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==Gene doping==
==Gene doping==
{{Main|Gene doping}}
{{Main|Gene doping}}
Athletes might adopt gene therapy technologies to improve their performance.<ref name="Gene Doping">{{cite web|url=http://www.wada-ama.org/en/Science-Medicine/Science-topics/Gene-Doping/ |title=WADA Gene Doping |publisher=WADA |access-date=27 September 2013 |archive-url=https://web.archive.org/web/20091121094012/http://www.wada-ama.org/en/Science-Medicine/Science-topics/Gene-Doping/ |archive-date=21 November 2009 }}</ref> [[Gene doping]] is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could [[Level playing field|level the playing field]] if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.<ref>{{cite journal | vauthors = Kayser B, Mauron A, Miah A | title = Current anti-doping policy: a critical appraisal | journal = BMC Medical Ethics | volume = 8 | issue = 1 | page = 2 | date = March 2007 | pmid = 17394662 | pmc = 1851967 | doi = 10.1186/1472-6939-8-2 | doi-access = free }}</ref>
Athletes might adopt gene therapy technologies to improve their performance.<ref name="Gene Doping">{{cite web|url=http://www.wada-ama.org/en/Science-Medicine/Science-topics/Gene-Doping/ |title=WADA Gene Doping |publisher=WADA |access-date=27 September 2013 |archive-url=https://web.archive.org/web/20091121094012/http://www.wada-ama.org/en/Science-Medicine/Science-topics/Gene-Doping/ |archive-date=21 November 2009 }}</ref> [[Gene doping]] is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could [[Level playing field|level the playing field]] if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.<ref>{{cite journal | vauthors = Kayser B, Mauron A, Miah A | title = Current anti-doping policy: a critical appraisal | journal = BMC Medical Ethics | volume = 8 | issue = 1 | page = 2 | date = March 2007 | pmid = 17394662 | pmc = 1851967 | doi = 10.1186/1472-6939-8-2 | doi-access = free }}</ref> Therefore, this technology, which is a subfield of genetic engineering commonly referred to as gene doping in sports, has been prohibited due to its potential risks.<ref>John R, Dhillon MS, Dhillon S. Genetics and the Elite Athlete: Our Understanding in 2020. Indian J Orthop. 2020 Mar 11;54(3):256-263. doi: 10.1007/s43465-020-00056-z. PMID: 32399143; PMCID: PMC720592.</ref>


İn a study,from history to today, human beings have always been in competition. While in the past warriors competed to be stronger in wars, today there is competition to be successful in every field, and it is understood that this psychology is a phenomenon that has always existed in human history until today. It is known that although an athlete has genetic potential, he cannot become a champion if he does not comply with the necessary training and lifestyle. However, as competition increases, both more physical training and more mental performance are needed. Just as warriors in history used some herbal cures to look stronger and more aggressive, it is a fact that today, athletes resort to doping methods to increase their performance. However, this situation is against sports ethics because it does not comply with the morality and understanding of the game.<ref>{{cite journal |vauthors=Wells DJ
İn a study,from history to today, human beings have always been in competition. While in the past warriors competed to be stronger in wars, today there is competition to be successful in every field, and it is understood that this psychology is a phenomenon that has always existed in human history until today. It is known that although an athlete has genetic potential, he cannot become a champion if he does not comply with the necessary training and lifestyle. However, as competition increases, both more physical training and more mental performance are needed. Just as warriors in history used some herbal cures to look stronger and more aggressive, it is a fact that today, athletes resort to doping methods to increase their performance. However, this situation is against sports ethics because it does not comply with the morality and understanding of the game.<ref>{{cite journal |vauthors=Wells DJ

Revision as of 20:33, 19 December 2023

An illustration of viral vector-mediated gene transfer using an adenovirus as the vector

Human genetic enhancement or human genetic engineering refers to human enhancement by means of a genetic modification. This could be done in order to cure diseases (gene therapy), prevent the possibility of getting a particular disease[1] (similarly to vaccines), to improve athlete performance in sporting events (gene doping), or to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. These genetic enhancements may or may not be done in such a way that the change is heritable (which has raised concerns within the scientific community).[2]

Gene therapy

Further information: Gene therapy

Genetic modification in order to cure genetic diseases is referred to as gene therapy. Many such gene therapies are available, made it through all phases of clinical research and are approved by the FDA. Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in phase I.[3] As of 2017, Spark Therapeutics' Luxturna (Adeno associated viral vector based gene therapy for RPE65 mutation-induced blindness) and Novartis' Kymriah (Chimeric antigen receptor T cell therapy) are the FDA's first approved gene therapies to enter the market. Since that time, drugs such as Novartis' Zolgensma and Alnylam's Patisiran have also received FDA approval, in addition to other companies' gene therapy drugs. Most of these approaches utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions, in vivo and ex vivo, respectively. ASO / siRNA approaches such as those conducted by Alnylam and Ionis Pharmaceuticals require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of GalNAc transporters. In addition, a CRISPR gene therapy approach has been approved for the first time by FDA. Casgevy is a cell based gene therapy which utilizes CRISPR/Cas9 technology to treat patients with sickle-cell disease[4].

Gene therapy and chronic disease treatments frequently depend on viral vector delivery systems such as adeno-associated virus AAV, adenovirus Ad, and lentivirus LV, which are known for their capacity to efficiently introduce genes and maintain stable expression. However, these systems face complications like immunogenicity, cost, specificity limitations, and the fact that one vector may not be suitable for all applications. Nonetheless, by employing appropriate engineering techniques and conducting thorough preclinical and clinical studies these obstacles can be overcome.[5][6]

To address some of these limitations, scientists have created Bioorthogonal Engineered Virus-Like Nanoparticles, known as reBiosomes. These nanoparticles have strong and rapid binding capabilities to LDL receptors on cell surfaces, allowing them to enter cells efficiently. Furthermore, reBiosomes reduce immunogenicity, increase blood circulation time, and improve gene delivery to specific target areas such as tumor and arthritic tissues, which have weakly acidic environments. As a result, these genetically modified virus-like nanoparticles hold promise for effective gene therapy in major diseases like cancer and inflammatory conditions. They may provide a potential solution to the issues associated with traditional viral vectors.[7]

AAV-based therapies have been extensively developed in the past few years for the treatment of a variety of complicated diseases, including Danon disease, a rare genetic disease caused by a mutation in the LAMP2 gene that results in downregulation of Lysosome-Associated Membrane Protein 2 (LAMP2) and thus deteriorated autophagy. One of the most demanding features of Danon disease is the rapidly progressive hypertrophic cardiomyopathy, which is the primary impetus for the ongoing significant research into potential treatments. Intravenous infusion of RP-A501, an AAV9-expressing LAMP2B, was efficacious in rectifying LAMP2 expression in myocardial tissues, resulting in normalized anatomical structures of the heart and enhanced exercise tolerance. Furthermore, the US Food and Drug Administration recognized RP-A501 as a novel therapy, and its second phase of clinical studies commenced in the second quarter of 2023.[8]

A further approach attempts to restore normal auditory function in neonatal mice by delivering vGlut3 cDNA into the inner ear of vGLut3-knockout mice via the Round Window Membrane (RWM) technique. Although this approach has succeeded in mice, it is not ideal for humans since vGlut3 mutations are linked to a rare kind of hearing loss known as hidden hearing loss (HHL). Furthermore, considering this condition is inherited in an autosomal dominant manner, gene replacement is not a feasible option. Rather, targeting some dominant HHL variants, such as KCNQ4 and EYA4, has promise for restoring hearing in humans[9]

Zilebesiran is an intriguing RNA interference-based therapy that depends on the subcutaneous administration of GalNAC-associated siRNA once every six months. The GalNAC tags on these siRNAs guide them to hepatocytes, where they block the production of angiotensinogen proteins through the degradation of angiotensinogen-encoding mRNA. Clinical trials on hypertensive patients proved a substantial dose-dependent reduction in both systolic and diastolic blood pressures over an extended period, with no adverse side effects other than a mild reaction at the injection site. Clinical trials are currently ongoing, and the emerging results are promising. However the constant suppression of the RAS system is a significant restriction of this therapy because it poses an immense risk to patients during situations of emergency such as severe hypotension, hypovolemia, and septic shock. In these circumstances, vasopressors such as norepinephrine and fludrocortisone are essential to overcome this issue.[10]

Since the discovery of the CRISPR-Cas9 system between 2010 and 2012, scientists have been able to alter genes by making specific breaks in their DNA. This technology has many uses, including genome editing and molecular diagnosis. However, one disadvantage is that it may result in nonspecific modifications at off-target sites.[11]

There are multiple approaches for identifying and assessing CRISPR-Cas9 off-target effects, which includes in silico prediction and laboratory experiments such as cell-free and cell culture-based methods. While the first two methods can be costly, the third method, known as in vivo detection, allows for immediate assessment of off-target effects in living tissue.[12]

To improve on Cas9's drawbacks, such as off-target editing, scientists developed an improved version called "eeCas9: efficiency-enhanced Cas9 " that enhances the editing activity of Cas9. Interestingly, when compared to the original Cas9, this modified version eeCas9 exhibited significantly reduced off-target editing rates.[13]

Ethics

Genetic engineering is a topic of moral debate among bioethicists. Even though the technological advancements in this field present exciting prospects for biomedical improvement, it also prompts the need for ethical, societal, and practical assessments to understand its impact on human biology, evolution, and the environment. Genetic testing, genetic engineering, and stem cell research are often discussed together due to the interrelated moral arguments surrounding these topics. The distinction between repairing genes and enhancing genes is a central idea in many moral debates surrounding genetic enhancement because some argue that repairing genes is morally permissible, but that genetic enhancement is not due to its potential to lead to social injustice through discriminatory eugenics initiatives.[14]

Moral questions related to genetic testing are often related to duty to warn family members if an inherited disorder is discovered, how physicians should navigate patient autonomy and confidentiality with regard to genetic testing, the ethics of genetic discrimination, and the moral permissibility of using genetic testing to avoid causing seriously disabled persons to exist, such as through selective abortion.[14]

Ethical issues related to gene therapy and human genetic enhancement concern the medical risks and benefits of the therapy, the duty to use the procedures to prevent suffering, reproductive freedom in genetic choices, and the morality of practicing positive genetics, which includes attempts to improve normal functions.[14]

In every genetic based study conducted for humanity, studies must be carried out in accordance with the ethics committee approval statement, ethical, legal norms and human morality. CAR T cell therapy, which is intended to be a new treatment. aims to change the genetics of T cells and transform immune system cells that do not recognize cancer into cells that recognize and fight cancer. it works with the T cell therapy method which is arranged with palindromic repeats at certain short intervals called with CRISPR.[15]

All research involving human subjects in healthcare settings must be registered in a public database before the recruitment of the first trial. The informed consent statement should include adequate information about possible conflicts of interest, the expected benefits of the study, its potential risks, and other issues related to the discomfort it may involve.[16]

Technological advancements are play integral role to new forms of human enhancement. While phenotypic and somatic interventions for human enhancement provide noteworthy ethical and sociological dilemmas, germline heritable genetic intervention necessitates even more comprehensive deliberations at the individual and societal levels.[17]

Moral judgments are empirically based and entail evaluating prospective risk-benefit ratios, with the goal of maximizing the latter and decreasing the former, particularly in the field of biomedicine. It is essential to take into account the variety of potential outcomes. The technology of CRISPR genome editing raises ethical questions for a several reasons. To be more specific, concerns exist regarding the capabilities and technological constraints of CRISPR technology. Furthermore, the long-term effects of the altered organisms and the possibility of the edited genes being passed down to succeeding generations and having unanticipated effects are two further issues to be concerned about. Making accurate predictions regarding the future of an edited organism and assessing potential dangers and advantages may be challenging owing to the some technological limits and also the complexity of the biological systems. Hence, decision-making on morality becomes more difficult when uncertainty from these circumstances prevents appropriate risk/benefit assessments. Last but not least, the skeptical position holds that the intricate connection between genetic information and bodily phenotypes is not fully known, even in the event that the genome is altered as anticipated and the intended functional output is attained at the appropriate moment. Therefore, depending on the situation, the biological impact of altering a gene in germline and/or somatic cells may not be evident.[18]

The potential benefits of revolutionary tools like CRISPR are endless. For example, because it can be applied directly in the embryo, CRISPR/Cas9 reduces the time required to modify target genes compared to gene targeting technologies that rely on the use of embryonic stem (ES) cells. Bioinformatics tools developed to identify the optimal sequences for designing guide RNAs and optimization of experimental conditions have provided very robust procedures that guarantee the successful introduction of the desired mutation[19]. Major benefits are likely to develop from the use of safe and effective HGGM, making a precautionary stance against HGGM unethical.[20]

Going forward, many people support the establishment of an organization that would provide guidance on how best to control the ethical complexities mentioned above. Recently, a group of scientists founded the Association for Responsible Research and Innovation in Genome Editing (ARRIGE) to study and provide guidance on the ethical use of genome editing.[21].[22]

In addition, Janasoff and Hurlbut have recently advocated for the establishment and international development of an interdisciplinary "global observatory for gene regulation".[23]

Researchers proposed that debates in gene editing should not be controlled by the scientific community. The network is envisioned to focus on gathering information from dispersed sources, bringing to the fore perspectives that are often overlooked, and fostering exchange across disciplinary and cultural divides.[24].

The interventions aimed at enhancing human traits from a genetic perspective are emphasized to be contingent upon the understanding of genetic engineering, and comprehending the outcomes of these interventions requires an understanding of the interactions between humans and other living beings. Therefore, the regulation of genetic engineering underscores the significance of examining the knowledge between humans and the environment. [25]

To cope with the ethical challenges and uncertainties arising from genetic advancements, it has been emphasized that the development of comprehensive guidelines based on universal principles is essential. The importance of adopting a cautious approach to safeguard fundamental values such as autonomy, global well-being, and individual dignity has been elucidated when overcoming these challenges.[26]

When contemplating genetic enhancement, genetic technologies should be approached from a broad perspective, using a definition that encompasses not only direct genetic manipulation but also indirect technologies such as biosynthetic drugs. It has been emphasized that attention should be given to expectations that can shape the marketing and availability of these technologies, anticipating the allure of new treatments. These expectations have been noted to potentially signify the encouragement of appropriate public policies and effective professional regulations. [27]

Clinical stem cell research must be conducted in accordance with ethical values. This entails a full respect for ethical principles, including the accurate assessment of the balance between risks and benefits, as well as obtaining informed and voluntary participant consent. The design of research should be strengthened, scientific and ethical reviews should be effectively coordinated, assurance should be provided that participants understand the fundamental features of the research, and full compliance with additional ethical requirements for disclosing negative findings has been addressed. [28]

Clinicians have been emphasized to understand the role of genomic medicine in accurately diagnosing patients and guiding treatment decisions. It has been highlighted that detailed clinical information and expert opinions are crucial for the accurate interpretation of genetic variants. While personalized medicine applications are exciting, it has been noted that the impact and evidence base of each intervention should be carefully evaluated. The human genome contains millions of genetic variants, so caution should be exercised and expert opinions sought when analyzing genomic results. [29]

Disease prevention

Main article: Preventive healthcare
Further information: DNA immunization
See also: Immunocompromisation

Some people are immunocompromised and their bodies are hence much less capable of fending off and defeating diseases (i.e. influenza, ...). In some cases this is due to genetic flaws[clarification needed] or even genetic diseases such as SCID. Some gene therapies have already been developed or are being developed to correct these genetic flaws/diseases, hereby making these people less susceptible to catching additional diseases (i.e. influenza, ...).[30]

In November 2018, Lulu and Nana were created.[31] By using clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9, a gene editing technique, they disabled a gene called CCR5 in the embryos, aiming to close the protein doorway that allows HIV to enter a cell and make the subjects immune to the HIV virus.

Gene doping

Main article: Gene doping

Athletes might adopt gene therapy technologies to improve their performance.[32] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[33] Therefore, this technology, which is a subfield of genetic engineering commonly referred to as gene doping in sports, has been prohibited due to its potential risks.[34]

İn a study,from history to today, human beings have always been in competition. While in the past warriors competed to be stronger in wars, today there is competition to be successful in every field, and it is understood that this psychology is a phenomenon that has always existed in human history until today. It is known that although an athlete has genetic potential, he cannot become a champion if he does not comply with the necessary training and lifestyle. However, as competition increases, both more physical training and more mental performance are needed. Just as warriors in history used some herbal cures to look stronger and more aggressive, it is a fact that today, athletes resort to doping methods to increase their performance. However, this situation is against sports ethics because it does not comply with the morality and understanding of the game.[35]

Other uses

Other hypothetical gene therapies could include changes to physical appearance, metabolism, mental faculties such as memory and intelligence, and well-being (by increasing resistance to depression or relieving chronic pain, for example).[36][37]

Physical appearance

See also: Morphological freedom

Some congenital disorders (such as those affecting the muscoskeletal system) may affect physical appearance, and in some cases may also cause physical discomfort. Modifying the genes causing these congenital diseases (on those diagnosed to have mutations of the gene known to cause these diseases) may prevent this.

Also changes in the myostatin gene[38] may alter appearance.

Behavior

Further information: Behavioural genetics and Genetics of aggression

Significant quantitative genetic discoveries were made in the 1970s and 1980s, going beyond estimating heritability. However, issues such as The Bell Curve resurfaced, and by the 1990s, scientists recognized the importance of genetics for behavioral traits such as intelligence. The American Psychological Association's Centennial Conference in 1992 chose behavioral genetics as a theme for the past, present, and future of psychology. Molecular genetics synthesized, resulting in the DNA revolution and behavioral genomics, as quantitative genetic discoveries slowed. Individual behavioral differences can now be predicted early thanks to the behavioral sciences' DNA revolution. The first law of behavioral genetics was established in 1978 after a review of thirty twin studies revealed that the average heritability estimate for intelligence was 46%.[39] Behavior may also be modified by genetic intervention.[40] Some people may be aggressive, selfish, and may not be able to function well in society. Mutations in GLI3 and other patterning genes have been linked to HH etiology, according to genetic research. Approximately 50%-80% of children with HH have acute wrath and violence, and the majority of patients have externalizing problems. Epilepsy may be preceded by behavioral instability and intellectual incapacity.[41] There is currently research ongoing on genes that are or may be (in part) responsible for selfishness (e.g. ruthlessness gene), aggression (e.g. warrior gene), altruism (e.g. OXTR, CD38, COMT, DRD4, DRD5, IGF2, GABRB2[42])

There has been a great anticipation of gene editing technology to modify genes and regulate our biology since the invention of recombinant DNA technology. These expectations, however, have mostly gone unmet. Evaluation of the appropriate uses of germline interventions in reproductive medicine should not be based on concerns about enhancement or eugenics, despite the fact that gene editing research has advanced significantly toward clinical application.[43]

Cystic fibrosis (CF) is a hereditary disease caused by mutations in the Cystic fibrosis transmembrane conductance regulator (CFTR) gene. While 90% of CF patients can be treated, current treatments are not curative and do not address the entire spectrum of CFTR mutations. Therefore, a comprehensive, long-term therapy is needed to treat all CF patients once and for all. CRISPR/Cas gene editing technologies are being developed as a viable platform for genetic treatment.[44] However, the difficulties of delivering enough CFTR gene and sustaining expression in the lungs has hampered gene therapy's efficacy. Recent technical breakthroughs, including as viral and non-viral vector transport, alternative nucleic acid technologies, and new technologies like mRNA and CRISPR gene editing, have taken use of our understanding of CF biology and airway epithelium.[45]

Human gene transfer has held the promise of a lasting remedy to hereditary illnesses such as cystic fibrosis (CF) since its conception and use. The emergence of sophisticated technologies that allow for site-specific alteration with programmable nucleases has greatly revitalized the area of gene therapy.[46] There is some research going on on the hypothetical treatment of psychiatric disorders by means of gene therapy. It is assumed that, with gene-transfer techniques, it is possible (in experimental settings using animal models) to alter CNS gene expression and thereby the intrinsic generation of molecules involved in neural plasticity and neural regeneration, and thereby modifying ultimately behaviour.[47]

In recent years, it was possible to modify ethanol intake in animal models. Specifically, this was done by targeting the expression of the aldehyde dehydrogenase gene (ALDH2), lead to a significantly altered alcohol-drinking behaviour.[48] Reduction of p11, a serotonin receptor binding protein, in the nucleus accumbens led to depression-like behaviour in rodents, while restoration of the p11 gene expression in this anatomical area reversed this behaviour.[36]

Recently, it was also shown that the gene transfer of CBP (CREB (c-AMP response element binding protein) binding protein) improves cognitive deficits in an animal model of Alzheimer's dementia via increasing the expression of BDNF (brain-derived neurotrophic factor).[49] The same authors were also able to show in this study that accumulation of amyloid-β (Aβ) interfered with CREB activity which is physiologically involved in memory formation.

In another study, it was shown that Aβ deposition and plaque formation can be reduced by sustained expression of the neprilysin (an endopeptidase) gene which also led to improvements on the behavioural (i.e. cognitive) level.[50]

Similarly, the intracerebral gene transfer of ECE (endothelin-converting enzyme) via a virus vector stereotactically injected in the right anterior cortex and hippocampus, has also shown to reduce Aβ deposits in a transgenic mouse model of Alzeimer's dementia.[51]

There is also research going on on genoeconomics, a protoscience that is based on the idea that a person's financial behavior could be traced to their DNA and that genes are related to economic behavior. As of 2015, the results have been inconclusive. Some minor correlations have been identified.[52][53]

Some studies show that our genes may affect some of our behaviors. For example, some genes may follow our state of stagnation, while others may be responsible for our bad habits. To give an example, the MAOA (Mono oxidase A) gene, the feature of this gene affects the release of hormones such as serotonin, epinephrine and dopamine and suppresses them. It prevents us from reacting in some situations and from stopping and making quick decisions in other situations, which can cause us to make wrong decisions in possible bad situations. As a result of some research, mood states such as aggression, feelings of compassion and irritability can be observed in people carrying this gene. Additionally, as a result of research conducted on people carrying the MAOA gene, this gene can be passed on genetically from parents, and mutations can also develop due to later epigenetic reasons. If we talk about epigenetic reasons, children of families growing up in bad environments begin to implement whatever they see from their parents. For this reason, those children begin to exhibit bad habits or behaviors such as irritability and aggression in the future.[54]

Military

In 2022, the People's Liberation Army Academy of Military Sciences reported that a team of military scientists inserted a gene from the tardigrade into human embryonic stem cells in an experiment with the stated possibility of enhancing soldiers' resistance to acute radiation syndrome to survive nuclear fallout.[55]

Databases about potential modifications

George Church has compiled a list of potential genetic modifications based on scientific studies for possibly advantageous traits such as less need for sleep, cognition-related changes that protect against Alzheimer's disease, disease resistances, higher lean muscle mass and enhanced learning abilities along with some of the associated studies and potential negative effects.[56][57]

See also

References

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