Team:UCL/Practice/Essay1

UCL IGEM ETHICS REPORT

The Neuroethics and Feasibility of Genetic Engineering on the Nervous System

Introduction

Our project deals with an idea which may seem, on the face of it, frightening to some; the insertion of modified brain cells, microglia, to try and alleviate Alzheimer’s disease (AD). Although more similar to a macrophage than a neuron, engineering microglial cells represents both a neuroscientific and a neuroethical challenge, not least because it seems like the stuff of zombie B-movies. In the interests of assessing the feasibility of the project in social terms, we are producing this report dealing with the potential use, and ethics of the use, of genetic engineering (GE) on the nervous system, as well as expounding a little on some of the scientific concepts behind various approaches. We felt that the ethics of the issues raised are best analysed in light of the science behind the various neuroscientific applications of GE, and so we present them together.

Synthetic Biology and Medicine

Synthetic biology is a broad and expanding discipline in which biological systems are modified on the genetic level to engineer new structures and functions of benefit to human kind, be that in the realms of industry, or art, or medicine, etc. Genetic engineering (GE) purports to improve our understanding of the mechanism of pathologies, create better diagnostic tools and even open up whole new ranges of methods with which to tackle human diseases, from cancer to neurodegenerative conditions. The later may be achieved via the cheap, efficient production of drugs, particularly gene products which can be administered therapeutically, or even through the insertion of genetically modified organisms (GMOs) or genetically modified host cells (GMCs) into the body, where they can produce proteins in situ and employ complex systems to tackle disease-state targets accurately and effectively. The ability to insert a synthetic genome in a chassis to the site of pathology in the human body could allow for specific drug delivery, synthesis and activation, and following a bottom-up approach help usher in an era of highly personalised medicine.

However, from its conception, the idea of engineering bacteria, let alone human cells, has met with opposition from people of many different beliefs and backgrounds for a variety of reasons, though even those who stalwartly defend GMOs in other arenas may be cautious with about their use in humans, in vivo. Opponents’ arguments vary from religious to safety concerns, especially over the malevolent potential of this Promethean technology and the possibility of unintended negative fallout, despite the fact that the use of biotechnology is already common place in medicine. In fiction, for example, GE is often portrayed as a part of some dystopia. The use of GE in medicine is entangled with engrained social values and politics, and therefore necessitates the participation of the extended patient community as well as academic experts and medical practioners in the field. Generally, scientists from all fields view GE more favourably than laymen, and tend to view the issues at hand in a more teleological fashion as opposed to the deontological outlook more prominent in the public, who express with greater frequency moral, spiritual and cultural unease (Small 2009).

It is important to clarify that we are talking here about intervening with GE technology at the post-natal stage, and that this discussion is not at all about ‘designer babies’ for any purpose. Specifically, we are interested in assessing the ethics of GMO/GMC insertion and neuro-genetic engineering (NGE). One of the first things we must accept, then, when considering GMO and GMC solutions, is that they will tend to suffer from the same social pitfalls that plague conventional medicine, in that they take responsibility away from the patient. These therapies would promise minimal lifestyle changes in favour of a non-preventative treatment that cures the ailment so those lifestyle choices can endure. Of course, in the case of cancer or AD, for example, there’s little (though not nothing) a patient can do to completely avoid its contraction and progression in terms of life style changes. Diseases such as these offer the most germane targets generally, given their public profile. Infamous conditions will tend to be able to demand more controversial treatment, and sway public opinion, purely due to their social profile, perhaps as a case of GE being seen as the lesser evil.

We could talk at great length about the use of GE across the human body, but in the interests of time it is best that we focus upon the insertion of GMOs for medicinal purposes, as this is less explored than general GE concerns in medicine and is directly relevant to our project. The idea of consuming GE ‘bugs’ is unsettling for many, as it poses risks to the integrity of human genetic systems as well as the possibility that a putative cure could become a new and formidable pathogen of science fictional proportions.

One of the most obvious uses of invasive GMOs in medicine is in cancer treatment. The activity and action of many a drug is constrained by metabolic limitations and drug delivery often suffers from lack of selectivity, which in cancer can lead to the death of non-cancerous cells. The use of bacteria to target cancer cells, given their anaerobic properties and ability to migrate through the body, is already an active area of research (Che-Hsin Lee 2011). Anaerobic bacteria grow and multiply in the vicinity of cancer cells, because they provide a low oxygen environment. Cell death may be induced by bacterial accumulation (Che-Hsin Lee 2011), but the ‘hunter-seeker’ ability of bacterial tumour killers could be greatly improved by synthetic biology techniques, which could increase their selectivity and cancer lethal potency. This could be achieved by making them express the correct binding proteins to latch onto certain cancerous cell types and to produce effective killing agents at the tumour site after a detection mechanism triggers their release. Because bacteria can proliferate around a tumour, their attack can be sustained and remain persistent for much longer periods of time than pharmaceuticals.

Such an application of inserted GE cells differs greatly from our project’s proposal to insert re-engineered microglial cells into the brain because it can be used in ‘ethically neutral’ tissue. That is to say, for example, that there is no intrinsic problem with manipulating the breasts to fight breast cancer, hence surgical interventions are common. However, even with this far more basic building block on the way to what our project posits has a serious ethical concerns. One of the first that springs to mind is safety. Most such GE constructs will have an engineered ‘kill-switch’ that induces the death of the cell in response to a certain signal or condition, for example temperature, a particular drug, radiation, etc. This can stop the genetically modified (GM) bacteria in a patient’s body from going out of control. Yet there is always a risk, however slight, that random mutations in bacterial DNA will overcome the kill-switch by chance, or that the switch will be ineffective for other reasons. There is also an issue of transfection; if the new genes inserted into the bacteria could transfer from bacterium to host and alter human genetic content, it may cause genetic disease – though since this could generally only effect somatic cells and not enter the germline, it is not heritable and in most cases would only persist as long as those affected cells survive. However, the distinction may not always be clear for the general public, for which the idea of gene transferral seems frightening.

The ethics here, then, may be more to do with fear than anything else. It is important to keep the public, primarily potential recipients of GM cell insertion treatments, informed on biology, including genetics and synthetic biology. Education is often seen as key to advancing patient-doctor interaction, but synthetic biology is all but completely overlooked in hospital education initiatives. This is because, while the field promises much, it has produced very little that can be brought into medicine. However, because it may one day deliver big time on its promises, we need to have a population capable of at least vaguely understanding technology that otherwise would seem more frightening.

One commonly touted argument against GE is that it is unnatural, and therefore a morally wrong practice to undertake. Those that adhere to this view would understandably be extremely concerned about being the host to millions of GM vassals, even if these cells are trying to dissolve tumours. Here, we have two underlying assumptions, one philosophical one ethical; genetic engineering is unnatural, what is biologically unnatural compromises the ‘sanctity of life’ and is therefore morally wrong.

If we take ‘nature’ to comprise, as John Stuart Mill defines it, ‘a collective name for everything that is’ (Mill 1904), GM cannot be unnatural, or ‘everything which is of itself, without voluntary human intervention’, in which case GM is no more unnatural than human thought (Vogel 1996). Scientifically, one could argue that genetic engineering is not, per se, unnatural, because evolution involves the rearrangement of gene motifs into shifting patchworks of genetic information that alter the phenotype of an organism simply through genes being differently positions or spliced and appended to generate new protein forms. Some cell types can undergo extensive genome reconfiguration within a few generations (Shapiro 1992). In other words, biochemical systems within cells naturally perform genetic engineering in order to evolve. Without this understanding, conventional evolutionary theory struggles to explain molecular genetics.

Yet, people do make distinctions between things that are not really synthetic and what they perceive as a more ‘natural’ version. For example, organic farm produce is often considered more ‘natural’, and contraceptive pills are considered ‘unnatural’. These brandings colour and reflect the moral stances people have on these issues. But is ‘natural’ simply an aesthetic and somewhat romantic tag? Not necessarily, biological nature is often felt to define the boundaries of human action, and in the case of other creatures comprise and arena of autonomy in which they can act and that must not be interfered with or otherwise adjusted by GM, as nature must ‘live and grow by itself’ (Verhoog et al 2003).

In the case of inserting GMCs/GMOs, we are impinging on this autonomy as well as expanding human action into ‘nature’. However, if feels very unscientific to treat nature as a distinct ‘otherness’ opaque to human understanding. Its ‘opaqueness’ is simply a product of the difference of opinion between those that are willing to analyse nature and those that are not. In the case of inserting GMOs/GMCs, the human is not genetically modified, only the therapeutic cellular agents. However, the consequences of any technology is a derivative of its intrinsic nature and the context of its use, this context being the human body. GMC/GMO insertion is particularly open to being deemed unnatural, because the synthetic cell will commonly contain genes not native to its own species and the insertion and growth encouragement the host cells receive could be ‘unnatural’, even without the GM, by because its receptor environment could be out of its indigenous range. Brian Goodwin proposed instead a conception of organisms as dynamic wholes, in which genes impact a cell’s development via the proteins they produce, and so do not on their own determine particular features of the organism (Goodwin 1994) but utterly depend on protein-protein interaction. Therefore, the consequence of transferring information from one organism to another, both in terms of inserting genes into GMCs/GMOS and inserting these cells themselves into human patients, is inherently unpredictable, because predicting protein-protein interactions is an un-mastered science. Perhaps this uncertainty is what people instinctively mean when they brand GM ‘unnatural’.

GMOs/GMCs are also ‘unnatural’ because they contain gene combinations that are so unlikely to arise in nature that they are effectively impossible outside the laboratory. They may also contain genes from other species that originate from entirely different domains and kingdoms of life. There are protestations that this technology can create ‘unnatural’ and undo ‘natural’ species, so that released GM cells, be they in the body or the wider natural environment, may damage delicate ecosystems and biodiversity (on an organismal or cellular level). However, ‘species’ are dynamic, genetic-boundary-less populations that constantly undergo genetic change (Straughan 1999), unintelligibly dividing into different species to varying degrees of genetic, ecological and geographic separation. Therefore, while GE technology may not need to overly concern itself with changing the nature of species, the impact of releasing GM entities is a very real danger. Kill-switches for organisms/cells inserted into the body should ensure that they do not become some sort of dominant life form in the body’s microbial ecosystems, but as discussed before, there are no absolute guarantees kill switches will be consistently effective.

The word ‘synthetic’ is, after all, in the name ‘synthetic biology’, so if we accept that GE is ‘unnatural’ at least as regards public perception, the next question is why is being unnatural bad or even amoral? In the context of applying GM to humans or the human environment, it is often said by opponents that GM compromises the ‘sanctity of life’. This was originally a concept of the Abrahamic religions that symbolised the unique holiness endowed upon human life because we share something of it with God. Genesis says that God created Adam as He ‘breathed into his nostrils the breath of life’ (Genesis 2:7). It has since evolved into a non-religion specific idea of human dignity that suggests human life is in some way special as compared to the rest of nature and not to be interfered with, or, alternatively, that human life epitomises the natural vs. synthetic distinction. However, many opponents of GM tend to use the phrase as a ‘culture wars slogan’ (Gushee 2006). Rationalised and de-relgionised, it is a moral conviction dictating how human life ought to be perceived and treated, a useful and progressive distinction in law for example, but perhaps a less useful one in science where the bioethical issues are more complex and viewing humans as immutable biological entities is not particularly helpful. At any rate, in the GE debate, the ‘sanctity of life’ is more of a fence sitter than anything as one might equally, rationally argue that not pursuing GE technologies compromises the sanctity of life as we fail to exploit an avenue to save lives, even if doing so may change it in somewhat disconcerting ways.

Another ethical worry with inserting GMOs/GMCs is that of ownership and patency. Could genetic circuit constructs, the sequences of genes added to otherwise ‘natural’ cells, be patented? Can genes of any organism be owned, whether entirely or as a certain component in a circuit? Should they? These are perhaps more practical and germane questions for synthetic biology. Being able to patent gene systems could boost failing industry interest in medical conditions, such as AD, for which pharmaceuticals have made little headway. There are many fears over the power of pharmaceutical and biotech companies, especially in terms of access to research and results, and any monopolisation on synthetic biological treatments that use inserted GM cells could come to exemplify C.S Lewis’ statement ‘What we call man's power over nature turns out to be a power exercised by some men over other men with nature as its instrument’ (Lewis 1947).

In summary, seeing GE as morally acceptable depends upon not seeing nature as a model to which we must conform. In terms at least of inserting GMCs and GMOs, the technology is not itself ethically neutral and this prematurely colours views on its applications. Because we are talking about medicine, when making decisions on bioethicality we must weigh this technology’s future potential to save lives against its potential to undermine some innate human dignity. Pitted against one another, I would hope that society would place its support behind furthering synthetic biology in medicine because it could one day be such an asset, and not limit medical progress to the confines of some especially amorphous philosophy of life, no matter how exalted and pertinent that philosophy is in the rest of modern human culture.

Overview