Team:UCL/Practice/Essay2

UCL IGEM ETHICS REPORT

The Neuroethics and Feasibility of Genetic Engineering on the Nervous System

Medical Neuro-Genetic Engineering

The brain is the command centre. It is the seat of power presiding over functions both cognitive and autonomic and it is the site of some of the most subtle, and many of the most crippling, medical conditions, congenital or contracted. Since it is the part of us that most makes oneself one’s self, attitudes towards infringing on its natural sovereignty with GE can be expected to vary to a greater degree compared to even GMOs. It is possible that the insertion of new genetic information into brain regions, using chassis from microglia, to bacteria, to viruses, to just gene products created elsewhere in the body, to grafts of new GM neurons and stem cells, will form the basis of viable medical treatments in the near future. Our iGEM project attempts to demonstrate this. In the discussion of various uses for neuro-genetic engineering (NGE) it is generally assumed that the ease of taking the proposed treatment is proportional to severity of the condition being discussed. For example, an Alzheimer’s patient may consider brain surgery to implant chassis with genetic circuits designed to mitigate their affliction, but someone who is sleep deprived would probably not consider micro-neurosurgery, though they may well consider a tablet with a retrovirus which, through one method or another, performed NGE in their brain to cure their insomnia.

Neuro-genetic treatment’s first port of call may well be to alter neurotransmitter expression levels and sensitivity in discrete brain areas, or the whole brain, because many brain conditions manifest through their disruption. GE would be advantageous over drugs that stimulate the production of, or inhibit, the same transmitters, because it could be more finely tuned, making it more patient specific, possibly with better side effect profiles because the mode of action is more direct.

Depression is a good example. The monoamine hypothesis holds that depression results from the depletion of monoamides, such as dopamine, serotonin, noradrenalin, etc., which can be bolstered by tricyclic drugs and selective-serotonin-reuptake inhibitors (SSRIs). Depression is not generally regarded as so simple nowadays; in reality it is more an umbrella term for many pleomorphic diseases (Holzheimer and Mayberg 2011). It is a multidimensional ailment for which a complex composite GE treatment system may be very useful. It is thought that increasing monoamides may not combat depression directly, but indirectly, through the promotion of secondary neuroplasticity (Krishan and Nestler 2008). Neuroplasticity underlies our ability to learn and remember, so these faculties may experience side effects in NGE treatment which enacts longer lasting changes than the drugs. Making neuroplastic changes with medical treatments already occurs via pharmaceuticals, so more directly promoting connection changes with NGE should not pose a significant ethical concern in this area, beyond those already associated with anti-depressants even if changes in connectivity alter behaviour and cognitive abilities. If, however, NGE proves to be more pervasive and persistent in this respect, we may want to abandon it is an option because the social aim, at least, with depression treatment is to salvage a person’s personality from the confines of depression, and if we change it too drastically in the process the treatment can be seen to have failed. However removing depression is itself a drastic personality alteration, but because it is ‘pathologised’ (and rightly so) it synthetically mediated removal is not considered an ethical issue in of itself.

Some of the current general concerns with anti-depressant drug treatments would apply to NGE, but are somewhat amplified by NGE’s potential to be longer lasting and more direct. For example, anti-depressants’ use with children is often criticised as a way to easily deal with a troubled child without proper analysis as to whether their depression is clinical i.e. using it as therapy for troubled times, not to combat medical depression. There is some evidence to suggest that administering SSRIs to children leads to an increased risk of suicidal thinking (Shearer and Bermingham 2008), demonstrating the dangers of making changes in the brain even with drugs, which whose effects are more temporary than the envisioned action of NGE.

The synapse is an extremely complicated neurological formation and is key to understanding and controlling neuronal systems. It is the suspected site of dysfunction for depression and other neuropsychiatric diseases, but the high specificity and targeting required of drugs to control minute and subtle details of synaptic function is too high for modern methods to deal with. A NGE approach that changes the genetic information in the neuron itself, perhaps influencing the local mRNA or inserting new mRNA at the synapse, would allow us to make more finely tuned changes.

Such delicate and personalised management could also go a long way towards helping manage other illnesses, such as schizophrenia, bi-polar disorder and autism spectrum disorders (ASDs). These are pervasive neurodevelopmental disorders with high genetic loads (~80%), and so if NGE was implemented early to change faulty genetic information, it is possible that such an intervention could promote healthy brain development and prevent developmental brain issues occurring.

ASDs have been described as an epidemic, and although this is largely attributable to increased public awareness and diagnosis, the rising age of fathers in the Western world, with their low quality mutation prone sperm, may be effecting a real increase. Despite being a developmental disease, it has been shown that it is possible to alter the ASD disease phenotype, including Fragile X and Rett’s syndrome, in animal models using genetic techniques. Rett’s syndrome is an X-linked condition. Full homosygosity and hemizygosity is usually fatal, though girls heterozygous for an MECP2 mutation can exhibit the disease phenotype due to lyonisation, leading to autistic, cognitive and motor defects. This can be modelled in mice by inserting confounding DNA code in the MECP2 gene to produce an analogous phenotype, which, with drug mediated removal of the insertion, can restore the fit phenotype (Guy et al. 2007). In humans, of course, this would not work because the MECP2 gene is mutated, not artificially confounded by an insertion, but in principle it could be spliced out and replaced with a working gene, or a genetic circuit could be inserted to produce the functional version. It would seem that ASDs comprise one family of phenotypes, which can be induced by a number of gene mutations, though a single de novo mutation can be responsible for ASD aetiology, as suggested by the 80-90% concordance in monozygotic twins. It is possible that other ASDs are caused by similar single mutations, as in Rett’s, with the similarity in phenotypes arising because these mutations all cause synaptic dysfunction which hampers experience dependent plasticity and synaptic modulation after initial synaptogenesis (Zoghbi 2003). Such could explain why ASD children develop normally for ~6-18 months.

What would ‘fixing’ these genes mean? In the case of a condition like Rett’s syndrome, it could mean life and a far greater increase in the quality of one’s life. But in the case of adult with milder ASDs, the sudden ability to ‘correct’ neuronal function in their brain and remove even some autistic symptoms could have a fairly drastic change to their personality, something they may be very unwilling to undergo, which is why such GE interventions, if developed, should perhaps not be advertised as a ‘cure’. In fact, the autistic rights movement believes that those on the spectrum are more disadvantaged by society than by their condition, and it is a fairly common feeling amongst the ASD community that prenatal testing for autism is a form of eugenic elimination in an effort to make individuals conform to neuro-typicality. Many autistics would consider their autism of part of who they are, not an appendage to their personality but ingrained in it, and its curing less a modular removal of something unwanted, than a cleansing for a new personality. There is also the colder question of what society itself would lose by curing all ASDs. Professor Baron-Cohen notes that ‘we do not inadvertently repeat the history of eugenics or inadvertently 'cure' not just autism but the associated talents that are not in need of treatment’. The ability to see the world differently as a result of a mild pathology can be useful. Savant skills and the focused genius of some autistics may well have helped human society to develop to where it is today, perhaps stereotypically, though not exclusively, through scientific/technological innovation.

Clearly, some ASDs such as Fragile X and Rett’s are so severe, affecting both peripheral and central nervous system and having larger anatomical and cognitive effects, that they are clearly in need of treatment, something NGE may be able to offer to even older sufferers. But at which point in the spectrum do we cut it off and decide that NGE is no longer appropriate? At which point does human neuro-variation end and neuro-pathology begin? The same problem arises with other conditions, such as obsessive compulsive disorder, hyperactivity disorders, etc. This kind of distinction could be made and a cut off region identified, but it is never going to satisfy all parties, and a whole area of NGE ‘cut-off’ justification ethics would have to spring up for spectrum diseases.

But how does NGE really differ from, say, psychological and pharmacological treatment? The distinction is instinctive, perhaps because GE involves directly tampering with genetic composition and gene expression. However, our environment affects our gene expression patterns and cellular structure just as surely. For example psychological interventions in children have been shown to ease ASD symptoms by encouraging the use of, and thereby strengthening, underused prefrontal networks (Just et al. 2012) for processing higher level social situations, while pharmacological treatments stimulate epigenetic changes. The raw changes induced by NGE treatments could be largely the same, stimulating increased connectivity and the expression of the correct proteins directly in a more complete and pervasive way. This raises the point that NGE is more a means than an end, a way of ensuring changes we are already seeking to make with other types of treatment.

Bi-polar disorder is an episodic disturbance of mood into elation or depression, and much current treatment is psycho-educational, to help patients regulate the mood swings. As such, as opposed to the personality removal concerns with ASDs, NGE treatment may focus more on giving patients more autonomy over swings, or removing extremes, though how this could be achieved is unclear. Perhaps the inositol phosphate metabolism could be targeted, as the current gold standard treatment is lithium, an ion which stabilises mood by increasing the availability of important signalling molecules from this system at synapses. Such would not be seen to compromise a person’s selfhood in the same manner as NGE ASD treatments as patients already live much of their lives in a stable mental state.

Schizophrenia is a heterogeneous syndrome characterised by hallucinations, delusions, disorganized thought, catatonia, alogia, avolition and anhedonia. Daniel Weinberger postulated that imbalance between two dopaminergic systems due to connectivity issues may cause the syndrome while others believe that spurious glutamatergic activity could disrupt synapse strength. Mutations in synaptic genes and genes like DISC1 (Blackwood et al. 2001) have also been associated with schizophrenia. A NGE solution may promote the correct connections and replace incorrect with correct genes, or produce working gene products from a plasmid. Such would be much easier in pre-prodromal patients, to transfect all the correct cells and encourage all the right connections. However, there is an ethical issue in that many patients will never develop full psychoses but early intervention could drastically help those that would have. Therefore, NGE treatments take a risk; they would, if effective, help those that would go on to develop schizophrenia in their early adulthood, but may change the brains of patients that would never have developed the syndrome, to unknown effect.

In AD, neuro-degeneration results in the loss of many cholinergic neurons, and the corresponding drop in acetylcholine levels in affected networks. A NGE system that boosts acetylcholine could stall memory loss in the early stages of the disease. In AD, a protein called β-amyloid is incorrectly created in the brain cells, and nucleates and aggregate with other abnormal protein, such as some isoforms of ApoE (Strittmatter 1993), into dense plaques that distort cells in the vicinity and disrupt synapses. They are thought to engender the creation of neurofibrillary tangles in surrounding neurons. These abnormal tangles are made up of poorly soluble hyperphosphorylated isoforms of tau, a microtubule-binding protein that normally is soluble. As the cytoskeleton is vital for cell structure and transport, these abnormalities impair synaptic function and trophic support, meaning that the neuron will eventually die and leave behind the neurofibrillary tangles. The entire process may be initiated by an imbalance in BDNF and pro-NGF signalling, as older brains produce more pro-NGF due to oxidative stress. This can initiate inappropriate cell cycle re-entry, and increase AD gene dosage. With time, the plaques and tangles grow and spread, leading to neuronal death. It is theoretically possible to insert a chassis, such as a microglial cell, with a genetic circuit that tackles multiple parts of this problem, for example producing BDNF to balance signalling and a protease to disperse the plaques. It is also possible to conceive of similar systems to deal with other plaque based diseases, such as Lewy bodies in Parkinson’s disease. This is a good example of one advantage of NGE over conventional medication: one treatment can tackle many related issues through the production of multiple gene products.

The ethical implications with diseases such as AD are a little different to those of neuropsychiatric conditions. In the case of AD, we are dealing mostly with older patients, who may not greatly benefit from an (assumedly) expensive NGE procedure, or may not have the presence of mind to fully appreciate treatments that they agree to or refuse. An uninformed decision is, really, no decision at all. If the procedure must be surgical in order to insert the new genetic information, there are auxiliary medical issues to consider, with its feasibility in old age being a concern. Moreover, GMC insertion would understandably likely be seen as a last resort and used only in patients that clearly suffer from dementia. For this reason it may be quite ineffectual at stopping a disease whose progression is already profound. Therein lies another issue, because AD can only be confirmed beyond doubt post-mortem when the histopathological signs can be observed, and a NGE treatment which tackles one dementia is unlikely to have much of an effect on another form. In any event, it may not ensure enough years of quality life and have a god enough cost-benefit ratio to be seen as a viable treatment by public health bodies, such as the NHS, though it may find its market in private medicine.

The question of whether or not to treat attention deficit hyperactivity disorder (ADHD) also courts the same sorts of questions. Its pathological status is somewhat questionable, and it is clear that NGE changes that are ‘too strong’ or are higher up the ‘scale’ will be more neuro-enhancements than medical treatments. Especially in the US, stimulant drugs, such as Ritalin, and non-stimulant drugs such as atomoxetine, are already commonly used in many communities and often supported by doctors and teachers – however, diagnosis of ADHD is mainly discerned using questionnaire responses and the disorder is so relatively mild in terms of impact on peoples’ quality of life, that NGE seems like a somewhat drastic response, though this would depend upon its ease of implementation in the future. This would be more a question of therapy, than of medicine.

As this example of ADHD has demonstrated, the line between illness and health is not a clear one, and brain conditions are infamously misdiagnosed. With no real biomarkers for many mental problems, such as schizophrenia, the use of NGE to treat the illness hinges entirely upon behavioural analysis, which is more subjective, more prone to human error. Because permanent NGE could represent a drastic change, the call for its use must be solid, or we risk building a separate problem atop one that was never really there.

There has also been enough advancement in the neurochemistry of the autonomic functions the nervous system handles, to make NGE there a tantalising possibility. Sleep disorders could be cured using NGE without the need to continually take drugs. For example, narcolepsy is kept at bay with the drug modafinil, which has a variety of effects on a range of neurotransmitter systems, for instance by increasing synaptic dopamine concentrations, an effect certainly possible using NGE technology. Funding for such NGE research may well come from military bodies, because a drug that could negate sleep entirely would be of great strategic value. This is a good theoretical example of medical GE breakthroughs running into the future enhancement market, and highlights the difficulty in separating the ethical issues of medicine from commerce and politics.

Similarly, body weight could be controlled by altering the levels of appetite hormones such as leptin, ghrelin and melanocortin, encouraging the obese to eat less, but could also be used as an enhancement to help the healthy loose more weight. So doing may even compromise health, a fact which, though against the spirit of the technology, would nevertheless be an ethical counterweight to its positive medicinal applications. There are, however, very few medications currently available for weight loss so NGE, again assuming easy implementation, could be very attractive. This is the same sort of slide that brought Viagra into sale as a sexual enhancer (and indirectly responsible for that slough of annoying e-mails in your spam box) from its use to combat male erectile dysfuntion. If society decides against widespread NGE enhancements, we would have to demand and tightly enforce the ring fencing of NGE technology.

NGE technology could also reduce or eradicate pain perception in certain areas, which would be a great relief to those suffering from chronic pain. Whilst ultimately pain is of great evolutionary advantage, its eradication in a wide range of circumstances and bodily locales has long been the goal of researchers, clinicians and sufferers alike, and where pharmaceuticals have failed to find a complete pain blocker, NGE might. The genetic deletion of sodium channels Nav1.7 and NaV1.8 results in a phenotype in mice where thermal, mechanical, visceral and inflammatory pain thresholds are significantly heightened, while neuropathic pain is unaltered (Drenth and Waxman 2007). Though pain thresholds could only be estimated by behavioural changes in the mice, the study indicates that an antinociceptive NGE treatment could practically eliminate most forms of pain by targeting these genes. In humans, a nonsense mutation in SCN9A results in loss of Nav1.7’s function, and while other perceptions remain intact the mutant suffers from channelopathy-associated insensitivity to pain (CIP), body-wide, including some forms of neuropathic pain. And NGE treatment which silenced these genes in regions of neuropathic pain may be able to ease patient’s suffering, and in the case of CIP, and NGE treatment could introduce a working version of the gene (CIP greatly reduces life expectancy).

In this case, there would be serious concerns about the leakage of this technology, because while the social use of NGE to lose weight or sleep well, complete pain eradication has more potential military use, a classic component of a ‘super soldier’. Otherwise, the case with the peripheral nervous system is a little clearer cut. Because the brain is not directly involved it is like having GE treatment in any other part of the body – it is not doing to undermine personhood. Although, having said that, pain processing does occur in the CNS, at the level of the spinal cord and in the brain, where pain is actually registered and from which peripheral nerves receive descending inputs that modulate their activity. Therefore, it is not inconceivable that pain NGE technology may encroach upon the brain, bringing with it the ethical uncertainty of what this may do to the mind of a patient.

Overview