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]

Genetics is the study of genes and inherited traits and while the ongoing advancements in this field have resulted in the advancement of healthcare at multiple levels, ethical consideration have become increasingly crucial especially alongside. Genetic engineering has always been a topic of moral debate among bioethicists.^[3] 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.^[4] 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.^[5]

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.^[5][6][7]

The responsibility of public health professionals is to determine potential exposures and suggest testing for communicable diseases that require reporting. Public health professionals may encounter disclosure concerns if the extension of obligatory screening results in genetic abnormalities being classified as reportable conditions.^[8] Genetic data is personal and closely linked to a person's identity. Confidentiality concerns not only work, health care, and insurance coverage, but a family's whole genetic test results can be impacted. Affected individuals may also have their parents, children, siblings, sisters, and even extended relatives if the condition is either genetically dominant or carried by them. Moreover, a person's decisions could change their entire life depending on the outcome of a genetic test. Results of genetic testing may need to be disclosed in all facets of a person's life.^[8][9]

Non-invasive prenatal testing (NIPT) has the capability to accurately determine the sex of the fetus at an early stage of gestation, raising concerns about the potential facilitation of sex-selective termination of pregnancy (TOP) due to its ease, timing, and precision. Even though the ultrasound technology has the capacity to do the same, NIPT is being explored recently because of it capability to accurately identify the fetus's sex at an early stage in the pregnancy is achievable, with increasing precision as early as 7 weeks' gestation. This timeframe precedes the typical timing for other sex determination techniques, such as ultrasound or chorionic villus sampling (CVS).^[10][11] The high early accuracy of NIPT reduces the uncertainty associated with other methods, such as the aforementioned, leading to more informed decisions and eliminating the risk of inaccurate results that could influence decision-making regarding sex-selective TOP. Additionally, NIPT enables sex-selective TOP in the first trimester, which is more practical, and allows pregnant women to postpone maternal-fetal bonding. These considerations may significantly facilitate the pursuit of sex-selective TOP when NIPT is utilized. Therefore, it is crucial to examine these ethical concerns within the framework of NIPT adoption.^[12]

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.^[5]

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.^[13]

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.^[14]

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.^[15]

Moral judgments are empirically based and entail evaluating prospective risk-benefit ratios particularly in the field of biomedicine. The technology of CRISPR genome editing raises ethical questions for 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. Decision-making on morality becomes more difficult when uncertainty from these circumstances prevents appropriate risk/benefit assessments.^[16]

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.^[17] Major benefits are likely to develop from the use of safe and effective HGGM, making a precautionary stance against HGGM unethical.^[18]

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.^[19][20]

In addition, Janasoff and Hurlbut have recently advocated for the establishment and international development of an interdisciplinary "global observatory for gene regulation".^[21]

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.^[22]

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.^[15]

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.^[23]

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.^[24]

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.^[25]

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.^[26]

With the discovery of various types of immune-related disorders, there is a need for diversification in prevention and treatment. Developments in the field of gene therapy are being studied to be included in the scope of this treatment, but of course more research is needed to increase the positive results and minimize the negative effects of gene therapy applications.^[27] The CRISPR/Cas9 system is also designed as a gene editing technology for the treatment of HIV-1/AIDS. CRISPR/Cas9 has been developed as the latest gene editing technique that allows the insertion, deletion and modification of DNA sequences and provides advantages in the disruption of the latent HIV-1 virus. However, the production of some vectors for HIV-1-infected cells is still limited and further studies are needed^[28] Being an HIV carrier also plays an important role in the incidence of cervical cancer. While there are many personal and biological factors that contribute to the development of cervical cancer, HIV carriage is correlated with its occurrence. However, long-term research on the effectiveness of preventive treatment is still ongoing. Early education, accessible worldwide, will play an important role in prevention.^[29] When medications and treatment methods are consistently adhered to, safe sexual practices are maintained and healthy lifestyle changes are implemented, the risk of transmission is reduced in most people living with HIV. Consistently implemented proactive prevention strategies can significantly reduce the incidence of HIV infections. Education on safe sex practices and risk-reducing changes for everyone, whether they are HIV carriers or not, is critical to preventing the disease.^[30] However, controlling the HIV epidemic and eliminating the stigma associated with the disease may not be possible only through a general AIDS awareness campaign. It is observed that HIV awareness, especially among individuals in low socio-economic regions, is considerably lower than the general population. Although there is no clear-cut solution to prevent the transmission of HIV and the spread of the disease through sexual transmission, a combination of preventive measures can help to control the spread of HIV. Increasing knowledge and awareness plays an important role in preventing the spread of HIV by contributing to the improvement of behavioral decisions with high risk perception.^[31] Genetics plays a pivotal role in disease prevention, offering insights into an individual's predisposition to certain conditions and paving the way for personalized strategies to mitigate disease risk. The burgeoning field of genetic testing and analysis has provided valuable tools for identifying genetic markers associated with various diseases, allowing for proactive measures to be taken in disease prevention ^[32] Disease prevention via genetic testing is made easier as genetic testing can unveil an individual's genetic susceptibility to certain diseases, enabling early detection and intervention which can be very crucial in disease like heritable cancers such and breast ^[33][34] and ovarian cancer.^[35][36] Having genetic information can inform the development of precision medicine approaches and targeted therapies for disease prevention in general. By identifying genetic factors contributing to disease susceptibility, such as specific gene mutations associated with autoimmune disorders, researchers can develop targeted therapies to modulate the immune response and prevent the onset or progression of these conditions.^[37][38][39]

There are many types of neurodegenerative diseases. Alzheimer's disease is the one of the most common one of these diseases and it affects millions of people worldwide. The CRISPR-Cas9 techniques can be used to prevent the Alzheimer's disease. For example, it has a potential to correct the autosomal dominant mutaitons, problematic neurons, restoring the associated electrophysiological deficits and decreased the Aβ peptides.^[40] Amyotrophic Lateral Sclerosis (ALS) is another highly lethal neurodegenerative disease. And CRISPR-Cas9 technology is simple and effective for changinc specific point mutations about ALS. Also with this technology Chen and his colleagues were found some important alterations in major indicators of ALS like decreasing in RNA foci, polypeptides and haplosufficiency.^[41][40]

Some individuals experience immunocompromise, a condition in which their immune systems are weakened and less effective in defending against various diseases, including but not limited to influenza. This susceptibility to infections can be attributed to a range of factors, including genetic flaws and genetic diseases such as Severe Combined Immunodeficiency (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, ).^[42] These genetic flaws and diseases can significantly impact the body's ability to mount an effective immune response, leaving individuals vulnerable to a wide array of pathogens. However, advancements in gene therapy research and development have shown promising potential in addressing these genetic deficiencies however not without associated challenges^[43][44]

CRISPR technology is a promising tool not only for genetic disease corrections but also for the prevention of viral and bacterial infections. Utilizing CRISPR–Cas therapies, researchers have targeted viral infections like HSV-1, EBV, HIV-1, HBV, HPV, and HCV, with ongoing clinical trials for an HIV-clearing strategy named EBT-101. Additionally, CRISPR has demonstrated efficacy in preventing viral infections such as IAV and SARS-CoV-2 by targeting viral RNA genomes with Cas13d, and it has been used to sensitize antibiotic-resistant S. aureus to treatment through Cas9 delivered via bacteriophages.^[45]

Advancements in gene editing and gene therapy hold promise for disease prevention by addressing genetic factors associated with certain conditions. Techniques like CRISPR-Cas9 offer the potential to correct genetic mutations associated with hereditary diseases, thereby preventing their manifestation in future generations and reducing disease burden. In November 2018, Lulu and Nana were created.^[46] 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.

Despite existing evidence of CRISPR technology, advancements in the field persist in reducing limitations. Researchers developed a new, gentle gene editing method for embryos using nanoparticles and peptide nucleic acids. Delivering editing tools without harsh injections, the method successfully corrected genes in mice without harming development. While ethical and technical questions remain, this study paves the way for potential future use in improving livestock and research animals, and maybe even in human embryos for disease prevention or therapy.^[47]

Informing prospective parents about their susceptibility to genetic diseases is crucial. Pre-implantation genetic diagnosis also holds significance for disease prevention by inheritance, as whole genome amplification and analysis help select a healthy embryo for implantation, preventing the transmission of a fatal metabolic disorder in the family.^[48]

Genetic human enhancement emerges as a potential frontier in disease prevention by precisely targeting genetic predispositions to various illnesses. Through techniques like CRISPR, specific genes associated with diseases can be edited or modified, offering the prospect of reducing the hereditary risk of conditions such as cancer, cardiovascular disorders, or neurodegenerative diseases. This approach not only holds the potential to break the cycle of certain genetic disorders but also to influence the health trajectories of future generations.

Furthermore, genetic enhancement can extend its impact by focusing on fortifying the immune system and optimizing overall health parameters. By enhancing immune responses and fine-tuning genetic factors related to general well-being, the susceptibility to infectious diseases can be minimized. This proactive approach to health may contribute to a population less prone to ailments and more resilient in the face of environmental challenges.

However, the ethical dimensions of genetic manipulation cannot be overstated. Striking a delicate balance between scientific progress and ethical considerations is imperative. Robust regulatory frameworks and transparent guidelines are crucial to ensuring that genetic human enhancement is utilized responsibly, avoiding unintended consequences or potential misuse. As the field advances, the integration of ethical, legal, and social perspectives becomes paramount to harness the full potential of genetic human enhancement for disease prevention while respecting individual rights and societal values.^[49]

Overall, the technology requires improvements in effectiveness, precision, and applications. Immunogenicity, off-target effects, mutations, delivery systems, and ethical issues are the main challenges that CRISPR technology faces. The safety concerns, ethical considerations, and the potential for misuse underscore the need for careful and responsible exploration of these technologies.^[50] CRISPR-Cas9 technology offers so much on disease prevention and treatment yet its future aspects, especially those that affect the next generations, should be investigated strictly.

Modification of human genes in order to treat genetic diseases is referred to as gene therapy. Gene therapy is a medical procedure that involves inserting genetic material into a patient's cells to repair or fix a malfunctioning gene in order to treat hereditary illnesses. Between 1989 and December 2018, over 2,900 clinical trials of gene therapies were conducted, with more than half of them in phase I.^[51] Since that time, many gene therapy based drugs became available, such as Zolgensma and Patisiran. Most of these approaches utilize viral vectors, such as adeno-associated viruses (AAVs), adenoviruses (AV) and lentiviruses (LV), for inserting or replacing transgenes in vivo or ex vivo.^[52][53]

In 2023, nanoparticles that act similarly to viral vectors were created. These nanoparticles, called bioorthgonal engineered virus-like recombinant biosomes, display strong and rapid binding capabilities to LDL receptors on cell surfaces, allowing them to enter cells efficiently and deliver genes to specific target areas, such as tumor and arthritic tissues.^[54]

RNA interference-based agents, such as zilebesiran, contain siRNA which binds with mRNA of the target cells, modifying gene expression.^[55]

Many diseases are complex and cannot be effectively treated by simple coding sequence-targeting strategies. CRISPR/Cas9 is one technology that targets double strand breaks in the human genome, modifying genes and providing a quick way to treat genetic disorders. Gene treatment employing the CRISPR/Cas genome editing method is known as CRISPR/Cas-based gene therapy. Mammalian cells can be genetically modified using the straightforward, affordable, and extremely specific CRISPR/Cas method. It can help with single-base exchanges, homology-directed repair, and non-homologous end joining. The primary application is targeted gene knockouts, involving the disruption of coding sequences to silence deleterious proteins. Since the development of the CRISPR-Cas9 gene editing method 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.

Genetic engineering has undergone a revolution because to CRISPR/Cas technology, which provides a flexible framework for building disease models in larger animals. This breakthrough has created new opportunities to evaluate possible therapeutic strategies and comprehend the genetic foundations of different diseases. But in order to fully realize the promise of CRISPR/Cas-based gene therapy, a number of obstacles must be removed. Improving CRISPR/Cas systems' editing precision and efficiency is one of the main issues. Although this technology makes precise gene editing possible, reducing off-target consequences is still a major challenge. Unintentional genetic changes resulting from off-target modifications may have unanticipated effects or difficulties. Using enhanced guide RNA designs, updated Cas proteins, and cutting-edge bioinformatics tools, researchers are actively attempting to improve the specificity and reduce off-target effects of CRISPR/Cas procedures. Moreover, the effective and specific delivery of CRISPR components to target tissues presents another obstacle. Delivery systems must be developed or optimized to ensure the CRISPR machinery reaches the intended cells or organs efficiently and safely. This includes exploring various delivery methods such as viral vectors, nanoparticles, or lipid-based carriers to transport CRISPR components accurately to the target tissues while minimizing potential toxicity or immune responses.

Despite recent progress, further research is needed to develop safe and effective CRISPR therapies. CRISPR/Cas9 technology is not actively used today, however there are ongoing clinical trials of its use in treating various disorders, including sickle cell disease, human papillomavirus (HPV)-related cervical cancer, COVID-19 respiratory infection, renal cell carcinoma, and multiple myeloma.^[56]

Gene therapy has emerged as a promising field in medical science, aiming to address and treat various genetic diseases by modifying human genes. The process involves the introduction of genetic material into a patient's cells, with the primary goal of repairing or correcting malfunctioning genes that contribute to hereditary illnesses. This innovative medical procedure has seen significant advancements and a growing number of clinical trials since its inception.

Between 1989 and December 2018, more than 2,900 clinical trials of gene therapies were conducted, with over half of them reaching the phase I stage. Over the years, several gene therapy-based drugs have been developed and made available to the public, marking important milestones in the treatment of genetic disorders. Examples include Zolgensma and Patisiran, which have demonstrated efficacy in addressing specific genetic conditions.

The majority of gene therapy approaches leverage viral vectors, such as adeno-associated viruses (AAVs), adenoviruses (AV), and lentiviruses (LV), to facilitate the insertion or replacement of transgenes either in vivo or ex vivo. These vectors serve as delivery vehicles for introducing the therapeutic genetic material into the patient's cells.

A notable development in 2023 was the creation of nanoparticles designed to function similarly to viral vectors. These bioorthogonal engineered virus-like recombinant biosomes represent a novel approach to gene delivery. They exhibit robust and rapid binding capabilities to low-density lipoprotein (LDL) receptors on cell surfaces, enhancing their efficiency in entering cells. This capability enables the targeted delivery of genes to specific areas, such as tumor and arthritic tissues. This advancement holds the potential to enhance the precision and effectiveness of gene therapy, minimizing off-target effects and improving overall therapeutic outcomes.

In addition to viral vector and nanoparticle-based approaches, RNA interference (RNAi) has emerged as another strategy in gene therapy. Agents like zilebesiran utilize small interfering RNA (siRNA) that binds with the messenger RNA (mRNA) of target cells, effectively modifying gene expression. This RNA interference-based approach provides a targeted and specific method for regulating gene activity, presenting further opportunities for treating genetic disorders.

The continuous evolution of gene therapy techniques, along with the development of innovative delivery systems and therapeutic agents, underscores the ongoing commitment of the scientific and medical communities to advance the field and provide effective treatments for a wide range of genetic diseases. ^[57]

Athletes might adopt gene therapy technologies to improve their performance.^[58] 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.^[59] 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.^[60] The primary objective of gene doping is to aid individuals with medical conditions. However, athletes, cognizant of its associated health risks, resort to employing this method in pursuit of enhanced athletic performance. The prohibition of the indiscriminate use of gene doping in sports has been enforced since the year 2003, pursuant to the decision taken by the World Anti-Doping Agency (WADA).^[61] A study conducted in 2011 underscored the significance of addressing issues related to gene doping and highlighted the importance of promptly comprehending how gene doping in sports and exercise medicine could impact healthcare services by elucidating its potential to enhance athletic performance. The article elucidates, according to the World Anti-Doping Agency (WADA), how gene doping poses a threat to the fairness of sports. Additionally, the paper delves into health concerns that may arise as a consequence of the utilization of gene doping solely for the purpose of enhancing sports performance.^[62] The misuse of gene doping to enhance athletic performance constitutes an unethical practice and entails significant health risks, including but not limited to cancer, viral infections, myocardial infarction, skeletal damage, and autoimmune complications. In addition, gene doping may give rise to various health issues, such as excessive muscle development leading to conditions like hypertonic cardiomyopathy, and render bones and tendons more susceptible to injuries^[63] Several genes such as EPO, IGF1, VEGFA, GH, HIFs, PPARD, PCK1, and myostatins are prominent choices for gene doping. Particularly in gene doping, athletes employ substances such as antibodies against myostatin or myostatin blockers. These substances contribute to the augmentation of the athletes' mass, facilitation of increased muscle development, and enhancement of strength. However, the primary genes utilized for gene doping in humans may lead to complications such as excessive muscle growth, which can adversely impact the cardiovascular system and increase the likelihood of injuries.^[64] However, due to insufficient awareness of these risks, numerous athletes resort to employing gene doping for purposes divergent from its genuine intent. Within the realm of athlete health, sports ethics and the ethos of fair play, scientists have developed various technologies for the detection of gene doping. Although in its early years the technology used wasn’t reliable, more extensive research has been done for better techniques to uncover gene doping instances that have been more successful. In the beginning, scientist resorted to techniques such as PCR in its various forms. This was not successful due to the fact that such technologies rely on exon-exon junctions in the DNA. This leads to a lack of precision in its detection as results can be easily tampered using misleading primers and gene doping would go undetected.^[65] With the emerge of new technologies, more recent studies utilized Next Generation Sequencing (NGS) as a method of detection. With the help of bioinformatics, this technology surpassed previous sequencing techniques in its in-depth analysis of DNA make up. Next Generation Sequencing (NGS) focuses on using an elaborate method of analyzing sample sequence and comparing it to a pre-existing reference sequence from a gene database. This way, primer tampering is not possible as the detection is on a genomic level. Using bioinformatic visualizing tools, data can be easily read and sequences that do not align with reference sequence can be highlighted.^[66][67] Most recently, One of the high-efficiency gene doping analysis methods conducted in the year 2023, leveraging cutting-edge technology, is HiGDA (High-efficiency Gene Doping Analysis), which employs CRISPR/deadCas9 technology.^[68]

The ethical issues concerning gene doping have been present long before its discovery. Although gene doping is relatively new, the concept of genetic enhancement of any kind has always been subject to ethical concerns. Even when used in a therapeutic manner, gene therapy poses many risks due to its unpredictability among other reasons. Factors other than health issues have raised ethical questions as well. These are mostly concerned with the hereditary factor of these therapies, where gene editing in some cases can be transmitted to the next generation with higher rates of unpredictability and risks in outcomes.^[69] For this reason, non-therapeutic application of gene therapy can be seen as a riskier approach to a non-medical concern.^[70]

In 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.^[71]

One of the negative effects is the risk of cancer, and as a positive effect is taking precautions against certain pathological conditions.Altering genes could lead to unintended and unpredictable changes in the body, potentially causing unforeseen health issues. Further effects of gene doping in sports is the constant fight against drugs not approved by the World Anti doping agency and unfairness regarding athletes that take drugs and don't. The long-term health consequences of gene doping may not be fully understood, and athletes may face health problems later in life.^[72]

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).^[73][74]

The exploration of challenges in understanding the effects of gene alterations on phenotypes, particularly within natural genetic diversity, is highlighted. Emphasis is placed on the potential of systems biology and advancements in genotyping/phenotyping technologies for studying complex traits. Despite progress, persistent difficulties in predicting the influence of gene alterations on phenotypic changes are acknowledged, emphasizing the ongoing need for research in this area.^[75]

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.

- Phenotypic Impacts of CRISPR-Cas9 Editing in Mice Targeting the Tyr Gene:

In a comprehensive CRISPR-Cas9 study on gene editing, the Tyr gene in mice was targeted, seeking to instigate genetic alterations. The analysis found no off-target effects across 42 subjects, observing modifications exclusively at the intended Tyr locus. Though specifics were not explicitly discussed, these alterations may potentially influence non-defined aspects, such as coat color, emphasizing the broader potential of gene editing in inducing diverse phenotype changes.^[76]

Also changes in the myostatin gene^[77] may alter appearance.

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%.^[78] Behavior may also be modified by genetic intervention.^[79] 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.^[80] 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^[81])

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.^[82]

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.^[83] 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.^[84]

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.^[85] 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.^[86]

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.^[87] 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.^[73]

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).^[88] 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.^[89]

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.^[90]

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.^[91][92]

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.^[93]

In December 2020, then-Director of National Intelligence John Ratcliffe said in an editorial for The Wall Street Journal that US intelligence shows China had conducted human testing on People's Liberation Army soldiers with the aim of creating "biologically enhanced" soldiers.^[94][95]

In 2022, the People's Liberation Army Academy of Military Sciences reported a notable experiment where military scientists inserted a gene from the tardigrade into human embryonic stem cells. This experiment aimed to explore the potential enhancement of soldiers' resistance to acute radiation syndrome, thereby increasing their ability to survive nuclear fallout. This development reflects the intersection of genetic engineering and military research, with a focus on bioenhancement for military personnel. ^[96]

CRISPR/Cas9 technologies have garnered attention for their potential applications in military contexts. Various projects are underway, including those focused on protecting soldiers from specific challenges. For instance, researchers are exploring the use of CRISPR/Cas9 to provide protection from frostbite, reduce stress levels, alleviate sleep deprivation, and enhance strength and endurance. The Defense Advanced Research Projects Agency (DARPA) is actively involved in researching and developing these technologies. One of their projects aims to engineer human cells to function as nutrient factories, potentially optimizing soldiers' performance and resilience in challenging environments. ^[97]

Additionally, military researchers are conducting animal trials to explore the prophylactic treatment for long-term protection against chemical weapons of mass destruction. This involves using non-pathogenic AAV8 vectors to deliver a candidate catalytic bioscavenger, PON1-IF11, into the bloodstream of mice. These initiatives underscore the broader exploration of genetic and molecular interventions to enhance military capabilities and protect personnel from various threats.^[98]

In the realm of bioenhancement, concerns have been raised about the use of dietary supplements and other biomedical enhancements by military personnel. A significant portion of American special operations forces reportedly use dietary supplements to enhance performance, but the extent of the use of other bioenhancement methods, such as steroids, human growth hormone, and erythropoietin, remains unclear. The lack of completed safety and efficacy testing for these bioenhancements raises ethical and regulatory questions. This concern is not new, as issues surrounding the off-label use of products like pyridostigmine bromide and botulinum toxoid vaccine during the Gulf War, as well as the DoD's Anthrax Vaccine Immunization Program in 1998, have prompted discussions about the need for thorough FDA approval for specific military applications.^[99]

The intersection of genetic engineering, CRISPR/Cas9 technologies, and military research introduces complex ethical considerations regarding the potential augmentation of human capabilities for military purposes. Striking a balance between scientific advancements, ethical standards, and regulatory oversight over classified projects remain crucial as these technologies continue to evolve.^[100]

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.^[101][102]

• Biohappiness
• Crossbreeding
• Directed evolution (transhumanism)
• Designer baby
• Epigenetics
• Genetic screening: allows detecting personal genetic weaknesses to be addressed
• Genetic factors of addiction
• Procreative beneficence
• New eugenics
• Life extension