Author: Priyanka Bhatnagar, Intern at Jeeva Informatics Solutions, 2018; Junior at Robbinsville High School in Robbinsville, New Jersey.
Greetings from the Central London Hatching and Conditioning Centre, where you will be genetically engineered as an embryo to belong to one of five castes: Alpha, Beta, Gamma, Delta, or Epsilon. Apologies if you are conditioned into Epsilon; each successive caste is modified into a more physically and intellectually inferior being.
Although Huxley’s Brave New World depicts the extreme ramifications of genetic engineering, he accurately warns about the dangers of the abuse of new and powerful technologies. Despite the fact that today’s society lacks genetic enhancement technologies, scientists possess its precursor: gene therapy.
Gene therapy involves the introduction of genetic material into human cells as treatment for genetic diseases. Contrary to conventional medicine, gene therapy remedies a disease’s root cause by directly altering genes rather than the symptoms (Wharam). In the case of somatic gene therapies, therapeutic genes are transferred to somatic cells (cells that constitute organs). Research to this date has mostly centered around somatic gene therapy (SGT), however, some scientists have recently focused their attention to germline gene therapy (GGT). This relatively new branch of gene therapy involves inserting genes into reproductive cells or embryos to treat genetic defects in the germ line (genetic material passed from generation to generation). In other words, GGT transforms the genetic makeup of future generations to prevent the recurrence of certain genetic disorders. Manipulating the genome of a germ line raises numerous ethical concerns like genetic enhancement (artificially enhancing human capabilities and traits). The ethical concerns surrounding GGT raises questions on whether SGT should be allowed, as bioethicists contend that widespread acceptance of somatic gene therapy may eventually justify germ line gene therapy. Therefore, due to the ethical concerns surrounding the modification of the genome, all governments must heavily regulate gene therapy to prevent its abuse.
The history of gene therapy stretches back to the early 1970s when scientists proposed “gene surgery” to cure inherited diseases by surgically replacing the faulty gene with a functional gene (“Gene therapy strategies,” n.d.). This demonstrates that they understood the biological basis of gene therapy, but such precise surgery was impossible to implement. A decade later, scientists began to see gene therapy as a promising cure for many genetic diseases. They began to acknowledge the role of genes, coupled with environmental factors, in making some people more susceptible to disease (“Gene therapy strategies”). By 1989, the NIH “approved the first clinical protocol to insert a foreign gene into the immune cells of persons with cancer” (Scheller & Krebsbach). A year later, a four-year-old girl suffering from severe combined immunodeficiency (SCID) was the first person to be treated with gene therapy (Scheller & Krebsbach). The treatment was successful but questions still arose regarding the efficacy of gene therapy, because the girl received it during a course of drug treatment (“Gene therapy strategies”). Regardless, the field grew with increased federal funding, including 300 clinical trials on various diseases on 3000 individuals in the next 10 years (Scheller & Krebsbach). Today, gene therapy development is in the experimental phase, but it has the potential to completely revolutionize the treatments for genetic diseases.
HOW GENE THERAPY WORKS
There are many steps involved in effectively introducing genetic material to the body. First, the gene responsible for the condition and the location of the affected cells is identified. Second, when a corresponding functional gene is located, the working gene is delivered to the cell (“Gene therapy”). Since raw genetic material cannot efficiently travel to the cell’s nucleus nor be replicated and expressed on its own, scientists use vectors to deliver the gene to its destination.
Gene therapy vectors vary with different genetic disorders. A vector must be customized to fit the unique characteristics (ex. gene length, the location’s cell division frequency) of the disease. A successful vector targets the correct cells, integrates into the host’s DNA, activates the gene to produce functional proteins, and must avoid an immune response (“Gene Delivery: Tools of the Trade”). Scientists have to choose the most suitable vector for a disorder and occasionally have to modify it with additional markers to get the job done. To accomplish the complex task of delivering gene therapy, the most popular and effective vectors are viruses.
Viruses make excellent vectors because they are skilled at DNA transduction. Some can also target specific cell types, making it easy to pick which virus is most suitable for a certain disease. Viral vectors are modified so that they cannot infect the host. For example, scientists have reduced the odds for infection by removing genetic information from the capsid to prevent viral replication (“Gene Delivery: Tools of the Trade”). Sometimes viruses cause immune responses which make the patient sick, or destroy the virus and render the treatment ineffective. Viral vectors have a limit on the amount of genetic material they can carry, so not all genes may fit in the capsids. Despite these drawbacks, viruses are currently the most practical vectors for gene therapy. Common viral vectors include retroviruses and adenoviruses.
Retroviruses carry single-stranded RNA and infect only actively dividing cells. Since most cells in the body do not divide that often, retroviruses are typically used ex vivo, “outside the body”, usually on a culture plate (“Gene therapy strategies”). When a retrovirus infects a cell, the RNA is released into the nucleus through one of the nuclear pores. Since the genes must be in DNA form to activate, retrovirus enzymes convert the RNA into DNA. The DNA is then randomly integrated into the genome and replicated during cell division (“Gene Delivery: Tools of the Trade”).
Adenoviruses carry double-stranded DNA and can effectively infect non-dividing cells. Scientists often equip adenoviruses with proteins that can detect special proteins on target cells. When an adenovirus infects the cell, the DNA activates once it travels into the nucleus. Unlike the retrovirus, it does not integrate into the genome so it cannot survive very long (“Gene Delivery: Tools of the Trade”). Nevertheless, adenovirus is relatively safe and limited, so it is the best vector for regular gene therapy treatments (Scheller & Krebsbach).
Gene therapy using an adenovirus vector.
Source credit: Emerging and future therapies for hemophilia – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/Gene-therapy-using-an-adenovirus-vector-Note-Reproduced-from-US-National-Library-of_fig1_281779310 [accessed 15 Oct, 2018]
Viruses are not always the best option in gene therapy. Occasionally a non-viral vector may be more effective in delivering larger genes, or in situations where scientists cannot risk triggering an immune response. A common non-viral vector is a plasmid. Plasmids are usually packaged inside “liposomes”, small vesicle-like wrappings that fuse with the cell membrane and deliver its contents. Since liposomes and plasmids are not as effective as viruses in delivery, scientists have created a synthetic vector that combines the capacities of all three vectors: virosomes, liposomes covered with viral surface proteins. Virosomes have the gene length capacity and immune benefits of a non-viral vector, but the target specificity and efficacy of a viral vector (“Gene Delivery: Tools of the Trade”).
In-vivo delivery using non-viral vectors and its barriers.
Source credit: Non-viral vectors for gene-based therapy – Scientific Figure on Nature Review | Genetics. Available from: https://www.nature.com/articles/nrg3763#references [accessed 15 Oct, 2018]
Methods of delivery
Gene therapy can work in two ways: in vivo and ex vivo. In vivo is when the vector is injected into the patient whereas ex vivo is when cells are removed from the body, placed in a culture, and treated with the vector. The cells are returned to the patient once the gene has successfully integrated and activated the healthy genes. Ex vivo is preferred when scientists want to avoid an immune response and confirm whether the cells are functioning properly after gene therapy (“Gene Delivery: Tools of the Trade”).
Steps involved in ex-vivo gene therapy
Source Credit: Biotechnology as a Cradle of Scientific Development: A Review on Historical Perspective – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/Steps-involved-in-gene-therapy_fig1_312311283 [accessed 15 Oct, 2018]
Types of Gene Therapy
Gene therapy is different for different cases. In most situations, scientists transfer the corresponding functional genes to cells with non-functional copies. Non-functional genes do not produce what they need to, so adding a working copy will enable the manufacturing of the proteins that were previously not being made (“Approaches To Gene Therapy”).
However, other cases exist and that have required an adjusted approach to standard gene therapy. For example, some mutations in single genes make dominant-negative proteins. These mutated proteins interact with normal proteins and disrupt their function. Likewise, the gain-of-function mutation creates abnormal proteins. These proteins may assume an extra function, like unnecessarily activating cell growth (leads to cancer). At times, a genetic condition arises from improper gene regulation. While the transplanted genes might create the correct proteins, there is always a risk that the healthy genes will be expressed too often, too infrequently, at the wrong time, or at the wrong location (“Approaches To Gene Therapy”).
In these situations, adding a functional gene will not work. Instead scientists must use gene therapy to repair mutations, silence genes, or alter immune cells to target certain molecules. One way to repair mutations is through the SMaRTTM (“Spliceosome-Mediated RNA Trans-splicing”) technique which targets and repairs parts of the mutant gene mRNA transcripts. Similarly, scientists have developed gene editing viral vectors that use enzymes to detect specific DNA sequences, cut them out, and replace them with functional genes. There are several ways to silence a gene; the most common methods are RNA interference (RNAi) and ribozyme gene therapy (“Approaches to Gene Therapy”). RNAi introduces a short piece of RNA complementary to an identified part of the mRNA transcript. The strand attaches to the sequence and forms a double-stranded RNA molecule, which is identified as a virus and killed by the cell. Ribozyme gene therapy requires the use of ribozymes (RNA molecules) cut the RNA so that the mutated protein is not produced. The last unique gene therapy involves the modification of immune cells to target certain molecules. Scientists isolate the patient’s immune cells, treat them with gene therapy to detect a specific antigen (ex. protein on the surface of a cancer cell), and return the cells to the patient’s body. The modified immune cells should recognize the antigens and destroy those cells (“Approaches to Gene Therapy”).
The Slippery Slope Argument
The basic structure of the slippery slope argument was outlined by Frederick Schauer in 1985: “‘… a particular act, seemingly innocent when taken in isolation, may yet lead to a future host of similar but increasingly pernicious events’” (McGleenan). In the context of gene therapy, both somatic and germline gene therapy offer nearly identical benefits; in fact, GGT may appear even more attractive since one treatment can eradicate a disease in the germ line. Therefore, critics argue that consenting to somatic cell therapy may involve the silent acceptance of germline gene therapy and other initially unintended applications of gene therapy (McGleenan). The main ethical concern with germline gene therapy lies in the possibility that the treatment is unsuccessful, hence endangering not one individual, but future generations as well.
Implications of Genetic Enhancement Technologies
The irreversible effects of germline gene therapy are not the only concerns in the slippery slope argument. Bioethicists fear the advent of the abuse of gene therapy for enhancement purposes. The ethical controversy behind genetic enhancement lies in the following implications: transgression of genetic diversity, unacceptable risks of harm, and amplified social stratification.
Firstly, genetic enhancement involves directly tinkering with human genetic diversity. Implementation in a free market – where genetic enhancement technologies would be available to consumers – could potentially result in genetic homogeneity. Hypothetically, if parents were given the choice to handpick their children’s traits, many of them would pick “universally desirable characteristics […] such as intelligence, athleticism, health[,] [and particular values for] height, eye color, and hair color” based on the “social pressures and obligations” (Wolfe). Ultimately, parental choices would produce a phenotypically and genetically homogeneous population, thus reducing genetic diversity. Unfortunately, “as genetic diversity decreases within a population, so does the fitness and survivability of that population” (Wolfe). Moreover, “actions that reduce the survivability of a population are unethical” (Wolfe). Therefore, genetic enhancement is ethically undesirable since it may result in genetic homogeneity, which decreases genetic diversity, and reduces the survivability of a population.
Secondly, genetic enhancement technologies may present inexplicable consequences. Current research on gene manipulation minimally addresses that “relationships between genes and phenotypic traits are many-to-many” (Baylis and Robert). In other words, this phenomenon known as pleiotropy maintains that toying with a single gene may have multiple, unexpected effects. Therefore, the potential for serious correlative physical and psychological harms is unusually high with genetic enhancement technologies. For instance, a gene therapy clinical trial conducted nearly two decades ago ended in a tragedy due to the researchers’ negligence. In an interview with James M. Wilson, the researcher responsible for the trial, Wilson acknowledged that “[i]n the 1990s, scientists such as himself were too caught up in the promise of gene therapy to realize that they did not know enough about it to warrant human testing” (Wenner). This case study elucidates the momentum with which scientists proceeded with testing despite being unaware of its potentially catastrophic consequences. If researchers can make this blunder with gene therapy, then the ramifications of genetic enhancement technologies can be disastrous, as there is far more pleiotropy in genetic enhancement than gene therapy.
Lastly, implementing genetic enhancement technologies in a free market may widen the gap between the ‘haves’ and ‘have-nots’. Understandably, genetic enhancements will initially be expensive, catering to only the rich and powerful who have the means to afford it. This differential access will accentuate the “vagaries of the natural lottery as well as socio-economic differences” (Baylis and Robert). In the worst-case scenario, the unequal access will “‘divide society into the enhanced and the un-enhanced’” (Baylis and Robert). Not only would such a divide threaten the principle of equality but it would also obstruct upward social mobility, ultimately dissolving thin link between the poor and rich.
The slippery slope argument and the related ethical concerns can only be prevented in the presence of strict government regulation. Fortunately, the evolution of Dutch euthanasia practice bears witness to the efficacy of government regulation in reversing a slippery slope. As the number of unjustified ‘mercy killings’ increased, legislators introduced legislation which established certain constraints without entirely banning euthanasia. These constraints reined in the number of ‘mercy killings’, since it required each doctor to thoroughly report his/her actions to the state prosecutor (McGleenan). If law was capable of stopping a downward slide in the Netherlands, then regulation should ensure that consenting to somatic gene therapy does not lead to the acceptance of other applications of genetic modification (i.e. germline gene therapy and genetic enhancement).
In addition, the regulation must be increasingly strict to counter corporate greed. In other words, multinational industries and corporations will embrace the commercial viability (profitability and marketability) of gene therapy technologies since “ethical concerns are easily swept aside when there is (serious) money to be made” (Baylis and Robert). For this reason, the government regulation must be rigid and mindful to tackle multinationals and their commercial interests.
Lastly, global regulation is crucial to prevent the abuse of genetic enhancement technologies in any particular nation-state. If any country lacks regulation, the emergence of abusive applications of gene therapy (genetic enhancement) is a strong possibility. Such happened two years ago in China, where researchers created the first genetically modified human embryo. In response to this shocking news, TED spokesperson Paul Knoepfler claimed that “they cracked the door ajar on a Pandora’s box […] and some people are going to run with this technology and try to make designer babies” (Knoepfler). Even if a couple countries strictly regulate their research industries, a spare few, like China, will abuse their technologies and violate basic ethical norms. Therefore, all governments must conceive strict regulation to entirely prohibit the exploitation of gene therapy.
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