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Gene Therapy

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Gene Therapy

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  1. Gene Therapy Emma Donnay, Javier Howard, Jessica Martinez, Michael Ostach and Jackie Viselli

  2. Overview • What is gene therapy? • Pros and cons • Do genes have a moral status? • Gene therapy in the medical context • Cosmetic gene therapy • FDA and NIH guidelines


  4. Gene Therapy Defined • Gene therapy is an approach to treating disease by either modifying the expression of an individual's genes or by the correction of abnormal genes. • The goal of gene therapy is the elimination of disease.

  5. A Brief History • One of the first papers to address gene therapy was published in 1972 in Science and was titled “Gene therapy for human genetic disease?” • An excerpt from the abstract: • “In our view, gene therapy may ameliorate some human genetic diseases in the future. For this reason, we believe that research directed at the development of techniques for gene therapy should continue…We …propose that a sustained effort be made to formulate a complete set of ethicoscientific criteria to guide the development and clinical application of gene therapy techniques. Such an endeavor could go a long way toward ensuring that gene therapy is used in humans only in those instances where it will prove beneficial, and toward preventing its misuse through premature application.” Friedmann, T.; Roblin, R. (1972). "Gene Therapy for Human Genetic Disease?". Science 175 (25): 949. doi:10.1126/science.175.4025.949.

  6. A Brief History cont. • The first “successful” experiment did not take place until 1990. • 4 year old girl treated for Severe Combined Immunodeficiency (SCID). • There have been no completely successful applications of gene therapy for human disease, although considerable progress has been made. • Many appoaches for gene therapy are currently being evaluated in animal models of human diseases and in clinical trials.

  7. Two Types of Gene Therapy Somatic Gene Therapy Germline Gene Therapy Image source: Image source:

  8. Somatic Gene Therapy • The alteration of somatic cells (non reproductive cells). • Alterations of somatic are restricted to that individual and will not be passed onto future generations.

  9. Germline Gene Therapy • The alteration of germ (sperm & egg) cells. • The alteration is made during the embryonic stage, such that the genes altered would be passed down to future generations. • Germline gene therapy can be done by altering the genes of a pre-embryo that carries a serious genetic defect before implantation into the mother or by altering the germ cells of an afflicted adult so that the defect does not get passed on to their offspring. • Because of the unknown effects germline therapy has on future generations, it is the most controversial.

  10. How Does Gene Therapy Work? • A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common. • An abnormal gene could be swapped for a normal gene through homologous recombination. • The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function. • The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered.

  11. Viral Vectors • Gene therapy typically uses inactivated viruses to deliver genes throughout the body. Image source:

  12. Issues and Advancements in Gene Delivery (Vectors) • Three types of vectors will be discussed: • Retrovirus vectors • HIV is a retrovirus. • Adenovirus vectors • Known for causing upper respiratory tract infections. • Liposome vectors • Imagine a liposome as being similar to a soap bubble.

  13. Retrovirus Vectors • The normal function of a retrovirus is to insert it's genetic material into the target cells genome to alter it permanently. • Scientists remove the viruses genetic material and replace it with the genetic material they wish to deliver to the defective cells. • Inactivation of the virus leads to its use in gene therapy. • Pros • Retroviruses target very specific cells depending on the type of virus. • Cons • Inserting new genes into a cells genome may cause mutations or disrupt a cell linked to cancer thereby causing cancer to develop

  14. Adenovirus Vectors • Like retrovirus, uses host cell to replicate. • Unlike retrovirus does not insert DNA into host cell's genome. • Pros • No risk of mutation of cells, or disruption of genome sequences. • Cons • Can trigger immune response from the body causing the body to kill off the altered cells rendering the therapy useless. • In addition, if the body has already naturally come into contact with an adenovirus it could have antibodies already formed against the virus initiating an immune response.

  15. Liposome Vectors • Uses a fatty cell, a liposome, to carry healthy human genes into target cell. • The gene to be delivered is "transformed" into a small circular ring of DNA (a plasmid), and is then inserted into a liposome. • Pros • Safer then modified viruses. • Cons • Requires a very large number of infected liposomes to have desired effect. Has to be directly introduced to infected cells. • Nose sprays have been developed to deliver liposomes directly to the lungs of cystic fibrosis patients. Image source: Lavorini-Doyle C., Gebremedhin S., Konopka K., Düzgüneş N. 2009. Gene delivery to oral cancer cells by nonviral vectors: why some cells are resistant to transfection. J Calif Dent Assoc, 37(12):855-8.


  17. Pros • Potential to cure inheritable genetic disorders such as Cystic Fibrosis, Parkinson's Disease, and Alzheimer's Disease which currently have no other permanent cures. • Medical necessity. • Parental autonomy: parents can make choices about what is best for their children. • Better to prevent a disease rather than just a temporary fix.

  18. Cons • “Playing god.” • We don't know the long term effects gene therapy will have on future generations. • Slippery slope: if we begin to alter genes for the purpose of curing diseases it might lead into altering genes for cosmetic purposes. • Too costly. • Lack of informed consent because a fetus/embryo cannot consent.


  20. Overview Arguments for moral status • "The sacred gene“ • Human DNA has been used as a symbol of individual human identity, and of the human spirit, soul, or essence. • Richard Dawkins • Argues that genes are the true locus of human agency. Arguments against moral status • Mary Anne Warren • The parts argument • Sentience and consciousness • Problems with the sacred gene argument • Environmental factors and epigenetics

  21. A determination of the moral status of a given gene has implications for deciding if genetic therapy is ethically appropriate.

  22. Richard Dawkins • Well known for his work in evolutionary biology and creationism. • Argues that genes are the true locus of human agency. • "Individuals are not stable things, they are fleeting ... the genes ... change partners and march on ...they are the replicators and we are their survival machines. When we have served our purpose we are cast aside. But genes are denizens of geological time; genes are forever." Dawkins, Richard (1976). The Selfish Gene. New York City: Oxford University Press. ISBN 0-19-286092-5. Image Source:

  23. Arguments Against Moral Status • Mary Anne Warren • Argues that genes do not have independent moral status. • Key components of her position: • The parts argument • Sentience and consciousness • Rebuttal of the "sacred gene" argument Anne Warren, M. (2008) The Moral Status of the Gene, in A Companion to Genethics (eds J. Burley and J. Harris), Blackwell Publishing Ltd, Oxford, UK. doi: 10.1002/9780470756423.ch11

  24. The Parts of Organisms Do Not Have Moral Status • One reason that we regard living organisms as worthy of moral status is because they are systems of their own that exhibit a purpose. They are organized to maintain and reproduce themselves, and to interact with their environments in ways that have evolved because they tended to serve these ends. • Parts of organisms (i.e. a foot or an organ) only act in the manifestation of the entire organisms purpose, and function to contribute to the survival of the entire organism, and not solely itself.

  25. Consider for a Moment: • Tissues and organs take on specific forms and functions in a given organism. • This is because the traits these components exhibit promote the reproductive success of the organism. • The "goals" of a liver, for example, are directed in ways that generally differ from the goals of the organism (i.e. the liver detoxifies drugs and stores glycogen). • Therefore, it is inappropriate to attribute independent moral status to the parts of organisms.

  26. Sentience and Consciousness • Sentience: the ability to feel or perceive. • The experience of pain, pleasure, and other mental state occurs at the level of the organism. • One may feel pain in his or her hand, although it is unlikely that the hand has private pains unfelt by the individual. In other words, organs/tissues/cells do not have central nervous systems of their own.

  27. Sentience and Consciousness cont. • We can therefore argue that we have special obligations to organisms, such as to not cause them pain or suffering. • This obligation does not translate to parts of organisms, as they do not experience pain and pleasure. • A similar argument for consciousness and memory: • Some organisms have moral agency, meaning that they posses a level of sophistication allowing them to tell right from wrong, and act in the pursuit of conscious goals. • Parts and organs are not moral agents, and do not have the rights that flow from moral agency.

  28. Warren's Conclusions from the Previous Arguments • We can extend the previous arguments to DNA. • In the context of gene therapy, Warren contests that: • There is no a priori reason not to permit genetic alterations, provided that we know enough to avoid the associated risks to current and future persons.

  29. Problems with the Sacred Gene Argument • Warren contests that the empirical evidence is not sufficient to hold genes in such high regard. • "DNA is not the sole source and shaper of organisms, and neither is it an immortal being. It is not an immaterial entity that is eternally reincarnated in new physical bodies. It is a physical part of living and mortal organisms, one that has a central but not omnipotent role in the organism's development, functioning, and reproduction.“ • Key components: • It takes more than DNA to create a functioning organism. For example, for a zygote to fully develop there needs to be: • Nutrients from the environment • A correct temperature range for biochemical reactions to occur. • Environmental factors can influence the expression of certain genes.

  30. Epigenetics • "Above the genes.“ • Modifications that are caused due to environmental factors, among other things. • Epigenetic modifications cause certain genes to be unexpressed, although does not change the sequence of the genes. • Some individuals may contest that the sequence, or "information," contained in ones genome is the most basic, or underlying, element that acts to create the organism. • There is evidence that epigenetic "information" can be passed on to progeny. Jablonka E., Raz G. 2009. Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution. The Quarterly Review of Biology 84(2):131–176.

  31. Epigenetics cont. • An example of an epigenetic process is genomic imprinting. • Genomic imprinting involves DNA methylation and histone modifications. • Involved in the manifestation of Prader-Willi and Angelman syndromes. Image source:

  32. Prader–Willi Syndrome • Symptoms: • Short stature • Poor motor skills • Weight gain • Underdeveloped sex organs • Mild mental retardation and learning disabilities Image source:

  33. Prader–Willi Syndrome cont. • Caused by genomic imprinting on a set of genes within chromosome 15. • Paternal chromosome undergoes imprinting. • Most cases of PWS are due to a spontaneous genetic error that occurs at or near the time of conception for unknown reasons. Image source:

  34. Angelman Syndrome Image source:



  37. “Bubble Boy” Syndrome • Also known as Severe Combined Immunodeficiency. • The first “successful” gene therapy experiment was done on four year old Ashanti DeSilva in 1990 to replace the defective enzyme adenoside deaminase (ADA). • She was not completely cured, as she still must continue to take a low dose of PEG-ADA, the traditional drug treatment for SCID. • After her treatment, the field of gene therapy flourished. David Vetter lived until the age of 12 with SCID. Image Source:

  38. Jesse Gelsinger • There have been major setbacks in the field. • In 1999, 18 year old Jesse Gelsinger died in a gene therapy trial for ornithine transcarbamylase deficiency, a condition in which the body is unable to metabolize ammonia. • He died from multiple organ failure due to a immune response to the adenovirus vector. • Jesse and his father were not informed of this complication, as there were two monkeys that had died in animal trials due to the same vector virus. Hartnett T. 2008. Regulatory and ethical issues in conducting gene therapy research. Research Practitioner, 9(1): 4-10. Image Source:


  40. What is Cosmetic Gene Therapy? • Similar in a sense to plastic therapy • Uses germline genetic engineering • Would allow parents to change characteristics of their children (and thus following generations as well) • Would be separate from medical gene therapy

  41. What Characteristics Can be Altered? • Height - Growth Hormone/Estrogen • Weight - Altering Leptin • Memory/Learning - Estrogen/Intracranial Gene Delivery • Muscle Strength/Buildup - Growth Hormones • Hair Color/Growth

  42. What Would Gene Therapy Change? • Appearance • Mental Capacity • Intelligence • Physical ability • Athletic potential

  43. Reasons Against Cosmetic Gene Therapy • Greater class differential (those who can afford vs. those who cannot) • Preferential coupling between the rich and attractive (pure blood) • Less sense of purpose and belonging for child • "Bad" parents predetermining child's future • More of a materialistic society - children as products • Increased discrimination • Constantly new technology, "outdated" by adulthood

  44. Reasons for Cosmetic Gene Therapy • Technological advance of the human race • Uses the further knowledge and ability of man • Can be related to putting the first man on the moon (and atomic bomb example) • High risk, high financial investment, could be deemed unnecessary. • Satisfies the human need for exploration and curiosity • "Human evolution will be self driven" - Lee Silver • Would be for the benefit and advancement of man

  45. Ethically Permissible? • Christopher Columbus example • Conclusion for the pro cosmetic gene therapy argument: • It is ethically permissible for humans to follow their impulse for advancement to improve as a race and the understanding of the world.

  46. Final Thoughts • If you could "create" the perfect child based on the physical and mental qualities available to be altered, which would you most likely consider actually altering on your future child? • What are some general qualities that all parents would hope for their children to have? • What are more important to you? Physical characteristics or character traits? • (i.e. would you rather have a genetically modified genius child that treats everyone else as inferiors or a mildly smart child by nature who is kind at heart and treats people fairly?) • Where do you find that your values lie?


  48. Gene Therapy Legislation in the U.S. • Both the National Institute of Health and the Food and Drug Administration serve to protect Americans by regulating the use of gene therapy. • NIH and the RAC • The National Institute of Health established the Recombinant DNA Advisory Committee (RAC) on October 7, 1974. This committee serves to aid the U.S. government in developing comprehensive legislation in the gene therapy field. NIH uses the RAC in order to have a critical forum for the discussion of the issues we face with recombinant DNA technology and it’s applications in our society. This forum not only looks at the scientific challenges, but also the ethical and legal repercussions of a greater use of the technology. • The main job of the RAC is the review of human gene transfer research. They analyze all of the studies involving recombinant DNA technology and then report back to the NIH about their findings and give recommendations for legislation regarding the technology. All human gene therapy trials that take place at institutions which receive federal funding from the NIH are reviewed by the Recombinant DNA Advisory Committee. • RAC reports are posted to the online so the public is able to stay informed about developments in the gene therapy field.

  49. Gene Therapy Legislation cont. • FDA & CBER • The U.S. Food and Drug Administration is a U.S. government agency put in place to protect the health of our citizens by making sure that drugs, medicine and other products are safe and effective before they are put in use. This includes the regulation of clinical trials testing controversial treatments, like gene therapy. • The FDA’s Center for Biologics Evaluation and Research (CBER) regulates human gene therapy because if falls under the legal definition of a “biologic," which is a biological product, like a vaccine, used in medicine.