guca1a</i>^COD3/COD3 mice. At 12 months of age (<b>e</b>), this has progressed to a 32% loss in <i>Guca1a</i>^+/COD3 and a 49% loss in <i>Guca1a</i>^COD3/COD3 mice. * indicates statistical significance at the 1% probability level. Note that in the lower panels of (a), PNA shows non-cone staining above the ONL and INL. INL inner nuclear layer, ONL outer nuclear layer, IS/OS inner segment/outer segment.</p

cGMP levels in retinae of <i>Guca1a</i>^COD3 ‘knock-in’ mice.

<p>cGMP levels were measured in six week-old mice, before the onset of degeneration as evidenced by retinal structure and function. Levels of cGMP were corrected for total protein content of each sample.</p

Reduced rod function in <i>Guca1a</i>^COD3 ‘knock-in’ mice.

<p>(<b>a</b>) Representative ERG traces taken from dark-adapted 5 month-old wild-type, <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice, showing a reduction in a- and b-wave amplitude in mutant mice in the rod-dominated ERG in response to a series of increasing stimulus intensities. (<b>b</b>) Representative ERG traces taken from dark-adapted 12 month-old wild-type, <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice, showing that rod function is relatively spared when compared with cone function. (<b>c</b>) Averaged scotopic, rod-dominated b-wave amplitudes from wild-type, <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice recorded over a twelve month period from birth. Mean values were calculated from b-wave amplitudes from 100 mcds/m² flash intensity, which corresponds to a rod-only response. Note the age-related decline in wild-type mice. (<b>d</b>) Rod b-wave amplitudes in <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice plotted as a percentage of wild-type amplitudes over a twelve month period from birth.</p

Generation of <i>Guca1a</i>^COD3 ‘knock-in’ mice with E155G mutation in GCAP1.

<p>(<b>a</b>) A vector targeting the endogenous <i>Guca1a</i> locus was constructed to include an A-to-G transversion at nucleotide position 19 in exon 4 of <i>Guca1a</i> (red circle), as well as a <i>loxP</i>-flanked (blue arrow heads) neomycin resistance gene within intron 3. Following <i>Cre</i>-mediated excision of the <i>Neo</i> selectable marker, the resulting locus contained the A-to-G change in exon 4 plus a residual 34 bp <i>loxP</i> sequence in intron 3. This was used to distinguish between mutant and native alleles by PCR – the position of the primers used is indicated by the small blue arrows on the <i>Cre</i>-deleted <i>Guca1a</i> locus. (<b>b</b>) PCR amplicons from wild-type, <i>Guca1a</i>^+/COD3 and <i>Guca1a</i>^COD3/COD3 mice (lanes 3, 4 and 5 respectively), with 1 kb DNA ladder (lane 1) and no-DNA control (lane 2). The wild type allele generates a band at 734 bp whereas the mutant allele generates a 768 bp band which includes the residual intronic <i>loxP</i> sequence. Wild-type mice have therefore a single band at 734 bp, homozygous <i>Guca1a</i>^COD3/COD3 mice have a single band at 768 bp, and heterozygous <i>Guca1a</i>^+/COD3 mice have both bands. (<b>c</b>) Sequence of wild type and targeted <i>Guca1a</i> allele showing A-to-G transversion at nucleotide position 19 of exon 4.</p