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Human genetic enhancement

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

Human genetic enhancement, human genetic modification 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 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 ethical and regulatory concerns within the scientific community.[2]

Ethics

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Genetic engineering has always been a topic of moral debate among bioethicists.[3] The distinction between repairing genes (therapy) and enhancing genes is a central idea in many moral debates. Some argue that repairing genes is morally permissible, but that genetic enhancement is not, due to its potential to lead to social injustice and discriminatory eugenics initiatives.[4]

Moral questions related to genetic testing often involve the duty to warn family members if an inherited disorder is discovered, the ethics of genetic discrimination, and the moral permissibility of using testing to avoid bringing seriously disabled persons into existence, such as through selective abortion.[4][5] For example, Non-invasive prenatal testing (NIPT) can accurately determine the sex of a fetus as early as 7 weeks' gestation, raising concerns about the potential facilitation of sex-selective termination of pregnancy.[6]

Technological advancements like CRISPR also present dilemmas regarding the long-term effects of altered organisms and the possibility of edited genes being passed down to succeeding generations (germline modification) with unanticipated effects.[7] Conversely, proponents argue that major benefits are likely to develop from safe and effective human germline genetic modification (HGGM), making a strictly precautionary stance against HGGM unethical.[8]

To navigate these complexities, researchers have advocated for robust regulatory frameworks. A group of scientists founded the Association for Responsible Research and Innovation in Genome Editing (ARRIGE) to provide guidance on the ethical use of genome editing.[9] Additionally, bioethicists like Sheila Jasanoff have advocated for the establishment of an interdisciplinary "global observatory for gene regulation" to ensure debates are not controlled solely by the scientific community, bringing in perspectives that are often overlooked.[10]

Disease prevention

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Gene editing holds potential for disease prevention by addressing genetic predispositions. Preimplantation genetic diagnosis allows for the whole genome amplification and analysis of embryos to select a healthy embryo for implantation, preventing the transmission of fatal metabolic disorders within families.[11]

The CRISPR/Cas9 system is also being explored to prevent viral infections. In November 2018, Chinese scientist He Jiankui announced the creation of Lulu and Nana, the first genetically edited human babies. He utilized CRISPR-Cas9 to disable the CCR5 gene in the embryos, attempting to close the protein doorway that allows HIV to enter cells, thereby making the subjects immune to the virus.[12] The experiment was met with widespread international condemnation.

CRISPR technology has also demonstrated efficacy in targeting 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, researchers are developing new, gentler gene editing methods for embryos using nanoparticles and peptide nucleic acids, which have successfully corrected genes in mice without the need for harsh injections.[13]

Disease treatment

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Gene therapy

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Modification of human genes in order to treat genetic diseases is referred to as gene therapy. Between 1989 and December 2018, over 2,900 clinical trials of gene therapies were conducted, with more than half of them in phase I.[14] Since that time, many gene therapy-based drugs have become available, such as Zolgensma and Patisiran.

Most 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.[15] In 2023, bioorthogonal engineered virus-like nanoparticles were created that act similarly to viral vectors. These nanoparticles 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.[16]

Gene therapy holds promise for conditions like Cystic fibrosis (CF), a hereditary disease caused by mutations in the CFTR gene. The emergence of sophisticated technologies, including viral and non-viral vector transport, mRNA, and CRISPR/Cas9, has revitalized the area of CF gene therapy, aiming to deliver and sustain CFTR gene expression in the lungs.[17][18]

CRISPR/Cas9

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CRISPR/Cas9 is a genome editing technology that targets double-strand breaks in the human genome, modifying genes and providing a highly specific way to treat genetic disorders. Mammalian cells can be genetically modified to facilitate single-base exchanges, homology-directed repair, and non-homologous end joining. Since its development, it has created new opportunities to evaluate possible therapeutic strategies by disrupting coding sequences to silence deleterious proteins.

Despite recent progress, ensuring the editing precision and efficiency of CRISPR/Cas systems remains an obstacle, as unintentional off-target genetic changes may have unanticipated effects. There are currently ongoing clinical trials of CRISPR/Cas9 in treating various disorders, including sickle cell disease, human papillomavirus (HPV)-related cervical cancer, renal cell carcinoma, and multiple myeloma.[19]

Gene doping

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Athletes might adopt gene therapy technologies to improve their performance.[20] While gene doping is not widely known to occur, multiple gene therapies possess enhancement effects. Critics claim that any therapeutic intervention for enhancement purposes compromises the ethical foundations of medicine and sports.[21] The prohibition of gene doping in sports has been enforced since 2003 by the World Anti-Doping Agency (WADA).[22]

Several genes—such as EPO, IGF1, VEGFA, GH, HIFs, PPARD, PCK1, and myostatins—are prominent choices for potential gene doping. Athletes might employ substances such as antibodies against myostatin or myostatin blockers to augment mass, facilitate muscle development, and enhance strength. However, the misuse of gene doping entails significant health risks, including cancer, viral infections, myocardial infarction, and autoimmune complications. Excessive muscle development can lead to conditions like hypertonic cardiomyopathy, and render bones and tendons more susceptible to injuries.[23]

Scientists have developed various technologies for the detection of gene doping. Early techniques such as PCR proved imprecise due to their reliance on exon-exon junctions, allowing manipulation through misleading primers. More recent detection utilizes Next Generation Sequencing (NGS), which conducts in-depth analysis of DNA makeup compared to reference sequences from gene databases, making primer tampering much harder.[24] A highly efficient gene doping analysis method developed in 2023, HiGDA (High-efficiency Gene Doping Analysis), employs CRISPR/deadCas9 technology for detection.[25]

Other uses

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Hypothetical gene therapies could include changes to physical appearance, metabolism, mental faculties such as memory and intelligence, and overall well-being (such as increasing resistance to depression or relieving chronic pain).[26][27]

Physical appearance

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Some congenital disorders (such as those affecting the muscoskeletal system) may affect physical appearance and cause physical discomfort. Modifying the genes causing these congenital diseases may prevent these effects. Gene editing has been shown to induce diverse phenotypic changes; for example, CRISPR-Cas9 modifications targeting the Tyr gene in mice have altered non-defined aspects such as coat color without off-target effects.[28] Changes in the myostatin gene can also significantly alter physical appearance.[29]

Behavior

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Since the 1990s, scientists have recognized the influence of genetics on behavioral traits such as intelligence. Individual behavioral differences can potentially be predicted through behavioral genomics.[30] Behavior may theoretically be modified by genetic intervention.[31] Research is ongoing regarding genes that may be partially responsible for selfishness (e.g. ruthlessness gene), aggression (e.g. warrior gene), and altruism.[32]

Experimental animal models have demonstrated that it is possible to alter central nervous system gene expression, thereby modifying behavior. By targeting the expression of the aldehyde dehydrogenase gene (ALDH2), researchers have significantly altered alcohol-drinking behavior in rodents.[33] Reduction of p11, a serotonin receptor binding protein, led to depression-like behavior in rodents, while restoration of the p11 gene expression reversed this behavior.[26] Other studies have shown that the gene transfer of CBP improves cognitive deficits in an animal model of Alzheimer's dementia via increasing the expression of brain-derived neurotrophic factor.[34]

Research also exists within genoeconomics, a field investigating whether a person's financial behavior could be traced to their DNA. As of 2015, results have been largely inconclusive with only minor correlations identified.[35] Other studies examine genes like MAOA (Monoamine oxidase A), mutations in which can affect the release of hormones like serotonin and dopamine. Such mutations have been linked in some studies to mood states like aggression and irritability.[36]

Military

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In December 2020, then-Director of National Intelligence John Ratcliffe stated in an editorial for The Wall Street Journal that US intelligence indicated China had conducted human testing on People's Liberation Army soldiers with the aim of creating "biologically enhanced" soldiers.[37][38] In 2022, the People's Liberation Army Academy of Military Sciences reported an experiment where military scientists inserted a gene from the tardigrade into human embryonic stem cells. This experiment aimed to explore enhancing soldiers' resistance to acute radiation syndrome.[39]

CRISPR/Cas9 technologies have garnered attention for their potential applications in military contexts, such as providing protection from frostbite, reducing stress levels, and enhancing strength and endurance. The Defense Advanced Research Projects Agency (DARPA) is actively involved in researching these technologies, including a project aimed at engineering human cells to function as nutrient factories to optimize soldier resilience in challenging environments.[40]

Databases about potential modifications

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Geneticist George Church has compiled a list of potential genetic modifications based on scientific studies for possibly advantageous traits. This list includes modifications for 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.[41][42]

See also

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References

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  1. ↑ Veit W (2018). "Procreative Beneficence and Genetic Enhancement". Kriterion – Journal of Philosophy. 32: 75–92. doi:10.1515/krt-2018-320105.
  2. ↑ "1990 The Declaration of Inuyama: Human Genome Mapping, Genetic Screening and Gene Therapy". Council for International Organizations of Medical Sciences. 5 August 2001. Archived from the original on 5 August 2001.
  3. ↑ Friedmann, Theodore (2019). "Genetic therapies, human genetic enhancement, and … eugenics?". Gene Therapy. 26 (9): 351–353. doi:10.1038/s41434-019-0088-1. PMID 31273325.
  4. 1 2 Vaughn L (2023). Bioethics: Principles, Issues, and Cases (5th ed.). Oxford University Press. p. 500. ISBN 978-0-19-760902-6.
  5. ↑ Asch A (November 1999). "Prenatal diagnosis and selective abortion: a challenge to practice and policy". American Journal of Public Health. 89 (11): 1649–57. doi:10.2105/ajph.89.11.1649. PMC 1508970. PMID 10553384.
  6. ↑ Bowman-Smart H, Savulescu J, Gyngell C, Mand C, Delatycki MB (March 2020). "Sex selection and non-invasive prenatal testing: A review of current practices, evidence, and ethical issues". Prenatal Diagnosis. 40 (4): 398–407. doi:10.1002/pd.5555. PMC 7187249. PMID 31499588.
  7. ↑ Brokowski C, Adli M (January 2019). "CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool". Journal of Molecular Biology. 431 (1): 88–101. doi:10.1016/j.jmb.2018.05.044. PMC 6286228. PMID 29885329.
  8. ↑ Smith KR, Chan S, Harris J (October 2012). "Human germline genetic modification: scientific and bioethical perspectives". Archives of Medical Research. 43 (7): 491–513. doi:10.1016/j.arcmed.2012.09.003. PMID 23072719.
  9. ↑ Montoliu L, Merchant J, Hirsch F, Abecassis M, Jouannet P, Baertschi B, et al. (April 2018). "ARRIGE Arrives: Toward the Responsible Use of Genome Editing". The CRISPR Journal. 1 (2): 128–9. doi:10.1089/crispr.2018.29012.mon. PMC 6636865. PMID 31021207.
  10. ↑ Jasanoff S; Hurlbut JB (March 2018). "A global observatory for gene editing". Nature. 555 (7697): 435–7. Bibcode:2018Natur.555..435J. doi:10.1038/d41586-018-03270-w. PMID 29565415.
  11. ↑ Habibzadeh P, Tabatabaei Z, Farazi Fard MA, Jamali L, Hafizi A, Nikuei P, et al. (February 2020). "Pre-implantation genetic diagnosis in an Iranian family with a novel mutation in MUT gene". BMC Medical Genetics. 21 (1) 22. doi:10.1186/s12881-020-0959-8. PMC 6998079. PMID 32013889.
  12. ↑ Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, et al. (August 2017). "Correction of a pathogenic gene mutation in human embryos". Nature. 548 (7668): 413–9. Bibcode:2017Natur.548..413M. doi:10.1038/nature23305. PMID 28783728. S2CID 205258702. (This paper currently has an expression of concern, see doi:10.1038/nature23305, PMID 28783728,  Retraction Watch. If this is an intentional citation to a such a paper, please replace {{expression of concern|...}} with {{expression of concern|...|intentional=yes}}.)
  13. ↑ Putman R, Ricciardi AS, Carufe KE, Quijano E, Bahal R, Glazer PM, Saltzman WM (May 2023). "Nanoparticle-mediated genome editing in single-cell embryos via peptide nucleic acids". Bioengineering & Translational Medicine. 8 (3) e10458. doi:10.1002/btm2.10458. PMC 10189434. PMID 37206203.
  14. ↑ "Gene Therapy Clinical Trials Worldwide Database". The Journal of Gene Medicine. June 2016.
  15. ↑ Li X, Le Y, Zhang Z, Nian X, Liu B, Yang X (April 2023). "Viral Vector-Based Gene Therapy". International Journal of Molecular Sciences. 24 (9): 7736. doi:10.3390/ijms24097736. PMC 10177981. PMID 37175441.
  16. ↑ Bao CJ, Duan JL, Xie Y, Feng XP, Cui W, Chen SY, et al. (August 2023). "Bioorthogonal Engineered Virus-Like Nanoparticles for Efficient Gene Therapy". Nano-Micro Letters. 15 (1) 197. Bibcode:2023NML....15..197B. doi:10.1007/s40820-023-01153-y. PMC 10423197. PMID 37572220.
  17. ↑ Wang G (June 2023). "Genome Editing for Cystic Fibrosis". Cells. 12 (12): 1555. doi:10.3390/cells12121555. PMC 10297084. PMID 37371025.
  18. ↑ Allen L, Allen L, Carr SB, Davies G, Downey D, Egan M, et al. (February 2023). "Future therapies for cystic fibrosis". Nature Communications. 14 (1) 693. Bibcode:2023NatCo..14..693A. doi:10.1038/s41467-023-36244-2. PMC 9907205. PMID 36755044.
  19. ↑ Sinclair F, Begum AA, Dai CC, Toth I, Moyle PM (May 2023). "Recent advances in the delivery and applications of nonviral CRISPR/Cas9 gene editing". Drug Delivery and Translational Research. 13 (5): 1500–19. doi:10.1007/s13346-023-01320-z. PMC 10052255. PMID 36988873.
  20. ↑ "WADA Gene Doping". World Anti-Doping Agency. WADA. Archived from the original on 21 November 2009. Retrieved 27 September 2013.
  21. ↑ Kayser B, Mauron A, Miah A (March 2007). "Current anti-doping policy: a critical appraisal". BMC Medical Ethics. 8 (1) 2. doi:10.1186/1472-6939-8-2. PMC 1851967. PMID 17394662.
  22. ↑ López S, Meirelles J, Rayol V, Poralla G, Woldmar N, Fadel B, et al. (June 2020). "Gene doping and genomic science in sports: where are we?". Bioanalysis. 12 (11): 801–811. doi:10.4155/bio-2020-0093. PMID 32558587. S2CID 219911239.
  23. ↑ Brzeziańska E, Domańska D, Jegier A (December 2014). "Gene doping in sport - perspectives and risks". Biology of Sport. 31 (4): 251–9. doi:10.5604/20831862.1120931. PMC 4203840. PMID 25435666.
  24. ↑ de Boer EN, van der Wouden PE, Johansson LF, van Diemen CC, Haisma HJ (August 2019). "A next-generation sequencing method for gene doping detection that distinguishes low levels of plasmid DNA against a background of genomic DNA". Gene Therapy. 26 (7–8): 338–346. doi:10.1038/s41434-019-0091-6. PMC 6760532. PMID 31296934.
  25. ↑ Yi JY, Kim M, Ahn JH, Kim BG, Son J, Sung C (June 2023). "CRISPR/deadCas9-based high-throughput gene doping analysis (HiGDA): A proof of concept for exogenous human erythropoietin gene doping detection". Talanta. 258 124455. doi:10.1016/j.talanta.2023.124455. PMID 36933297.
  26. 1 2 Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Lievano M, Ghose S, et al. (October 2010). "Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens". Science Translational Medicine. 2 (54): 54ra76. doi:10.1126/scitranslmed.3001079. PMC 3026098. PMID 20962330.
  27. ↑ Doctrow B (March 30, 2021). "Gene therapy for chronic pain relief". Archived from the original on November 21, 2021. Retrieved February 23, 2022.
  28. ↑ Parikh BA, Beckman DL, Patel SJ, White JM, Yokoyama WM (2015-01-14). "Detailed phenotypic and molecular analyses of genetically modified mice generated by CRISPR-Cas9-mediated editing". PLOS ONE. 10 (1) e0116484. Bibcode:2015PLoSO..1016484P. doi:10.1371/journal.pone.0116484. PMC 4294663. PMID 25587897.
  29. ↑ Gavish B, Gratton E, Hardy CJ (February 1983). "Adiabatic compressibility of globular proteins". Proceedings of the National Academy of Sciences of the United States of America. 80 (3): 750–4. Bibcode:1983PNAS...80..750G. doi:10.1073/pnas.80.3.750. PMC 393457. PMID 6572366.
  30. ↑ Plomin R (March 2023). "Celebrating a Century of Research in Behavioral Genetics". Behavior Genetics. 53 (2): 75–84. doi:10.1007/s10519-023-10132-3. PMC 9922236. PMID 36662387.
  31. ↑ Lupton ML (1994). "Behaviour modification by genetic intervention--the law's response". Medicine and Law. 13 (5–6): 417–431. PMID 7845173.
  32. ↑ Thompson GJ, Hurd PL, Crespi BJ (23 December 2013). "Genes underlying altruism". Biology Letters. 9 (6) 20130395. doi:10.1098/rsbl.2013.0395. PMC 3871336. PMID 24132092.
  33. ↑ Ocaranza P, Quintanilla ME, Tampier L, Karahanian E, Sapag A, Israel Y (January 2008). "Gene therapy reduces ethanol intake in an animal model of alcohol dependence". Alcoholism: Clinical and Experimental Research. 32 (1): 52–57. doi:10.1111/j.1530-0277.2007.00553.x. hdl:10533/139024. PMID 18070247.
  34. ↑ Caccamo A, Majumder S, Richardson A, Strong R, Oddo S (April 2010). "Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments". The Journal of Biological Chemistry. 285 (17): 13107–20. doi:10.1074/jbc.M110.100420. PMC 2857107. PMID 20178983.
  35. ↑ Neyfakh L (May 13, 2012). "In search of the money gene". The Boston Globe.
  36. ↑ Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA (October 1993). "Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A". Science. 262 (5133): 578–580. Bibcode:1993Sci...262..578B. doi:10.1126/science.8211186. PMID 8211186.
  37. ↑ Ratcliffe, John (2020-12-03). "China Is National Security Threat No. 1". The Wall Street Journal. Retrieved 2024-11-19.
  38. ↑ Gabbatt, Adam (2020-12-04). "China conducting biological tests to create super soldiers, US spy chief says". The Guardian. ISSN 0261-3077. Retrieved 2024-11-19.
  39. ↑ Karl JP, Margolis LM, Fallowfield JL, Child RB, Martin NM, McClung JP (January 2022). "Military nutrition research: Contemporary issues, state of the science and future directions". Eur J Sport Sci. 22 (1): 87–98. doi:10.1080/17461391.2021.1930192. PMID 33980120.
  40. ↑ Pang C, Chen ZD, Wei B, Xu WT, Xi HQ (July 2022). "Military training-related abdominal injuries and diseases: Common types, prevention and treatment". Chin J Traumatol. 25 (4): 187–192. doi:10.1016/j.cjtee.2022.03.002. PMC 9252930. PMID 35331607.
  41. ↑ Tangermann V. "George Church told us why he's listing "superhuman" gene hacks". Futurism. Retrieved 25 July 2021.
  42. ↑ Wu SS, Li QC, Yin CQ, Xue W, Song CQ (2020). "Advances in CRISPR/CAS-based gene therapy in human genetic diseases". Theranostics. 10 (10): 4374–82. doi:10.7150/thno.43360. PMC 7150498. PMID 32292501.
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