case studies of genetic engineering in humans

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Article Contents

Introduction, human enhancement, genetic engineering, conclusions.

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Human enhancement: Genetic engineering and evolution

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Mara Almeida, Rui Diogo, Human enhancement: Genetic engineering and evolution, Evolution, Medicine, and Public Health , Volume 2019, Issue 1, 2019, Pages 183–189, https://doi.org/10.1093/emph/eoz026

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Genetic engineering opens new possibilities for biomedical enhancement requiring ethical, societal and practical considerations to evaluate its implications for human biology, human evolution and our natural environment. In this Commentary, we consider human enhancement, and in particular, we explore genetic enhancement in an evolutionary context. In summarizing key open questions, we highlight the importance of acknowledging multiple effects (pleiotropy) and complex epigenetic interactions among genotype, phenotype and ecology, and the need to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). We also propose that a practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations. Overall, we suggest that it is essential for ethical, philosophical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

Lay Summary: This Commentary explores genetic enhancement in an evolutionary context. We highlight the multiple effects associated with germline heritable genetic intervention, the need to consider the unit of impact to human populations and their natural environment, and propose that a practicable distinction between ‘therapy’ and ‘enhancement’ is needed.

There are countless examples where technology has contributed to ameliorate the lives of people by improving their inherent or acquired capabilities. For example, over time, there have been biomedical interventions attempting to restore functions that are deficient, such as vision, hearing or mobility. If we consider human vision, substantial advances started from the time spectacles were developed (possibly in the 13th century), continuing in the last few years, with researchers implanting artificial retinas to give blind patients partial sight [ 1–3 ]. Recently, scientists have also successfully linked the brain of a paralysed man to a computer chip, which helped restore partial movement of limbs previously non-responsive [ 4 , 5 ]. In addition, synthetic blood substitutes have been created, which could be used in human patients in the future [ 6–8 ].

The progress being made by technology in a restorative and therapeutic context could in theory be applied in other contexts to treat non-pathological conditions. Many of the technologies and pharmaceutical products developed in a medical context to treat patients are already being used by humans to ‘enhance’ some aspect of their bodies, for example drugs to boost brain power, nutritional supplements, brain stimulating technologies to control mood or growth hormones for children of short stature. Assistive technology for disabled people, reproductive medicine and pharmacology, beside their therapeutic and restorative use, have a greater potential for human ‘enhancement’ than currently thought. There are also dual outcomes as some therapies can have effects that amount to an enhancement as for example, the artificial legs used by the South African sprinter Oscar Pistorius providing him with a competitive advantage.

This commentary will provide general ethical considerations on human enhancement, and within the several forms of so-called human biomedical enhancement, it will focus on genetic engineering, particularly on germline (heritable) genetic interventions and on the insights evolutionary biology can provide in rationalizing its likely impact. These insights are a subject often limited in discussions on genetic engineering and human enhancement in general, and its links to ethical, philosophical and policy discussions, in particular [ 9 ]. The rapid advances in genetic technology make this debate very topical. Moreover, genes are thought to play a very substantial role in biological evolution and development of the human species, thus making this a topic requiring due consideration. With this commentary, we explore how concepts based in evolutionary biology could contribute to better assess the implications of human germline modifications, assuming they were widely employed. We conclude our brief analysis by summarizing key issues requiring resolution and potential approaches to progress them. Overall, the aim is to contribute to the debate on human genetic enhancement by looking not only at the future, as it is so often done, but also at our evolutionary past.

The noun ‘enhancement’ comes from the verb ‘enhance’, meaning ‘to increase or improve’. The verb enhance can be traced back to the vulgar Latin inaltiare and late Latin inaltare (‘raise, exalt’), from ‘ altare ’ (‘make high’) and altus (‘high’), literally ‘grown tall’. For centuries human enhancement has populated our imagination outlined by stories ranging from the myths of supernormal strengths and eternal life to the superpowers illustrated by the 20th century comic books superheroes. The desire of overcoming normal human capacities and the transformation to an almost ‘perfect’ form has been part of the history of civilization, extending from arts and religion to philosophy. The goal of improving the human condition and health has always been a driver for innovation and biomedical developments.

In the broadest sense, the process of human enhancement can be considered as an improvement of the ‘limitations’ of a ‘natural version’ of the human species with respect to a specific reference in time, and to different environments, which can vary depending on factors such as, for example, climate change. The limitations of the human condition can be physical and/or mental/cognitive (e.g. vision, strength or memory). This poses relevant questions of what a real or perceived human limitation is in the environment and times in which we are living and how it can be shifted over time considering social norms and cultural values of modern societies. Besides, the impact that overcoming these limitations will have on us humans, and the environment, should also be considered. For example, if we boost the immune system of specific people, this may contribute to the development/evolution of more resistant viruses and bacteria or/and lead to new viruses and bacteria to emerge. In environmental terms, enhancing the longevity of humans could contribute to a massive increase in global population, creating additional pressures on ecosystems already under human pressure.

Two decades ago, the practices of human enhancement have been described as ‘biomedical interventions that are used to improve human form or functioning beyond what is necessary to restore or sustain health’ [ 10 ]. The range of these practices has now increased with technological development, and they are ‘any kind of genetic, biomedical, or pharmaceutical intervention aimed at improving human dispositions, capacities, or well-being, even if there is no pathology to be treated’ [ 11 ]. Practices of human enhancement could be visualized as upgrading a ‘system’, where interventions take place for a better performance of the original system. This is far from being a hypothetical situation. The rapid progress within the fields of nanotechnology, biotechnology, information technology and cognitive science has brought back discussions about the evolutionary trajectory of the human species by the promise of new applications which could provide abilities beyond current ones [ 12 , 13 ]. If such a possibility was consciously embraced and actively pursued, technology could be expected to have a revolutionary interference with human life, not just helping humans in achieving general health and capabilities commensurate with our current ones but helping to overcome human limitations far beyond of what is currently possible for human beings. The emergence of new technologies has provided a broader range of potential human interventions and the possibility of transitioning from external changes to our bodies (e.g. external prosthesis) to internal ones, especially when considering genetic manipulation, whose changes can be permanent and transmissible.

The advocates of a far-reaching human enhancement have been referred to as ‘transhumanists’. In their vision, so far, humans have largely worked to control and shape their exterior environments (niche construction) but with new technologies (e.g. biotechnology, information technology and nanotechnology) they will soon be able to control and fundamentally change their own bodies. Supporters of these technologies agree with the possibility of a more radical interference in human life by using technology to overcome human limitations [ 14–16 ], that could allow us to live longer, healthier and even happier lives [ 17 ]. On the other side, and against this position, are the so-called ‘bioconservatives’, arguing for the conservation and protection of some kind of ‘human essence’, with the argument that it exists something intrinsically valuable in human life that should be preserved [ 18 , 19 ].

There is an ongoing debate between transhumanists [ 20–22 ] and bioconservatives [ 18 , 19 , 23 ] on the ethical issues regarding the use of technologies in humans. The focus of this commentary is not centred on this debate, particularly because the discussion of these extreme, divergent positions is already very prominent in the public debate. In fact, it is interesting to notice that the ‘moderate’ discourses around this topic are much less known. In a more moderate view, perhaps one of the crucial questions to consider, independently of the moral views on human enhancement, is whether human enhancement (especially if considering germline heritable genetic interventions) is a necessary development, and represents an appropriate use of time, funding and resources compared to other pressing societal issues. It is crucial to build space for these more moderate, and perhaps less polarized voices, allowing the consideration of other positions and visions beyond those being more strongly projected so far.

Ethical and societal discussions on what constitutes human enhancement will be fundamental to support the development of policy frameworks and regulations on new technological developments. When considering the ethical implications of human enhancement that technology will be available to offer now and in the future, it could be useful to group the different kinds of human enhancements in the phenotypic and genetic categories: (i) strictly phenotypic intervention (e.g. ranging from infrared vision spectacles to exoskeletons and bionic limbs); (ii) somatic, non-heritable genetic intervention (e.g. editing of muscle cells for stronger muscles) and (iii) germline, heritable genetic intervention (e.g. editing of the C–C chemokine receptor type 5 (CCR5) gene in the Chinese baby twins, discussed later on). These categories of enhancement raise different considerations and concerns and currently present different levels of acceptance by our society. The degree of ethical, societal and environmental impacts is likely to be more limited for phenotypic interventions (i) but higher for genetic interventions (ii and iii), especially for the ones which are transmissible to future generations (iii).

The rapid advances in technology seen in the last decades, have raised the possibility of ‘radical enhancement’, defined by Nicholas Agar, ‘as the improvement of human attributes and abilities to levels that greatly exceed what is currently possible for human beings’ [ 24 ]. Genetic engineering offers the possibility of such an enhancement by providing humans a profound control over their own biology. Among other technologies, genetic engineering comprises genome editing (also called gene editing), a group of technologies with the ability to directly modify an organism’s DNA through a targeted intervention in the genome (e.g. insertion, deletion or replacement of specific genetic material) [ 25 ]. Genome editing is considered to achieve much greater precision than pre-existing forms of genetic engineering. It has been argued to be a revolutionary tool due to its efficiency, reducing cost and time. This technology is considered to have many applications for human health, in both preventing and tackling disease. Much of the ethical debate associated with this technology concerns the possible application of genome editing in the human germline, i.e. the genome that can be transmitted to following generations, be it from gametes, a fertilized egg or from first embryo divisions [ 26–28 ]. There has been concern as well as enthusiasm on the potential of the technology to modify human germline genome to provide us with traits considered positive or useful (e.g. muscle strength, memory and intelligence) in the current and future environments.

Genetic engineering: therapy or enhancement and predictability of outcomes

To explore some of the possible implications of heritable interventions we will take as an example the editing (more specifically ‘deletion’ using CRISPR genome editing technology) of several base pairs of the CCR5 gene. Such intervention was practised in 2018 in two non-identical twin girls born in China. Loss of function mutations of the CCR5 had been previously shown to provide resistance to HIV. Therefore, the gene deletion would be expected to protect the twin baby girls from risk of transmission of HIV which could have occurred from their father (HIV-positive). However, the father had the infection kept under control and the titre of HIV virus was undetectable, which means that risk of transmission of HIV infection to the babies was negligible [ 29 ].

From an ethical ground, based on current acceptable practices, this case has been widely criticized by the scientific community beside being considered by many a case of human enhancement intervention rather than therapy [ 29 , 30 ]. One of the questions this example helps illustrate is that the ethical boundary between a therapy that ‘corrects’ a disorder by restoring performance to a ‘normal’ scope, and an intervention that ‘enhances’ human ability outside the accepted ‘normal’ scope, is not always easy to draw. For the sake of argument, it could be assumed that therapy involves attempts to restore a certain condition of health, normality or sanity of the ‘natural’ condition of a specific individual. If we take this approach, the question is how health, normality and sanity, as well as natural per se, are defined, as the meaning of these concepts shift over time to accommodate social norms and cultural values of modern societies. It could be said that the difficulty of developing a conceptual distinction between therapy and enhancement has always been present. However, the potential significance of such distinction is only now, with the acceleration and impact of technological developments, becoming more evident.

Beyond ethical questions, a major problem of this intervention is that we do not (yet?) know exactly the totality of the effects that the artificial mutation of the CCR5 may have, at both the genetic and phenotypic levels. This is because we now know that, contrary to the idea of ‘one gene-one trait’ accepted some decades ago, a gene—or its absence—can affect numerous traits, many of them being apparently unrelated (a phenomenon also known as pleiotropy). That is, due to constrained developmental interactions, mechanisms and genetic networks, a change in a single gene can result in a cascade of multiple effects [ 31 ]. In the case of CCR5, we currently know that the mutation offers protection against HIV infection, and also seems to increase the risk of severe or fatal reactions to some infectious diseases, such as the influenza virus [ 32 ]. It has also been observed that among people with multiple sclerosis, the ones with CCR5 mutation are twice as likely to die early than are people without the mutation [ 33 ]. Some studies have also shown that defective CCR5 can have a positive effect in cognition to enhance learning and memory in mice [ 34 ]. However, it’s not clear if this effect would be translated into humans. The example serves to illustrate that, even if human enhancement with gene editing methods was considered ethically sound, assessing the totality of its implications on solid grounds may be difficult to achieve.

Genetic engineering and human evolution: large-scale impacts

Beyond providing the opportunity of enhancing human capabilities in specific individuals, intervening in the germline is likely to have an impact on the evolutionary processes of the human species raising questions on the scale and type of impacts. In fact, the use of large-scale genetic engineering might exponentially increase the force of ‘niche construction’ in human evolution, and therefore raise ethical and practical questions never faced by our species before. It has been argued that natural selection is a mechanism of lesser importance in the case of current human evolution, as compared to other organisms, because of advances in medicine and healthcare [ 35 ]. According to such a view, among many others advances, natural selection has been conditioned by our ‘niche-construction’ ability to improve healthcare and access to clean water and food, thus changing the landscape of pressures that humans have been facing for survival. An underlying assumption or position of the current debate is that, within our human species, the force of natural selection became minimized and that we are somehow at the ‘end-point’ of our evolution [ 36 ]. If this premise holds true, one could argue that evolution is no longer a force in human history and hence that any human enhancement would not be substituting itself to human evolution as a key driver for future changes.

However, it is useful to remember that, as defined by Darwin in his book ‘On the Origin of the Species’, natural selection is a process in which organisms that happen to be ‘better’ adapted to a certain environment tend to have higher survival and/or reproductive rates than other organisms [ 37 ]. When comparing human evolution to human genetic enhancement, an acceptable position could be to consider ethically sound those interventions that could be replicated naturally by evolution, as in the case of the CCR5 gene. Even if this approach was taken, however, it is important to bear in mind that human evolution acts on human traits sometimes increasing and sometimes decreasing our biological fitness, in a constant evolutionary trade-off and in a contingent and/or neutral—in the sense of not ‘progressive’—process. In other worlds, differently from genetic human enhancement, natural selection does not ‘ aim ’ at improving human traits [ 38 ]. Human evolution and the so-called genetic human enhancement would seem therefore to involve different underlying processes, raising several questions regarding the implications and risks of the latter.

But using genetic engineering to treat humans has been proposed far beyond the therapeutic case or to introduce genetic modifications known to already occur in nature. In particular, when looking into the views expressed on the balance between human evolution and genetic engineering, some argue that it may be appropriate to use genetic interventions to go beyond what natural selection has contributed to our species when it comes to eradicate vulnerabilities [ 17 ]. Furthermore, when considering the environmental, ecological and social issues of contemporary times, some suggest that genetic technologies could be crucial tools to contribute to human survival and well-being [ 20–22 ]. The possible need to ‘engineer’ human traits to ensure our survival could include the ability to allow our species to adapt rapidly to the rate of environmental change caused by human activity, for which Darwinian evolution may be too slow [ 39 ]. Or, for instance, to support long-distance space travel by engineering resistance to radiation and osteoporosis, along with other conditions which would be highly advantageous in space [ 40 ].

When considering the ethical and societal merits of these propositions, it is useful to consider how proto-forms of enhancement has been approached by past human societies. In particular, it can be argued that humans have already employed—as part of our domestication/‘selective breeding’ of other animals—techniques of indirect manipulation of genomes on a relatively large scale over many millennia, albeit not on humans. The large-scale selective breeding of plants and animals over prehistoric and historic periods could be claimed to have already shaped some of our natural environment. Selective breeding has been used to obtain specific characteristics considered useful at a given time in plants and animals. Therefore, their evolutionary processes have been altered with the aim to produce lineages with advantageous traits, which contributed to the evolution of different domesticated species. However, differently from genetic engineering, domestication possesses inherent limitations in its ability to produce major transformations in the created lineages, in contrast with the many open possibilities provided by genetic engineering.

When considering the impact of genetic engineering on human evolution, one of questions to be considered concerns the effects, if any, that genetic technology could have on the genetic pool of the human population and any implication on its resilience to unforeseen circumstances. This underlines a relevant question associated with the difference between ‘health’ and biological fitness. For example, a certain group of animals can be more ‘healthy’—as domesticated dogs—but be less biologically ‘fit’ according to Darwin’s definition. Specifically, if such group of animals are less genetically diverse than their ancestors, they could be less ‘adaptable’ to environmental changes. Assuming that, the human germline modification is undertaken at a global scale, this could be expected to have an effect, on the distribution of genetically heritable traits on the human population over time. Considering that gene and trait distributions have been changing under the processes of evolution for billions of years, the impact on evolution will need to be assessed by analysing which genetic alterations have been eventually associated with specific changes within the recent evolutionary history of humans. On this front, a key study has analysed the implications of genetic engineering on the evolutionary biology of human populations, including the possibility of reducing human genetic diversity, for instance creating a ‘biological monoculture’ [ 41 ]. The study argued that genetic engineering will have an insignificant impact on human diversity, while it would likely safeguard the capacity of human populations to deal with disease and new environmental challenges and therefore, ensure the health and longevity of our species [ 41 ]. If the findings of this study were considered consistent with other knowledge and encompassing, the impact of human genetic enhancements on the human genetic pool and associated impacts could be considered secondary aspects. However, data available from studies on domestication strongly suggests that domestication of both animals and plans might lead to not only decreased genetic diversity per se, but even affect patterns of variation in gene expression throughout the genome and generally decreased gene expression diversity across species [ 42–44 ]. Given that, according to recent studies within the field of biological anthropology recent human evolution has been in fact a process of ‘self-domestication’ [ 45 ], one could argue that studies on domestication could contribute to understanding the impacts of genetic engineering.

Beyond such considerations, it is useful to reflect on the fact that human genetic enhancement could occur on different geographical scales, regardless of the specific environment and geological periods in which humans are living and much more rapidly than in the case of evolution, in which changes are very slow. If this was to occur routinely and on a large scale, the implications of the resulting radical and abrupt changes may be difficult to predict and its impacts difficult to manage. This is currently highlighted by results of epigenetics studies, and also of the microbiome and of the effects of pollutants in the environment and their cumulative effect on the development of human and non-human organisms alike. Increasingly new evidence indicates a greater interdependence between humans and their environments (including other microorganisms), indicating that modifying the environment can have direct and unpredictable consequences on humans as well. This highlight the need of a ‘systems level’ approach. An approach in which the ‘bounded body’ of the individual human as a basic unit of biological or social action would need to be questioned in favour of a more encompassing and holistic unit. In fact, within biology, there is a new field, Systems Biology, which stresses the need to understand the role that pleiotropy, and thus networks at multiple levels—e.g. genetic, cellular, among individuals and among different taxa—play within biological systems and their evolution [ 46 ]. Currently, much still needs to be understood about gene function, its role in human biological systems and the interaction between genes and external factors such as environment, diet and so on. In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of human evolution enable us to better understand the implications of genetic interventions.

New forms of human enhancement are increasingly coming to play due to technological development. If phenotypic and somatic interventions for human enhancement pose already significant ethical and societal challenges, germline heritable genetic intervention, require much broader and complex considerations at the level of the individual, society and human species as a whole. Germline interventions associated with modern technologies are capable of much more rapid, large-scale impacts and seem capable of radically altering the balance of humans with the environment. We know now that beside the role genes play on biological evolution and development, genetic interventions can induce multiple effects (pleiotropy) and complex epigenetics interactions among genotype, phenotype and ecology of a certain environment. As a result of the rapidity and scale with which such impact could be realized, it is essential for ethical and societal debates, as well as underlying scientific studies, to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). An important practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations, although a distinct line between the two may be difficult to draw.

In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of humans and other organisms, including domesticated ones, enable us to better understand the implications of genetic interventions. In particular, effective regulation of genetic engineering may need to be based on a deep knowledge of the exact links between phenotype and genotype, as well the interaction of the human species with the environment and vice versa .

For a broader and consistent debate, it will be essential for technological, philosophical, ethical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) of Portugal [CFCUL/FIL/00678/2019 to M.A.].

Conflict of interest : None declared.

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November 1, 2021

Four Success Stories in Gene Therapy

The field is beginning to fulfill its potential. These therapies offer a glimpse of what’s to come

By Jim Daley

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After numerous setbacks at the turn of the century, gene therapy is treating diseases ranging from neuromuscular disorders to cancer to blindness. The success is often qualified, however. Some of these therapies have proved effective at alleviating disease but come with a high price tag and other accessibility issues: Even when people know that a protocol exists for their disease and even if they can afford it or have an insurance company that will cover the cost—which can range from $400,000 to $2 million—they may not be able to travel to the few academic centers that offer it. Other therapies alleviate symptoms but don’t eliminate the underlying cause.

“Completely curing patients is obviously going to be a huge success, but it’s not [yet] an achievable aim in a lot of situations,” says Julie Crudele, a neurologist and gene therapy researcher at the University of Washington. Still, even limited advances pave the way for ongoing progress, she adds, pointing to research in her patients who have Duchenne muscular dystrophy: “In most of these clinical trials, we learn important things.”

Thanks to that new knowledge and steadfast investigations, gene therapy researchers can now point to a growing list of successful gene therapies. Here are four of the most promising.

Gene Swaps to Prevent Vision Loss

Some babies are born with severe vision loss caused by retinal diseases that once led inevitably to total blindness. Today some of them can benefit from a gene therapy created by wife-and-husband team Jean Bennett and Albert Maguire, who are now ophthalmologists at the University of Pennsylvania.

When the pair first began researching retinal disease in 1991, none of the genes now known to cause vision loss and blindness had been identified. In 1993 researchers identified one potential target gene, RPE65 . Seven years later Bennett and Maguire tested a therapy targeting that gene in three dogs with severe vision loss—it restored vision for all three.

In humans, the inherited condition that best corresponds with the dogs’ vision loss is Leber congenital amaurosis (LCA). LCA prevents the retina, a layer of light-sensitive cells at the back of the eye, from properly reacting or sending signals to the brain when a photon strikes it. The condition can cause uncontrolled shaking of the eye (nystagmus), prevents pupils from responding to light and typically results in total blindness by age 40. Researchers have linked the disease to mutations or deletions in any one of 27 genes associated with retinal development and function. Until gene therapy, there was no cure.

Mutations in RPE65 are just one cause of inherited retinal dystrophy, but it was a cause that Bennett and Maguire could act on. The researchers used a harmless adeno-associated virus (AAV), which they programmed to find retinal cells and insert a healthy version of the gene, and injected it into a patient’s eye directly underneath the retina. In 2017, after a series of clinical trials, the Food and Drug Administration approved voretigene neparvovecrzyl (marketed as Luxturna) for the treatment of any heritable retinal dystrophy caused by the mutated RPE65 gene, including LCA type 2 and retinitis pigmentosa, another congenital eye disease that affects photoreceptors in the retina. Luxturna was the first FDA-approved in vivo gene therapy, which is delivered to target cells inside the body (previously approved ex vivo therapies deliver the genetic material to target cells in samples collected from the body, which are then reinjected).

Spark Therapeutics, the company that makes Luxturna, estimates that about 6,000 people worldwide and between 1,000 and 2,000 in the U.S. may be eligible for its treatment—few enough that Luxturna was granted “orphan drug” status, a designation that the FDA uses to incentivize development of treatments for rare diseases. That wasn’t enough to bring the cost down. The therapy is priced at about $425,000 per injection, or nearly $1 million for both eyes. Despite the cost, Maguire says, “I have not yet seen anybody in the U.S. who hasn’t gotten access based on inability to pay.”

Those treated show significant improvement: Patients who were once unable to see clearly had their vision restored, often very quickly. Some reported that, after the injections, they could see stars for the first time.

While it is unclear how long the effects will last, follow-up data published in 2017 showed that all 20 patients treated with Luxturna in a phase 3 trial had retained their improved vision three years later. Bennett says five-year follow-up with 29 patients, which is currently undergoing peer review, showed similarly successful results. “These people can now do things they never could have dreamed of doing, and they’re more independent and enjoying life.”

Training the Immune System to Fight Cancer

Gene therapy has made inroads against cancer, too. An approach known as chimeric antigen receptor (CAR) T cell therapy works by programming a patient’s immune cells to recognize and target cells with cancerous mutations. Steven Rosenberg, chief of surgery at the National Cancer Institute, helped to develop the therapy and published the first successful results in a 2010 study for the treatment of lymphoma.

“That patient had massive amounts of disease in his chest and his belly, and he underwent a complete regression,” Rosenberg says—a regression that has now lasted 11 years and counting.

CAR T cell therapy takes advantage of white blood cells, called T cells, that serve as the first line of defense against pathogens. The approach uses a patient’s own T cells, which are removed and genetically altered so they can build receptors specific to cancer cells. Once infused back into the patient, the modified T cells, which now have the ability to recognize and attack cancerous cells, reproduce and remain on alert for future encounters.

In 2016 researchers at the University of Pennsylvania reported results from a CAR T cell treatment, called tisagenlecleucel, for acute lymphoblastic leukemia (ALL), one of the most common childhood cancers. In patients with ALL, mutations in the DNA of bone marrow cells cause them to produce massive quantities of lymphoblasts, or undeveloped white blood cells, which accumulate in the bloodstream. The disease progresses rapidly: adults face a low likelihood of cure, and fewer than half survive more than five years after diagnosis.

When directed against ALL, CAR T cells are ruthlessly efficient—a single modified T cell can kill as many as 100,000 lymphoblasts. In the University of Pennsylvania study, 29 out of 52 ALL patients treated with tisagenlecleucel went into sustained remission. Based on that study’s results, the FDA approved the therapy (produced by Novartis as Kymriah) for treating ALL, and the following year the agency approved it for use against diffuse large B cell lymphoma. The one-time procedure costs upward of $475,000.

CAR T cell therapy is not without risk. It can cause severe side effects, including cytokine release syndrome (CRS), a dangerous inflammatory response that ranges from mild flulike symptoms in less severe cases to multiorgan failure and even death. CRS isn’t specific to CAR T therapy: Researchers first observed it in the 1990s as a side effect of antibody therapies used in organ transplants. Today, with a combination of newer drugs and vigilance, doctors better understand how far they can push treatment without triggering CRS. Rosenberg says that “we know how to deal with side effects as soon as they occur, and serious illness and death from cytokine release syndrome have dropped drastically from the earliest days.”

Through 2020, the remission rate among ALL patients treated with Kymriah was about 85 percent. More than half had no relapses after a year. Novartis plans to track outcomes of all patients who received the therapy for 15 years to better understand how long it remains effective.

Precision Editing for Blood Disorders

One new arrival to the gene therapy scene is being watched particularly closely: in vivo gene editing using a system called CRISPR, which has become one of the most promising gene therapies since Jennifer Doudna and Emmanuelle Charpentier discovered it in 2012—a feat for which they shared the 2020 Nobel Prize in Chemistry. The first results from a small clinical trial aimed at treating sickle cell disease and a closely related disorder, called beta thalassemia, were published this past June.

Sickle cell disease affects millions of people worldwide and causes the production of crescent-shaped red blood cells that are stickier and more rigid than healthy cells, which can lead to anemia and life-threatening health crises. Beta thalassemia, which affects millions more, occurs when a different mutation causes someone’s body to produce less hemoglobin, the iron-rich protein that allows red blood cells to carry oxygen. Bone marrow transplants may offer a cure for those who can find matching donors, but otherwise treatments for both consist primarily of blood transfusions and medications to treat associated complications.

Both sickle cell disease and beta thalassemia are caused by heritable, single-gene mutations, making them good candidates for gene-editing therapy. The method, CRISPR-Cas9, uses DNA sequences from bacteria (clustered regularly interspaced short palindromic repeats, or CRISPR) and a CRISPR-associated enzyme (Cas for short) to edit the patient’s genome. The CRISPR sequences are transcribed onto RNA that locates and identifies DNA sequences to blame for a particular condition. When packaged together with Cas9, transcribed RNA locates the target sequence, and Cas9 snips it out of the DNA, thereby repairing or deactivating the problematic gene.

At a conference this past June, Vertex Pharmaceuticals and CRISPR Therapeutics announced unpublished results from a clinical trial of beta thalassemia and sickle cell patients treated with CTX001, a CRISPR-Cas9-based therapy. In both cases, the therapy does not shut off a target gene but instead delivers a gene that boosts production of healthy fetal hemoglobin—a gene normally turned off shortly after birth. Fifteen people with beta thalassemia were treated with CTX001; after three months or more, all 15 showed rapidly improved hemoglobin levels and no longer required blood transfusions. Seven people with severe sickle cell disease received the same treatment, all of whom showed increased levels of hemoglobin and reported at least three months without severe pain. More than a year later those improvements persisted in five subjects with beta thalassemia and two with sickle cell. The trial is ongoing, and patients are still being enrolled. A Vertex spokesperson says it hopes to enroll 45 patients in all and file for U.S. approval as early as 2022.

Derailing a Potentially Lethal Illness

Spinal muscular atrophy (SMA) is a neurodegenerative disease in which motor neurons—the nerves that control muscle movement and that connect the spinal cord to muscles and organs—degrade, malfunction and die. It is typically diagnosed in infants and toddlers. The underlying cause is a genetic mutation that inhibits production of a protein involved in building and maintaining those motor neurons.

The four types of SMA are ranked by severity and related to how much motor neuron protein a person’s cells can still produce. In the most severe or type I cases, even the most basic functions, such as breathing, sitting and swallowing, prove extremely challenging. Infants diagnosed with type I SMA have historically had a 90 percent mortality rate by one year.

Adrian Krainer, a biochemist at Cold Spring Harbor Laboratory, first grew interested in SMA when he attended a National Institutes of Health workshop in 1999. At the time, Krainer was investigating how RNA mutations cause cancer and genetic diseases when they disrupt a process called splicing, and researchers suspected that a defect in the process might be at the root of SMA. When RNA is transcribed from the DNA template, it needs to be edited or “spliced” into messenger RNA (mRNA) before it can guide protein production. During that editing process, some sequences are cut out (introns), and those that remain (exons) are strung together.

Krainer realized that there were similarities between the defects associated with SMA and one of the mechanisms he had been studying—namely, a mistake that occurs when an important exon is inadvertently lost during RNA splicing. People with SMA were missing one of these crucial gene sequences, called SMN1 .

“If we could figure out why this exon was being skipped and if we could find a solution for that, then presumably this could help all the [SMA] patients,” Krainer says. The solution he and his colleagues hit on, antisense therapy, employs single strands of synthetic nucleotides to deliver genetic instructions directly to cells in the body [see “ The Gene Fix ”]. In SMA’s case, the instructions induce a different motor neuron gene, SMN2 , which normally produces small amounts of the missing motor neuron protein, to produce much more of it and effectively fill in for SMN1 . The first clinical trial to test the approach began in 2010, and by 2016 the FDA approved nusinersen (marketed as Spinraza). Because the therapy does not incorporate itself into the genome, it must be administered every four months to maintain protein production. And it is staggeringly expensive: a single Spinraza treatment costs as much as $750,000 in the first year and $375,000 annually thereafter.

Since 2016, more than 10,000 people have been treated with it worldwide. Although Spinraza can’t restore completely normal motor function (a single motor neuron gene just can’t produce enough protein for that), it can help children with any of the four types of SMA live longer and more active lives. In many cases, Spinraza has improved patients’ motor function, allowing even those with more severe cases to breathe, swallow and sit upright on their own. “The most striking results are in patients who are being treated very shortly after birth, when they have a genetic diagnosis through newborn screening,” Krainer says. “Then, you can actually prevent the onset of the disease—for several years and hopefully forever.”

This article is part of “ Innovations In: Gene Therapy ,” an editorially independent special report that was produced with financial support from Pfizer .

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The CRISPR Revolution

He inherited a devastating disease. a crispr gene-editing breakthrough stopped it.

Patrick Doherty volunteered for a new medical intervention of gene-editor infusions for the treatment of genetically-based diseases. Patrick Doherty hide caption

Patrick Doherty volunteered for a new medical intervention of gene-editor infusions for the treatment of genetically-based diseases.

Patrick Doherty had always been very active. He trekked the Himalayas and hiked trails in Spain.

But about a year and a half ago, he noticed pins and needles in his fingers and toes. His feet got cold. And then he started getting out of breath any time he walked his dog up the hills of County Donegal in Ireland where he lives.

"I noticed on some of the larger hill climbs I was getting a bit breathless," says Doherty, 65. "So I realized something was wrong."

Doherty found out he had a rare, but devastating inherited disease — known as transthyretin amyloidosis — that had killed his father. A misshapen protein was building up in his body, destroying important tissues, such as nerves in his hands and feet and his heart.

Doherty had watched others get crippled and die difficult deaths from amyloidosis.

"It's terrible prognosis," Doherty says. "This is a condition that deteriorates very rapidly. It's just dreadful."

So Doherty was thrilled when he found out that doctors were testing a new way to try to treat amyloidosis. The approach used a revolutionary gene-editing technique called CRISPR , which allows scientists to make very precise changes in DNA.

"I thought: Fantastic. I jumped at the opportunity," Doherty says.

On Saturday, researchers reported the first data indicating that the experimental treatment worked, causing levels of the destructive protein to plummet in Doherty's body and the bodies of five other patients treated with the approach.

"I feel fantastic," Doherty says. "It's just phenomenal."

The advance is being hailed not just for amyloidosis patients but also as a proof-of-concept that CRISPR could be used to treat many other, much more common diseases. It's a new way of using the innovative technology.

"This is a major milestone for patients," says Jennifer Doudna of the University of California, Berkeley, who shared a Nobel Prize for her work helping develop CRISPR.

"While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place," Doudna says.

CRISPR has already been shown to help patients suffering from the devastating blood disorders sickle cell disease and beta thalassemia . And doctors are trying to use it to treat cancer and to restore vision to people blinded by a rare genetic disorder.

But those experiments involve taking cells out of the body, editing them in the lab, and infusing them back in or injecting CRISPR directly into cells that need fixing.

The study Doherty volunteered for is the first in which doctors are simply infusing the gene-editor directly into patients and letting it find its own way to the right gene in the right cells. In this case, it's cells in the liver making the destructive protein.

"This is the first example in which CRISPR-Cas9 is injected directly into the bloodstream — in other words systemic administration — where we use it as a way to reach a tissue that's far away from the site of injection and very specifically use it to edit disease-causing genes," says John Leonard, the CEO of Intellia Therapeutics , which is sponsoring the study.

Doctors infused billions of microscopic structures known as nanoparticles carrying genetic instructions for the CRISPR gene-editor into four patients in London and two in New Zealand. The nanoparticles were absorbed by their livers, where they unleashed armies of CRISPR gene-editors. The CRISPR editor homed in on the target gene in the liver and sliced it, disabling production of the destructive protein.

Within weeks, the levels of protein causing the disease plummeted, especially in the volunteers who received a higher dose. Researchers reported at the Peripheral Nerve Society Annual Meeting and in a paper published in The New England Journal of Medicine .

"It really is exciting," says Dr. Julian Gillmore , who is leading the study at the University College London, Royal Free Hospital.

"This has the potential to completely revolutionize the outcome for these patients who have lived with this disease in their family for many generations. It's decimated some families that I've been looking after. So this is amazing," Gillmore says.

The patients will have to be followed longer, and more patients will have to be treated, to make sure the treatment's safe, and determine how much it's helping, Gillmore stresses. But the approach could help those struck by amyloidosis that isn't inherited, which is a far more common version of the disease, he says.

Moreover, the promising results potentially open the door for using the same approach to treatment of many other, more common diseases for which taking cells out of the body or directly injecting CRISPR isn't realistic, including heart disease, muscular dystrophy and brain diseases such as Alzheimer's.

"This is really opening a new era as we think about gene-editing where we can begin to think about accessing all kinds of different tissue in the body via systemic administration," Leonard says.

Other scientists who are not involved in the research agree.

"This is a wonderful day for the future of gene-editing as a medicine," agree Fyodor Urnov , a professor of genetics at the University of California, Berkeley. "We as a species are watching this remarkable new show called: our gene-edited future."

Doherty says he started feeling better within weeks of the treatment and has continued to improve in the weeks since then.

"I definitely feel better," he told NPR. "I'm speaking to you from upstairs in our house. I climbed stairs to get up here. I would have been feeling breathless. I'm thrilled."

Biotech potatoes: A case study of how genetic engineering can improve our food supply

To help demonstrate the power of biotechnology, consider the following analogy: Imagine you have two decks of cards, one red and one blue, and each deck contains all the genes of a potato. The red deck makes a great potato, but lacks resistance to late blight disease. The blue deck has late blight resistance …. but these potatoes are unmarketable.

To get the blue ace of spades (LB resistance) together with the rest of the red deck (good potatoes), you could shuffle the two together and divide the deck in two …. You can keep shuffling this new deck with more red cards, but imagine how many times you would have to shuffle the cards to get a perfect deck ….

Compare this with simply picking out the blue ace of spades and placing it into the red deck. Wouldn’t that be easier? …. This is essentially the difference between using traditional breeding (shuffling) and biotechnology (stacking the deck). …

Together with new breeding technologies …. genetic modification remains a useful tool in the genetic improvement of potatoes. The 100-plus wild species relatives of potato provide a virtually endless source of traits that can be incorporated into elite varieties relatively easily and quickly.

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• Published: 14 May 2020

Legal reflections on the case of genome-edited babies

• Shuang Liu 1  

Global Health Research and Policy volume  5 , Article number:  24 ( 2020 ) Cite this article

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Human genome-editing is banned by guidelines, laws and regulations in most countries. However, the first criminal case on genome-edited babies was sentenced in China in 2019. In this commentary we discuss our legal reflections on this case. Genome-editing on healthy embryos of human may lead to irreversible mutations and serious consequences on the heredity of future generations, while its long-term safety is unpredictable. A full set of laws, regulations along with the guidelines should be formulated to penalize genome-editing behaviors and prevent similar negative events in the future. More effective and binding mechanisms should be constructed and implemented among different countries. A collaborative network should be strengthened for better global registry and surveillance of human genome-editing technologies and research.

Introduction

On December 30, 2019, a Chinese researcher, Jiankui He, was sentenced by Chinese local Court in Shenzhen City to 3 years of imprisonment with a fine of 3 million RMB Yuan for committing the crime of “Illegal Medical Practice”, and the other two defendants in the same case were also sentenced. One was sentenced to imprisonment of 2 years with a fine of 1 million RMB Yuan, another was sentenced to imprisonment of 1 year and 6 months (with probation of 2 years) with a fine of 0.5 million RMB Yuan [ 1 ]. The court concluded that each of the three defendants did not have a doctor’s practice license, and they applied the genome-editing technology (known as Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR) to human assisted reproductive medicine, which caused the genetic changes of babies. In this case, the fathers are HIV positive and the mothers are HIV negative. Eggs were extracted from their body and the twin pregnancy gestated after the genome-edited embryos were transferred to their uterus. Genome-editing was undertaken to remove the CCR5 gene which allows the HIV to infect cells. The birth of babies represented a controversial leap in genome editing [ 2 ]. One day later when He announced the research of his team, more than 100 Chinese scientists and scholars signed a joint statement to denounce the trial. They reasserted that both the accuracy of the CRISPR and the potential off-target effects are controversial in the scientific community. Any attempt to directly transform human embryos and produce babies before rigorous tests poses tremendous risks. Such experiment is forbidden by the international biomedical community.

Genome-editing technology can bring great positive influence to the human being. It can be used to treat certain genome-related diseases [ 3 ]. However, it can also lead to some problems, such as how to (1) use it ethically and legally; (2) acquire the real consent from the experimental subjects; (3) how to penalize the genome-editing research for non-medical reasons, etc. Specific laws and regulations are important to resolve these problems because they are the last line of defense for social governance.

Current laws and regulations of genome-editing in different countries

Human genome-editing is largely forbidden by laws or guidelines even in countries permissive to human embryonic stem cell research [ 4 ]. Many countries have banned human genome-editing. Thirty nine countries were surveyed and categorized as “Ban based on legislation” (25 countries), “Ban based on guidelines” (4), “Ambiguous” (9) and “Restrictive” (1). China, India, Ireland, and Japan forbid genome-editing based on guidelines which are less enforceable than laws and are subject to amendment [ 3 ]. In the USA, Human genome-editing is not banned, but a moratorium is imposed under vigilance of the Food and Drug Administration (FDA) and the guidelines of the National Institutes of Health (NIH). Any clinical trial proposals for germline alterations will be rejected by the Recombinant DNA Advisory Committee (RAC) of the NIH. Clinical studies are regulated by FDA [ 5 ]. In the UK, the legislation of medical use of mitochondrial replacement is likely to lead to legal permission for the modification of germline nuclear genome that can be readily changed by genome-editing technology [ 6 ].

Although genome-editing is banned in many countries, necessary and practical laws, regulations and guidelines should be developed, and appropriate penalty should be applied in proportion to the crime. Preventive measures should also be stipulated in a specific law. Early embryo genome-editing for fertility purposes violates the ethical principles provided in the “Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects” (hereafter referred to as “Declaration of Helsinki”), which has been widely accepted by the international community. In He’s case, early human embryos were edited artificially. Consequently, the genome-editing babies not only face the risk of uncertainty, but also are deprived of the right to an open future. The Article 9 of “Declaration of Helsinki” states that the responsibility for the protection of research subjects must always rest with the physicians or other health care professionals and never with the research subjects, even though they have been given consent. He and his team violated the provisions of both Article 9 of Declaration of Helsinki and the Chinese criminal law, and their misconducts should be punished.

The sentence of genome-editing babies in China

Current Chinese laws are insufficient to deal with new challenges posed by new expertise and technologies. The regulations prohibit the development of genome-editing embryos beyond 14 days. The Chinese Guideline on Human Assisted Reproductive Technologies stipulates that the use of human egg plasma and nuclear transfer technology for the purpose of reproduction, and manipulation of the genomes in human gametes, zygotes or embryos for the purpose of reproduction are prohibited. In He’s case, it is unknown whether his team had acquired the true informed consent and they were convicted the crime of “Illegal Medical Practice”. The local court concluded that their behaviors deliberately violated the National Regulations on Scientific Research and Medical Management, crossed an ethical bottom line, and rashly applied genome-editing technology. Genome-editing on embryos with existing technologies and methods is not the only way to prevent mother-to-child transmission of AIDS [ 7 ]. Besides, the experimental procedure was unclear and nontransparent, but the consequence is full of risks. However, according to the Chinese Criminal Law, three-year imprisonment and below is regarded as misdemeanor. In contrast, the punishment of similar behavior could be 10 years of imprisonment in the UK and 20 years in France at maximum [ 8 ]. It is obvious that He and his team were eager for quick success, and their misconducts were irresponsible and dangerous. Moreover, their genome-editing behavior may cause irreversible damage to the entire human genome chain. Therefore, He’s case is very typical to warn other scientists not to commit similar misconducts. Fortunately, on May 28, 2019, the Chinese government promulgated the Regulation of the People’s Republic of China on the Administration of Human Genetic Resources, which aims to protect public health, national security, and public interest through effective protection and rational use of China’s human genetic resources.

Human genome-editing technology is a two-sided sword. The advantage of its benefit can be explored. However, further legislation is required to punish misconducts and avoid potential risks.

A specific crime and more severe penalty should be formulated in the Chinese Criminal Law. Civil responsibility should be assumed if a medical institution or a person in charge do not truthfully and fully informed patients of potential risks.

Better governance is needed. According to the Administrative Penalty Law, local government and other administrative agencies should assume responsibilities if they fail to carry out their duties in ethical review, supervision and management.

More effective and binding mechanisms to constrain the use of genome-editing technology should be developed. More specific guidelines and preventive measures should be formulated in consistent with the international regulations.

A collaborative network should be strengthened for better global registry and surveillance of human genome-editing technologies and research, led by the World Health Organization (WHO) Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing.

Availability of data and materials

Not applicable.

Abbreviations

Clustered Regularly Interspaced Short Palindromic Repeats.

Food and Drug Administration

National Institutes of Health

Recombinant DNA Advisory Committee

World Health Organization

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Acknowledgements

The author would like to thank the comments and advices of reviewers in improving the quality of the article.

This work is supported by a project Research on the Recent Expansion of Chinese Criminal Law and Its Reasonable Limits funded by National Social Science Fund Project of China (grant No.: 16BFX056).

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Liu, S. Legal reflections on the case of genome-edited babies. glob health res policy 5 , 24 (2020). https://doi.org/10.1186/s41256-020-00153-4

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Committee on Gene Drive Research in Non-Human Organisms: Recommendations for Responsible Conduct; Board on Life Sciences; Division on Earth and Life Studies; National Academies of Sciences, Engineering, and Medicine. Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. Washington (DC): National Academies Press (US); 2016 Jul 28.

Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values.

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3 Case Studies to Examine Questions About Gene-Drive Modified Organisms

To examine the questions surrounding gene drive research, this report relies heavily on an extended, iterative exploration of a set of plausible case studies. The case studies are first described in a preliminary fashion in this chapter. Other chapters build on these case studies with deeper discussion of issues pertinent to value-based concerns, scientific techniques to mitigate harms, risk assessment, public engagement, and governance.

The case studies offer practical scenarios on which to base the report's analysis and recommendations and to provide a sound foundation for the further discussions that will necessarily follow this report as gene drive research advances. Given those two goals, the committee used the following three criteria to select case studies:

• Plausibility: Selection of organisms suitable for the development of a gene drive.
• Likelihood: Selection of areas for gene drive research or applications that are expected to be pursued in the near term.
• Diversity: Selections are intended to reflect a range of plausible target organisms, applications, mechanisms of action, and locations (in terms of where gene drive research is carried out and where organisms could potentially be released).
• BASIC CRITERIA FOR THE DEVELOPMENT OF GENE-DRIVE MODIFIED ORGANISMS

It is particularly important to understand what is meant by plausibility . Many organisms and traits are not suitable for gene drive research. The two most basic requirements for a target organism of gene drive work are that it reproduces sexually and that it reproduces rapidly (see Box 3-1 ). For this reason, many insects and rodents are good candidates for gene drive research. Organisms such as viruses, many plants, and most bacteria, which use other means to reproduce, are not good targets for gene drive research (see Box 3-2 for additional considerations for plants). Humans, elephants, and trees are also not good targets for gene drive research because they have long generation times; any modification introduced into such a population could require decades or centuries to become established. However, a gene drive could work in an organism that has alternating sexual and asexual phases of reproduction, as in Plasmodium falciparum , the parasite that causes malaria ( de Koning-Ward et al., 2015 ), even though its population structure may render spread of the gene drive difficult.

Basic Criteria for the Development of Gene-Drive Modified Organisms.

Additional Considerations for Gene-Drive Modified Plants.

In addition, some traits may simply be too complex to alter because they are governed by many genes, their expression is shaped by the external environment, or they are modified by internal or development cues (e.g., epigenetics) that are not yet fully elucidated. For example, flowering time in maize is determined by the cumulative effects of many genes ( Buckler et al., 2009 ).

In some cases, many applications of gene drive research may not be necessary, because efficient non-gene drive approaches are able to generate the desired outcome.

Given these and other technical and regulatory challenges (discussed in detail in the other chapters), predictions about how gene drives might be used need to be treated critically. The committee developed case studies to illustrate the issues highlighted in Table 3-1 .

Selected Case Studies on Gene Drive Research and Related Applications.

• CASE STUDY 1: USING AEDES AEGYPTI AND AEDES ALBOPICTUS MOSQUITOES TO MANAGE DENGUE

Establish gene drives in Aedes aegypti and Aedes albopictus mosquitos to control the spread of dengue throughout the world.

Dengue, a debilitating viral infection, is one of the leading causes of sickness and death in subtropical and tropical countries around the world. Adults and children who contract dengue often experience a flu-like illness. Severe dengue, also called Dengue Hemorrhagic Fever, causes bleeding, persistent vomiting, breathing difficulties, and other complications that may lead to death. Severe dengue disproportionately affects children.

Dengue is caused by infection with any of five serotypes of dengue virus (which is a flavivirus). The virus is transmitted to humans via the bite of female 1 Aedes aegypti , the primary vector (carrier) in urban areas, or Aedes albopictus , the primary vector in rural areas. In April 2016, the World Health Organization endorsed the use of the first-ever dengue vaccine, Dengvaxia (CYD-TDF) by Sanofi Pasteur, in countries where dengue is endemic. 2 Research is ongoing for other vaccine candidates. Patient recovery for those who are unvaccinated depends heavily on an early diagnosis and careful management of fever symptoms.

Current Mitigation Efforts

Prevention of dengue relies entirely on vector control, mostly through ultra-low volume spraying of insecticides. Insecticide resistance is challenging the efficacy of such dengue vector control methods using currently available chemicals. Another vector control intervention is the management of mosquito vector breeding sites, which are typically man-made containers. However, because dengue disease exhibits spatiotemporal heterogeneity epidemic activity (alternating as high and low incidences between years and seasons), and because of the potential serotype interaction and co-circulations, predicting possible epidemics is extremely complex as is effective prevention. These strategies are laborious and typically reactive rather than proactive ( Achee et al., 2015 ). Additional control strategies are listed in Appendix C .

Biological controls also exist, such as the use of cyclopoid copepods ( Marten et al., 1994 ), population reduction via community participation ( Scholte et al., 2006 ; Majambere et al., 2007 ) and the use of larvivorous fish, but the maintenance of the distributed containers is a limiting factor to effective control. Another type of biological control is through the release of Wolbachia -infected mosquitoes. The bacterial symbionts in the genus Wolbachia are widely distributed in insects ( Werren et al., 1995 ; Werren and O'Neil, 1997 ; Bourtzis and Braig, 1999 ; Stouthamer et al., 1999 ). Wolbachia infection reduces the lifespan of the insect hosts ( Sinkins et al., 1997 ; Dobson et al., 2002 ; Ahantarig et al., 2011 ; Bull and Turelli, 2013 ). In addition, Wolbachia infection of Aedes aegypti confers resistance to infection with dengue and chikungunya viruses ( McMeniman et al., 2009 ; Moreira et al., 2009 ; Bian et al., 2010 ). In light of these results, small-scale trials to reduce dengue transmission using Wolbachia started in 2011 in Australia and further expanded to Vietnam, Indonesia, and Brazil. 3 Although on-going large field trials suggest a reduction of dengue incidence, there remain important considerations concerning the unanticipated evolution of the dengue virus (or other viruses infecting the same mosquito vector) that need to be addressed.

In summary, despite many available methods of mosquito control, existing methods are not yet fully effective at reducing dengue transmission.

Plausibility of a Gene Drive Solution

It may be possible to create two types of gene drives in Aedes species: one that prevents the transmission of the dengue virus and another that causes sterility. Research with Wolbachia demonstrates, in principle, the potential for those two approaches. In 2010, researchers showed that Wolbachia can be used to induce resistance in Aedes aegypti to the dengue virus. Wolbachia also can be used to shorten the life-span of Aedes aegypti ( McMeniman et al., 2009 ). Similarly, the U.K.-based company Oxitec has developed a technology to suppress Aedes aegypti populations in which male Aedes aegypti mosquitoes are genetically engineered to be sterile. 4 The first proofs-of-concept experiments demonstrating the creation of a gene drive in the fruit fly, a model organism for invertebrate research, and in other mosquito species (discussed below) also provide evidence that a gene drive could be developed in Aedes aegypti ( Gantz and Bier, 2015 ; Gantz et al., 2015 ; Hammond et al., 2016 ). These applications would require initial release of a number of the gene-drive modified mosquitoes within an urban setting where dengue is endemic or where dengue outbreaks are known.

• CASE STUDY 2: USING ANOPHELES GAMBIAE MOSQUITOES TO COMBAT HUMAN MALARIA

Create gene drives in Anopheles gambiae mosquitoes to reduce the spread of human malaria in sub-Saharan Africa.

Malaria is a serious and sometimes fatal parasitic infection that occurs in nearly 100 countries worldwide. Adults and children who contract malaria often experience high fever and anemia. If the infection is severe, coma and death can occur. Malaria disproportionately affects people, particularly children, in low and middle income countries in sub-Saharan Africa, South Asia, and South America.

Human malaria is caused by any of the five protozoan parasites of the Plasmodium genus. The mosquito Anopheles gambiae is the primary vector (carrier) of Plasmodium in sub-Saharan Africa.

Current methods for malaria control focus on two themes, drug therapy and vector control. The ability to treat infection requires detection of the parasite and access of infected persons to healthcare, which can be extremely challenging in many, if not most, malaria-endemic settings. Malaria vaccines are under development and have shown promise, but will take many more years before they can be fully recommended for wide application. Prevention of transmission targeting the Anopheline mosquito vector is based on interventions recommended by the World Health Organization. These include measures to eliminate breeding sites, spraying insecticides with residual properties onto the walls of houses, and using insecticide-treated bed nets in areas where malaria is endemic. Additional control strategies are listed in Appendix C . However, all of these measures require organized campaigns and sustained resource availability. In addition, efforts to control malaria are in jeopardy due to the spread of insecticide resistance in Anopheles gambiae populations ( Edi et al., 2012 ; Namountougou et al., 2012 ; Cisse et al., 2015 ).

A gene drive that alters the female mosquito's ability to become infected with the malaria parasite, or one that prevents parasite development within the mosquito, could block malarial transmission without affecting mosquito populations. In November 2015, researchers demonstrated that CRISPR/Cas9 can be used to create a gene drive that could spread anti- Plasmodium genes in populations of a malaria-carrying Anopheline mosquito, Anopheles stephensi ( Gantz et al., 2015 ). However, the system transmits the drive construct at Mendelian frequencies in some crosses, suggesting that this valuable proof-of-principle needs further modification and research before field release ( Gantz et al., 2015 ). Alternatively, a gene drive that alters the fitness of the female mosquito could result in reducing vector populations over time. In December 2015, researchers demonstrated that CRISPR/Cas9 can be used to create a gene drive that causes sterility in female Anopheles gambiae mosquitoes ( Hammond et al., 2016 ). Although one of the research team's constructs is predicted to spread through a population, it has not yet been shown to spread to high frequency in a population containing heterogeneous genetic backgrounds. Nonetheless, the anti- Plasmodium and the female sterility gene drive approaches theoretically have the potential to eliminate malaria in sub-Saharan African villages where malaria is endemic.

• CASE STUDY 3: USING CULEX QUINQUEFASCIATUS MOSQUITOES TO COMBAT AVIAN MALARIA IN HAWAII

Create gene drives in southern house mosquitoes, Culex quinquefasciatus , to reduce the spread of avian malaria to threatened and endangered honeycreeper birds in the Hawaiian Islands.

Avian malaria is a disease caused by protozoan parasites that infect birds. Birds become infected when they are “bitten” by female mosquitoes carrying the parasite. Birds without immune resistance to the parasite become anemic, grow progressively weaker, and ultimately die. Avian malaria is common in most continents, but absent from many isolated islands where mosquitoes (and hence Plasmodium ) do not naturally occur ( Atkinskon, 2005 ). 5 Thus, native birds in Hawaii, the Galapagos, and other archipelagoes, which evolved without natural exposure to Plasmodium parasites, are highly susceptible to avian malaria. The southern house mosquito, Culex quinquefasciatus , is the primary mosquito vector of Plasmodium relictum in Hawaii. The displacement and extinction of native birds has greatly impacted ecological systems and biodiversity in Hawaii, and climate change threatens to expand mosquito ranges into higher elevations, thereby presenting greater harm to bird populations at these elevations.

Prevention of avian malaria transmission has historically been through interventions that target mosquito vector populations using insecticide spraying and larval source management. Similar to resistance of parasites to drugs, many mosquito species are resistant to currently available chemicals, making control difficult. In Hawaii, attempts to control the mosquitoes through such methods have not eliminated the threat. See Appendix C for a comprehensive list of mosquito control strategies.

The use of gene drives could be used as a new strategy to target the mosquito vector to control avian malaria. As described in the first two case studies, there is strong potential to develop gene drives that alter the female mosquito's ability to become infected with the malaria parasite, or that prevent mosquitoes from reproducing. The first proofs-of-concepts in which gene drives were created in the fruit fly and in other mosquito species provide evidence that a gene drive could also be developed in Culex quinquefasciatus ( Gantz and Bier, 2015 ; Gantz et al., 2015 ; Hammond et al., 2016 ).

• CASE STUDY 4: CONTROLLING POPULATIONS OF NON-INDIGENOUS MUS MUSCULUS MICE TO PROTECT BIODIVERSITY ON ISLANDS

Reduce or eliminate populations of the non-indigenous mouse, Mus musculus , to protect native biodiversity on islands around the world.

Invasive species are a leading cause of extinction of native wildlife and plants on islands. Nearly half of all species included on the International Union for the Conservation of Nature's list of species that are threatened with extinction live on islands. In addition, roughly 70%, 90%, and 95% of all extinctions of mammals, reptiles, and birds occur on islands, respectively ( Campbell et al., 2015 ; Godwin, 2015 ). The activities of the house mouse, Mus musculus , and other introduced rodents reduce the ability of native species to reproduce, alter or destroy habitats so that they no longer support the needs of native species, and in other ways negatively affect island ecosystem dynamics. Approximately 80% of the world's islands now have invasive rodents ( Campbell et al., 2015 ; Godwin, 2015 ).

Efforts to eradicate rodents from islands include the use of traps, poisons, and biological controls, such as the introduction of predators or diseases. Application of rodenticides can be cost-prohibitive due to expenses associated with regulation compliance, dispersal method, size of the treated area, and cost of the toxicant itself ( Meerburg et al., 2008 ; Williams, 2013 ). Mechanical traps are often considered more humane than rodenticides because they do not involve the use of chemicals that could adversely affect human, animal, and overall ecosystem health ( Lorvelec and Pascal, 2005 ; Witmer et al., 2011 ). However, placing traps and collecting the caught animals is labor intensive, traps do not discriminate between target and non-target organisms ( Lorvelec and Pascal, 2005 ), and traps are insufficient to fully eradicate a rodent population without the use of other methods. Other research aims to use genetic engineering approaches to control rodent populations including RNA interference and developing transgenes that cause female progeny to develop as males or prevent all progeny from developing ( Gemmell et al., 2013 ; He et al., 2015 ). It remains to be seen if such genetic engineering approaches will be effective, scalable and affordable ( Jacob et al., 2008 ; Campbell et al., 2015 ). Additional discussion of these methodologies and a more comprehensive list of other approaches used to control rodent populations are presented in Appendix D .

Scientists are studying a sex-determining gene drive that causes house mice to produce more male offspring than females ( Cocquet et al., 2012 ). If this occurs over multiple generations, it should lead to a reduction in population size over time. The molecular mechanism takes advantage of an endogenous region of high meiotic drive (meaning it is more likely to be inherited) in the mouse genome found on chromosome 17 (an autosome) called the t-complex. In this scenario, male mice are genetically engineered to possess the Sry gene, which promotes male characteristics ( Goodfellow and Lovell-Badge, 1993 ), on chromosome 17 instead of its usual location on the Y chromosome. An XY Sry male is fertile, and upon mating to a wild-type XX female, both the XY and XX offspring (both male and females) possess Sry and physically develop into male mice, with XX male mice being sterile and the XY mice still able to reproduce and transmit Sry. Over time, the population of mice would tend to become all male, leading to a decrease in reproduction and eventual population decline and suppression due to the loss of female mice ( Campbell et al., 2015 ). Male mice are promiscuous, and so have nearly an unlimited amount of reproductive potential, as long as fertile female mice are present. Female mice must go through a gestation period after mating, limiting their ability to contribute their genetic information to future generations. Hence, female mice are the limiting factor in the change of population densities over time. A description of the technique, and elements that helped in the development of a case study in this report can be found on a website dedicated to island conservation created by students from North Carolina State University. 6

Other potential gene drive mechanisms based upon Medea or underdominance strategies could also be used to achieve the same purpose and would involve inducing targeted translocations into the mouse genome.

• CASE STUDY 5: CONTROLLING NON-INDIGENOUS CENTAUREA MACULOSA KNAPWEEDS TO PROTECT BIODIVERSITY IN RANGELANDS AND FORESTS

Create gene drives in the non-indigenous knapweed species, Centaurea maculosa , to protect biodiversity of native plant species in rangelands and forests in the United States.

The spotted knapweed ( Centaurea maculosa ) is native to Eastern Europe but was introduced to the United States in the late 1800s. By the year 2000, spotted knapweed could be found in 45 of the 50 states and covered nearly 7 million acres of rangeland and pine forest ( Zouhar, 2001 ). Spotted knapweed first invades disturbed habitats; once established, it spreads to native ecosystems, causing soil erosion in the process.

Several attempts have been made to slow the spread of spotted knapweed by using biological controls; these reduce seed production but have not had large effects on the density of Centaurea maculosa plants ( Sheley et al., 1998 ). In addition to biological controls, management of knapweed populations has focused on physical removal, fire, and chemical treatment for infestations ( Sheley et al., 1998 ; Zouhar, 2001 ).

Spotted knapweed is obligately outcrossing ( Harrod and Taylor, 1995 ), meaning that there is little or no self-fertilization and that gene drives would be able to spread throughout knapweed populations. Another factor that makes it potentially suitable for a gene drive is that the basis for its ability to outcompete native plants is thought to come from the production of a compound called catechin ( Thelen et al., 2005 ), which it exudes from its the roots. Catechin inhibits the germination and growth of native plant species, thereby conferring a competitive advantage to spotted knapweed ( Bais et al., 2003 ).

There are two possible gene drive approaches to help limit the spread of spotted knapweed, which could potentially be employed together. The first option is to engineer a suppression gene drive by targeting sex-specific genes, thereby biasing gender ratios and facilitating a population crash. The second is to modify the population by targeting the catechin biosynthetic pathway, which in theory would negatively affect the knapweed's ability to compete against endemic plants, although this effect is still debated (Perry et al., 2005). In either case, the rate of spread of either of these gene drives is expected to be slow, because spotted knapweed is a perennial plant that lives for approximately 9 years ( Zouhar, 2001 ). In addition, the success of a suppression drive is likely to depend critically on the fertility advantages of sex-modified plants compared to hermaphrodites and also on features such as pollen availability and spatial structure ( Hodgins et al., 2008 ).

• CASE STUDY 6: CONTROLLING PALMER AMARANTH TO INCREASE AGRICULTURE PRODUCTIVITY

Create gene drives in Palmer amaranth ( Amaranthus palmeri also called pigweed), to reduce or eliminate the weed on agricultural fields in the Southern United States.

Palmer amaranth infests agricultural fields throughout the American South. It has evolved resistance to the herbicide glyphosate, the world's most-used herbicide ( Powles, 2008 ), and this resistance has become geographically widespread.

Whether a plant is considered a weed is context-dependent. In one region, a plant is desirable, whereas in another place, the same plant may be a weed. A plant is typically viewed as a “weed” when it has little recognized value in the locale where it is growing and when it grows rapidly and competes with a crop or pastureland for space, light, water, and nutrients. Weed management is a continual and major challenge. In addition to competition for resources and interfering with the management of desirable plants, poisonous weeds can negatively impact human health, crops and livestock ( Bridges et al., 1994 ). Management strategies fall into four major categories: physical and mechanical methods, cultural methods, chemical methods, and biological methods. Examples of mechanical practices include manual removal of weeds, which is labor intensive, or tilling, which can increase soil erosion. Examples of cultural practices include crop rotations using plants that choke out weeds (often there are limited choices available) and using drip irrigation to limit water to planting rows, which only works well in dry regions that extensively irrigate. Examples of biological methods include animal grazing and the use of natural enemies (microbes, insects, and other animals such as nematodes, fish, and birds); these strategies are primarily used in low-intensity management of rangelands, forests, preserved natural areas, and waterways.

In much of production agriculture, the primary approach to control weeds is to use herbicides. Glyphosate, the most commonly used herbicide, is a systemic herbicide that, when applied, moves throughout the plant thus destroying more tissues as compared to contact herbicides. The generation of herbicide-resistant crops has revolutionized weed control. Glyphosate-resistant crops have been rapidly adopted in multiple crops because of economic advantages, strong weed control, and the observation that the glyphosate-resistant crop system confers a lower environmental impact than the approaches it replaced ( Duke and Powles, 2009 ). Unfortunately, after decades of glycophosate use weeds are now adapting, and herbicide resistance is increasing among weed population, reducing the efficacy of glyphosate for weed control ( Powles and Yu, 2010 ). The current strategy to deal with herbicide-resistant weeds is to adopt diverse tactics, combining multiple weed control approaches ( Duke and Powles, 2009 ; Norsworthy et al., 2012 ). The particular combinations of strategies chosen depend on the crop, the region, and the major weeds impacting the particular agricultural system. Details on specific practices can be found on agricultural extension websites at land grant institutions throughout the United States and at equivalent international institutions' websites.

Palmer amaranth is a likely candidate for gene drive technology, for five reasons. First, it is an annual plant, so it has yearly sexual reproduction and a rapid generation time. Second, Palmer amaranth and some other members of the genus are dioecious (male and female flowers occur on separate plants) ( Steckel, 2007 ), which ensures the outcrossing necessary to spread gene drives. Third, it does not have an extensive seed bank; studies suggest that most seeds do not persist in the soil, so that there is unlikely to be a seed repository that is immune to the gene drive. Fourth, an Amaranthus species has been transformed genetically ( Pal et al., 2013 ), suggesting that it will be technologically feasible to insert gene drives into Palmer amaranth. Finally, Palmer amaranth is wind-pollinated, implying that the eradication of species will, at the very least, not harm insect pollinators.

In theory, Palmer amaranth could be subjected to two types of gene drive. In the first, a modification drive would target the genes that confer resistance to glyphosate and reestablish the population's susceptibility to glycophosate herbicides. The potential targets of this gene drive are known, because the glyphosate herbicide acts by interrupting the function of 5-enolpyruvylshikimate-3-phosphate synthase. In Palmer amaranth, this synthase gene has been duplicated extensively, leading to enzyme overexpression and glyphosate resistance ( Gaines et al., 2010 ). Thus, a candidate gene drive would need to target multiple 5-enolpyruvylshikimate-3-phosphate synthase copies that are scattered throughout the genome. If the gene drive succeeded and susceptibility became fixed, glyphosate could then be used again as a tool to limit Palmer amaranth populations.

A second approach would be to build a suppression drive. Although the target and content of such a drive is not yet clear, the fact that there are separate male and female plants implies that there are sex-specific genes that are suitable targets for biasing the sex ratio. Under this approach, the goal would be skew sex ratios until the entire population (or species) collapses.

CASE STUDY 7: DEVELOPING A VERTEBRATE MODEL FOR GENE DRIVE RESEARCH USING ZEBRAFISH 7

Create gene drives in the zebrafish, Danio rerio , to study gene drive mechanisms in a vertebrate animal.

As of April 2016, researchers have not developed a gene-drive modified vertebrate for use in fundamental research in the laboratory but proofs-of-concept for gene drives have been demonstrated in yeast, the fruit fly, and mosquitoes, with the expectation that this technique will be translated to a vertebrate animal at a future date ( DiCarlo et al., 2015 ; Gantz and Bier, 2015 ; Gantz et al., 2015 ; Hammond et al., 2016 ). These current animal models, and the behavior of gene drives in them, will not necessarily recapitulate the behavior of gene drives in vertebrate species. Given the fundamental differences between vertebrates and invertebrates, a vertebrate species for gene drive research will be needed to address a variety of fundamental research topics before using gene drives in other vertebrate animals, particularly those intended for release into the environment; and also potentially to make comparisons with gene drive mechanisms in invertebrates.

Containment of zebrafish is straightforward due to the requirement for appropriate aquatic facilities, while other potential vertebrate models for gene drives, such as the mouse, could more easily escape from, and survive outside, the laboratory. In addition, it may be possible to develop a self-limiting gene drive in zebrafish by making the drive active only in the presence of tetracycline, which could be required to activate the promoter needed to express the gene drive construct ( Hammond et al., 2016 ).

A gene-drive modified zebrafish could be developed specifically for laboratory studies with no intention for environmental release. The zebrafish provides an outstanding model to address basic research questions about gene drives in a vertebrate species for many reasons ( Shah and Moens, 2016 ). The zebrafish genome has been fully sequenced, and zebrafish have well-characterized traits associated with reproduction and other behaviors ( Howe et al., 2013 ). Zebrafish are also low cost and easy to maintain, have a short generation time, and produce large numbers of offspring ( Lawrence et al., 2012 ; Harris et al., 2014 ). They are also preferred from a regulatory standpoint (e.g., from the standpoint of Institutional Animal Care and Use Committee) with regards to using animal models for research. Moreover, gene editing has already been used successfully in this organism ( Ma and Liu, 2015 ; D'Agostino et al., 2016 ; Lin et al., 2016 ; Prykhozhij et al., 2016 ).

A gene-drive modified zebrafish could be created by inserting a gene drive construct into the fish consisting of Cas9, a gRNA targeting a non-essential locus (e.g., a gene expressed in the eye) and a green fluorescent protein marker to identify the gene-drive modified organism. The latter characteristic would give rise to a visible phenotype upon insertion of the donor template on the construct.

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A mouse could also potentially be a candidate vertebrate model for gene drive research. Research on the naturally occurring t-complex in mice offers insight into how regions of high meiotic drive function and affect characteristics associated with vertebrate development and behavior (see Case Study 4 ). However, these studies may not be broadly applicable to other vertebrates. Also, the gestation period, and thus the generation time, is longer in mice than in zebrafish, which could make it more difficult for research to keep pace with rapid advances in invertebrates. However, existing approaches for gene editing through transient introduction of CRISPR/Cas9 (or other mechanisms) have been successful; thus, the committee considers development of a gene-drive modified mouse for laboratory research plausible, a close second to the case study on zebrafish presented in this report.

• Cite this Page Committee on Gene Drive Research in Non-Human Organisms: Recommendations for Responsible Conduct; Board on Life Sciences; Division on Earth and Life Studies; National Academies of Sciences, Engineering, and Medicine. Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. Washington (DC): National Academies Press (US); 2016 Jul 28. 3, Case Studies to Examine Questions About Gene-Drive Modified Organisms.
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Human Genetic Enhancement: Methods & Case studies

Human genetic engineering. CRISPR/cas9 DNA editing of humans. What is the current status? What are the benefits and risks? Including three case studies of DIY Human genetic enhancement and two documentary tips!

By the way, I have written an extensive article about this topic:  what is Human enhancement , and also about  technologies  (like  drugs ),  ethics , and  movies .

Human Genetic Enhancement

Genetic modification is a method that has increasingly been in the media in recent years. It is also known as genetic manipulation or genetic engineering. With CRISPR/cas9 technology, we can change the building-blocks or operating systems of an organism’s life. Human Genetic Enhancement includes human, animal, plant, bacteria, or virus.

On my Youtube Channel I made a video about human genetic enhancement. Watch the video:

DIY genetic enhancement

In this article, I write about human guinea pigs, like Josiah Zayner. Josiah did CRISPR on himself to grow his muscles. Muscle mass should be more of an aesthetic goal. However, some people think of do-it-yourself genetic modification as the ultimate way to improve their health. That’s also true for Tristan Roberts. He was diagnosed with HIV and became frustrated with the daily medication regime.

Some time ago, scientists published research on a particular genetic mutation existing to protect people from  HIV . That’s possible because the body can produce antibodies against HIV, called N6. Roberts’s idea was to genetically modify himself so that his stomach fat cells began generating N6 themselves.

I interviewed him on my  YouTube channel . Feel free to check out the interview:

This list is the outline of the article:

• Genetics : DNA, RNA, Chromosomes, etc.
• Genetic modification : techniques like CRISPR/cas9.
• Methods : 5x, with 3 case studies (Josiah Zayner, Tristan Roberts and Jiankui He)
• Artificial Selection : the destiny of our species?
• Future  of human genetic engineering.
• Chimeras and xenotransplantation : special applications of genetic engineering.

Furthermore, I have written a section with the best  documentaries  and a  reading list . You can find more information if you want to  hire me  for a keynote, webinar , or consultancy on this topic.

Enjoy reading the article!

1.  Genetics

Genetics, as the name implies, is all about genes. To recap its essence: almost every cell in our body contains 3.2 billion base pairs. These base pairs consist of AC and TG molecules, and they intertwine in the form of a double helix.

The shape of the double helix is now considered an iconic image for DNA. Francis Crick, James Watson, and Rosalind Franklin discovered it. DNA contains inbred information. In human biological reproduction, you get half of your DNA from your father and the other half from your mother.

Chromosomes

The base pairs consist of 23 chromosomes. They construct about 25,000 genes in total. Moreover, each gene contains a DNA code for a particular function or characteristic. For example, the DNA sequence in the HERC2-gene determines the eye color [link at the bottom].

Because of the double helix structure, the DNA code can transform into either new DNA or RNA. The best-known form of RNA is “messenger RNA”. The mRNA molecule is a significant link in the transcription or reading of the genetic code. Consequently, the ribosome reads the mRNA outside of the cell nucleus. Secondly, the ribosome starts to build one of the twenty possible amino acids.

The amino acids form proteins. Moreover, it performs all kinds of cell functions, such as building, maintaining, decomposing, communicating tissue. It also includes transporting amino acids to other cells and more. This entire process, DNA to producing proteins, is the ‘Central Dogma’ of molecular biology.

The genotype is the collection of genetic or inherited information. Conversely, the phenotype is the composite of the organism’s observable characteristics. In an interview with the Flemish comedian and science journalist Lieven Scheire, he gave the following example:

‘If you are curious about the genotype influence on the phenotype, look at identical twins. You could say that what they have in common in appearance and behavior is encoded in their DNA.’

If you are curious about the genotype influence on the phenotype, look at identical twins. Lieven Scheire (comedian and presenter)

Geneticists roughly distinguish three factors that influence a person’s characteristics.

• The shared family environment
• Non-shared environmental factors outside of the family (such as school, friends, and unique experiences)

The influence of these factors varies enormously on our characteristics. For example, my gender depends entirely on my genes, whereas it does not affect my Dutch-speaking ability.

Mapping DNA

With the completion of the Human Genome (HGP) project in 2003, expectations were high. The HGP intended to map the entire human genome. Subsequently, President Clinton (USA) and Prime Minister Blair (UK) declared it ‘the book of life.’

However, it was challenging to identify physical traits, diseases, intelligence, speed, and empathy within the DNA code. Scientists were amazed by the number of genes per individual. Presently, they estimate the total number of genes between twenty to twenty-five thousand, similar to a mouse [link at the bottom].

Epigenetics

How come humans are more complex than mice, but the number of genes is approximately the same? One reason for this is probably the additional layer of code on top of our DNA. It is the field of study that looks into this is called epigenetics.

To sum up: gene expression depends primarily on the cell environment. It is on a higher level of abstraction and the conditions in which the organism lives.

DNA sequencing

Research into the relationship between the genotype (the DNA code) and the phenotype focuses on DNA sequencing. This focus means that the DNA is analyzed and converted into the code of AC and TG base pairs. Then, researchers look at the phenotypes. Does the selected genetic code influence an organism’s characteristics?

Let’s look at an example of the HERC2 gene, which occurs in humans [link at the bottom]. The layer of code on this gene, the so-called SNP (single-nucleotide polymorphism), has a significant influence on your eye color. Still, it is lesser on, for example, hair color and whether or not you get sunburned easily.

Scientists all over the world are researching these processes and their relationships. The Chinese government and companies are very active in this field. Bregtje van der Haak captured this research very well in the documentary ‘DNA Dreams.’

The company Beijing Genomics Institute (BGI) intends to examine every organism genetically. Furthermore, the institute is also looking specifically for the genes that influence positive characteristics like intelligence. In the documentary, you can see how young children undergo all kinds of IQ tests at the company. Moreover, how BGI compares the results with the child’s DNA?

2.  Genetic modification  of humans

Genetic modification, genetic engineering, or genetic manipulation take things a step further than just examining and analyzing DNA.

When I give a  keynote  or  webinar , I often explain that modifying DNA is something humans have been doing for a long time. Think, for example, of how we first started breeding plants and breeding animals. Of course, these methods were initially very unrefined. There was a large degree of unreliability. After all, at that time, we did not know how the underlying DNA code appeared.

Modifying DNA in a lab is accurate and precise. A scientific breakthrough was due to the work of Cohen and Boyer in 1973.  Recombinant DNA  refers to artificially combining DNA from multiple sources. In the past few decades, scientists developed additional methods. These include TALEN (Transcription activator-like effector nucleases) and Zinc finger nuclease.

The principal breakthrough took place in 2014 when Jennifer Doudna and Emmanuelle Charpentier presented their discovery of CRISPR/Cas9 in Science Magazine [link at the bottom]. In 2020, they won the  Nobel  Prize  for their research.

Compared to TALEN and Zinc finger nuclease, CRISPR/Cas9 is much cheaper, faster, and more effective. Subsequently, the discovery of CRISPR/Cas9 was a massive step for the scientific community. They quickly applied it in research on crops, animals, and humans.

This method reminds us of the series Orphan Black. That’s the picture at the top of this article. Watch this trailer if you have not seen this series yet:

Modifying human DNA

DNA modification in humans is beneficial for the healthcare sector. A few examples are listed below. However, they did not use the CRISPR/cas9 technique in all of these instances:

• Genetically modifying the white blood cells of  leukemia  patients to better target and destroy cancer cells. In 2011, the American Emily Whitehead was the first to be successfully treated using this technique [link at the bottom];
• In 2017, a blind British patient got a cure after DNA modification of the  retina  [link at the bottom];
• Several biotechnology  start-ups  work on gene therapies to treat infectious diseases, inherent diseases, and HIV [link at the bottom].

The majority of research using genetic modification techniques concerns crops, bacteria, and smaller organisms. There are high expectations for this field. Consequently, humans can be in charge of biology. The most exciting part is the possibility to apply these techniques to ourselves as well. What opportunities do we have there?

3.  Methods

Undoubtedly, in the future, we (humans) will want to enhance and modify ourselves. The most pressing question, which I will return to later when I discuss the ethical implications, is to which extent we will want to do so. Do we restrict the use of these techniques to, for example, when a patient’s health is at stake? Or will they soon be available to everyone (commercially)? I have roughly divided genetic modification in humans into the following categories:

• A. Somatic modification (editing people’s DNA)
• B. Germline modification (DNA modification in embryos, the so-called ‘designer’ babies)

C. Epigenetic programming

• D. Modification of intestinal flora (microbiota)

I’ll explain these categories below and conclude by looking at their proven efficacy. Scientists use Categories A and B in medical and biological research. However, C, D, and E are much more speculative and hardly proven (as of now).

A. Somatic modification

‘Soma’ is a Greek word for ‘the body.’ Somatic modification refers to genetically modifying the body. The British patient I mentioned before, with an eye impairment, is an excellent example of this. In his case, the genes responsible for maintaining the light-sensitive cells in the back of the eye missed half of their DNA code. Researchers were able to  reprogram the genes  in a lab and then insert them in the right place, behind the eye, using a virus.

The experimental CRISPR/Cas9 procedures, currently used to treat leukemia patients, use a similar method. They administer Blood, and the blood cells are genetically modified. Then, the patient’s body receives the modified Blood.

Delivering genes

As both examples illustrate, the greatest challenge is to deliver the modified genes or cells to the right place in the body. We are still a long way from a scenario where you can place a syringe of modified cells in your arm. Subsequently, the modifications arrive at the selected organs, cells, and DNA.

Nonetheless, this doesn’t stop some people from experimenting on themselves with these methods.

CRISPR biohackers

People who genetically modify themselves are also called biohackers. I think of the term ‘biohacking’ as a broader concept. That’s why I’ll refer to people who experiment with genetic modification on themselves as ‘CRISPR biohackers’ for now.

Josiah Zayner

• Tristan Roberts

Two other well-known biohackers, discussed in my biohacking article, are Brian Hanley and Lizz Parish.

Josiah Zayner created quite a controversy at the end of 2017 when he injected himself with modified cells. In particular, his action caused a great deal of commotion. He broadcasted it live on a Facebook video. His goal was to grow extra muscle mass [link at the bottom]. He wanted to gain muscle mass by suppressing the gene activity that codes for the  muscle growth  inhibitor myostatin.

Here is an interview with Joziah:

B.  Germline modification

Germline Modification refers to a genetic material alteration in the embryonic state, the sperm, or the egg cell. The essential difference compared to Somatic Modification is that DNA changes pass onto the next generation. Consequently, such modifications are not limited to an individual but also extend to the offspring.

This type of treatment is in combination with in-vitro fertilization (IVF). It means that scientists modify the embryo in the laboratory and then insert it into the uterus. In 2017, such treatment took place in England, which led to newspaper headlines saying that a three-parent child had been born [link at the bottom].

Replacing embryo DNA

During the treatment, they replaced the mother’s mitochondrial DNA in the embryo with another woman. The mitochondria in the cell are responsible for energy supply. It has a particular DNA and transfers exclusively by the mother. Moreover, in the scenario in England, the mother had a hereditary mutation in her mitochondrial DNA. Hence, by replacing this in the laboratory, her child was relieved of this disorder.

Lulu and Nana controversy

The treatment in England that I described in the previous paragraph was carefully discussed, debated in politics, and enshrined in legislation. The same does not apply to the best-known case (so far) of germline modification. The doubted credit is to the Chinese scientist Jiankui He [link at the bottom].

In the autumn of 2018, he announced he had given birth to two babies  Lulu and Nana , genetically modified as embryos. The treatment aimed to change the CCR5 gene, which would make the children resistant to HIV. The father of both children was a carrier of the virus.

Watch the announcement of Jiankui He:

There were problems with the procedure by He Jiankui.

• The procedure was not permissible by law
• Permission  of the parents was granted or not
• The genetic cut did not go well

Later, however, stories appeared that this particular gene also influences one’s cognitive capabilities [link at the bottom]. Nonetheless, there’s certainly a moral, ethical, and political discussion about genetic modification. They use it for enhancement purposes. More on that later.

Reproduction

The example of Lulu and Nana illustrates the rapid pace at which reproductive technology is developing. I spoke about this in a podcast with professor Sjoerd Repping of the VU Medical Center in Amsterdam, the Netherlands.

For example, there are already discussions about making egg cells from skin cells. Moreover, making it possible for two men to play genetic father and genetic mother [link at the bottom].

During the interview, he talked about the revolution we experienced concerning Vitro fertilization (IVF). IVF is a fertility treatment in which fertilization takes place outside the body. Another term for this is test-tube fertilization.

The first treatment using this technique in the Netherlands took place in 1980, but nowadays, an average of one child in every school class was born in this way. In the eighties, there was a big commotion about this method. After all, having a baby was a gift from God. Recently, the use of IVF is hardly a topic of discussion. Could the same apply to the genetic modification of embryos in the future?

Programming superhumans

Politicians and bioethicists all over the world were tumbling over each other to condemn Jiankui He’s action. They argued that the modifications were sloppy. Moreover, he didn’t have permission from the government or his research institute. They perceived much easier ways to stop HIV from passing onto future generations [link at the bottom].

Another reason for the commotion, however, may stem from a primary human reaction: jealousy. Professor Robert Zwijnenberg of Leiden University mentioned that Harvard University (Boston, United States) is modifying sperm cells to reduce the risk of Alzheimer’s [link at the bottom].

The reactions to Jiankui news are probably affected by a twinge of  envy . It is no coincidence that there seems to be an arms race going on between China and the United States concerning genetics and genetic modification. More about that later.

George Church

Professor George Church is a prominent scientist and pioneer in the field of genetics and genetic modification. Halfway through 2019, he published a list of several genes that lead to improved human traits in the correct mutation [link at the bottom].

• LRP5: stronger bones;
• MSTN: larger muscles;
• FAAH-OUT: lower sensitivity to pain;
• PCSK9: better resistance to cardiovascular disease;
• GRIN2B: memory improvement;
• BDKRB2: being able to hold the breath for a long time;

Some genes in his list have remarkable qualities, for instance, ABCC11. A mutation on this gene links to the production of less sweat. He also mentions the adverse effects of some genes. The variation on PCSK9 with the advantage of better resistance to cardiovascular diseases can also lead to an increased risk of diabetes.

In short, you will have to make trade-offs here.

Interview Eben Kirksey

The Mutant Project: Inside the Global Race to Genetically Modify Humans is a book written by Eben Kirksey. In this interview we talk about the first genetically engineered babies Lulu and Nana, the scientist Jianku He, the work of biohackers, and much more.

Watch the interview here or on my YouTube Channel :

According to professor Michael Bess, author of the book  Make Way for the Superhumans , it is unlikely that germline modification will be used much [link at the bottom]. That’s because it raises all kinds of moral issues regarding the autonomy of the unborn child. With this in mind, he expects more from so-called epigenetic programming.

Changing the DNA of the embryo raises many moral issues regarding the autonomy of the unborn child. Professor Michael Bess

Epigenetics is like a piano. Michael Bess: ‘DNA can compare to the piano. But the pianist plays the piano. You get a different melody and rhythm, depending on which keys the pianist plays. Now that’s epigenetics.’ Epigenetics is a layer that lies on top of the DNA and influences DNA expression.

In the future, scientists will probably find out more and more about the effects of epigenetics and, in due time, how to influence them. Although speculative, this is also called  epigenetic programming . Perhaps a scenario would arise where people are allowed to make (epi)genetic changes at a certain age, for example, when reaching the age of being a legal adult.

D. Gut flora

In the book  Evolving Ourselve s, Enriquez and Gullans write about the ‘Omen’ model. This model includes:

• Genome (DNA)
• Epigenome (epigenetics)

The microbiome stands for the composition of the intestinal flora [link at the bottom].

Your intestinal flora consists of bacteria (about 700 to 1,000 strains), yeasts, viruses, and parasites. Each person’s intestinal flora is unique – as unique as a fingerprint. These  microorganisms  don’t just live in your gut; they are found on all of our body’s surfaces and form an ecosystem of their own everywhere. It is comparable to a jungle: a massive forest area with plants, herbivores, and carnivores.

Nonetheless, it is a crowded jungle. There are ten times more bacteria than cells in your body. Your intestinal flora weighs an average of 2.5 to 3 kilos. Besides, it contains 360 times  more DNA  than the rest of your body. Consequently, some scientists say that humans are carriers of bacteria. But what kind of influence do these bacteria have, and how do they work?

Role of intestinal flora

The intestinal flora breaks down molecules from the food we eat and produces biologically significant molecules useful to our bodies. Short-chain fatty acids, for instance, serve as a signaling agent for the metabolism. The bacteria also produce vitamins (K, B12, and folic acid) and amino acids.

The intestinal flora also plays a vital role in maintaining your immune system. Besides, more knowledge has become available in recent years. It shows that the intestinal flora role is much impressive than we initially thought.

At the beginning of 2019, the Catholic University of Leuven published a study. It demonstrated two types of intestinal bacteria, Dialister and Coprococcus. These types occur less frequently in people who report that they are  depressed  [link at the bottom]. The researchers haven’t made up their minds about this. Moreover, people with depression could eat differently; therefore, a different intestinal flora.

I also had my microbiome tested. Luckily I seemed to have enough Dialister and Coprococcus bacteria!

Gut flora transportation

The intestinal flora has a massive influence on our health (especially in chronic conditions, from obesity to rheumatism and depression). Besides, their experts have different opinions about the degree of this influence and a causal link. However, they treated multiple patients successfully with  intestinal flora transplants .

The operation is simple: the patient receives part of the intestinal flora from a healthy donor. The donor can also be the patient himself. For example, when the intestinal flora is stored before the patient starts a heavy antibiotic treatment. In the Netherlands, they use this technique for particular medical situations. Therefore, patients often have to go into the alternative circuit or abroad, like the UK.

DIY transplantations

I mentioned Josiah Zayner when I described how he applied genetic modification on himself. Josiah went one step further. In 2016, he prepared his intervention, explained in an extensive article on The Verge [link at the bottom]. He collected the feces of a (healthy) friend to adjust the composition of his intestinal bacteria.

It remains somewhat unclear whether – and if so, to what extent – it has helped him. Still, he has noticed some other effects. For example, after the transplantation, he is much more inclined to sweets. Keep in mind; he never had such a sweet tooth before.

He did not immediately report massive improvements (and it seems a bit gross to me). Still, I wouldn’t be quick to have such an operation. However, I do try to keep my intestinal flora in excellent condition by eating well:

• Enough fiber from vegetables and whole-grain products
• Fermented food such as kefir and sauerkraut
• Occasionally special supplements in the form of pro and prebiotics

The human virome consists of all viruses in and on the body. Compared to the microbiome, the virome constitutes an additional step in the order of magnitude. As per estimates, the virome consists of 380 trillion  viruses  [link at the bottom]. The vast majority of the virome consists of bacteriophages. A bacteriophage (‘phage’ for short) is a small virus that only infects a specific bacterium.

Viruses are not living organisms, unlike bacteria. That’s because a virus is a piece of floating DNA. The only purpose of the virus is to inject itself into a bacterium, then duplicate and spread. Because of this mechanism, viruses are often used in molecular biology to introduce foreign DNA into bacteria.

Bacteriophages

Another technique currently studied is the use of bacteriophages as an alternative to antibiotics in bacterial infections. Specific bacteriophages can then infect and destroy the bacteria. Subsequently, bacteria cannot become resistant to bacteriophages by mutation because the phages also mutate themselves. This method is the so-called  evolutionary arms race.

At the moment, little is available about how all of the different viruses in our bodies work. We do know, however, that there is no point in destroying all viruses. Although viruses have a terrible reputation, think of Ebola and Dengue, for instance. They also play a vital role in symbiosis with bacteria in and around the body.

Besides, we know less about the effects of viruses in the body than the microbiome. Especially in the following:

• Combination with bacteria
• The epigenome
• Situational factors
• Nutrition and lifestyle.

Nevertheless, I do expect that as we learn more about the virome. We will, consequently, see other uses of bacteriophages in the future. Not just in the healthcare sector, e.g., as an alternative to antibiotics, but also as a method to keep the microbiome condition (and the body health) in order.

4. Artificial selection?

It is possible to replace natural with artificial. The development has been going on for some time but is now becoming more focused and specific. In some cases, this is reasonable. For example, there are (hereditary) disorders caused by a mutation of one gene. These include Huntington’s disease, sickle cell anemia, and cystic fibrosis. The social consensus at the moment is that it is excellent to use CRISPR / cas9 for this (if safe).

Human Genetic improvement

It is different when we decide to start using this technology to remedy conditions that are not life-threatening. Think of changing the eye color, improving intelligence, or making sure that you do not become bald. It becomes even more exciting when you think of social intervention: switching off the genes related to alcoholism or violence.

Again, that is the difference between healing and improving. Sometimes that is a gray area, for example, body height. Footballer Lionel Messi had injections of human growth hormone from an early age, for instance, to help his body grow. [link at the bottom].

Is that healing or improving?

5. Future genetic improvement

A common mechanism within human enhancement is that a method is initially developed in (medical) science to help patients. The next step is to use non-patients to improve one’s self.

The question is whether this also plays a role in the editing of genes. Scientific progress continues to help patients (or their future offspring) with a genetic disorder. The  grey area  is to determine when there is healing or an improvement. Take the earlier example of the height of Lionel Messi. Is changing genes so that your child becomes taller a form of healing or improving?

These questions are challenging to answer unambiguously. As I have argued before, the answers we provide are time-dependent and culturally determined. You can read more about these types of questions in my article about  human enhancement ethics .

An exciting application at the cutting edge of lower medicine and biotechnology is the cultivation of mini-organs or organoids. A personal mini-version of an organ is made based on skin cells to test whether it is working or not.

This method has already been used successfully by the Hubrecht Institute in Utrecht. They tested whether a cure for cystic fibrosis would work in a boy or not. This procedure turned out to be the case with the mini-organ and later also with the treatment. Since it is a risky or expensive treatment, it can be a godsend to make a test model for testing.

Clones are genetically identical copies of an organism. Besides, there are two techniques for human cloning: embryo cleavage and nuclear transfer.

• Embryo bifurcation  is a primitive form of cloning where a fertilized egg splits. This separation sometimes is natural because that is how identical twins or multiples arise.
• Cell nucleus transfer  is a more advanced cloning technique. This process removes the cell nucleus from a body cell of an existing person. Hence, transplanted into an egg without the Nucleus. This egg can develop into an embryo in the test tube and after implantation in the uterus. Koops writes in De Maakbare Mens that the clone is entirely genetically identical. It is because the mitochondrial DNA outside the cell nucleus comes from the owner.

Function cloning

Furthermore, cloning has two functions. In therapeutic cloning, cloned embryos or cells are for medical research or therapy. The clones are not implanted and do not grow into a fully grown organism. Reproductive cloning does develop cloned cells.

Successfully, since the iconic sheep Dolly in 1996, cloning was completed on Numerous species. For a long time, this was not possible in primates until two macaques were cloned by Chinese researchers in early 2018 [link at the bottom]. These figures show that this is not yet an infallible process. The scientists needed 63 surrogate mothers and 417 eggs. Still, it resulted in only six pregnancies.

Due to such flight error probabilities, experts do not expect human cloning to take place. Regular reproduction is much comfortable, safer, and more ethical. Besides, a human clone is not a copy of the original, best seen in identical twins. Despite the biological similarities, they are two individuals. As an individual, you become powerful through your genes, but also your environment.

Movie The Island

A scenario from the science-fiction film The Island from 2005 does not seem realistic [link below]. In that movie, starring Ewan McGregor and Scarlett Johansson, clones were on an island for their organs. If the original person needs an organ, they use the clone.

Other fictional works exploring the concept of cloning:

• Book Brave New World  (imposed by the government)
• Book The Boys from Brazil  (a clone of Hitler in the jungles of Brazil)
• In the film Replicas (a bioscientist loses his family and decides to clone them)

Regulations

According to the Center for Genomics and Society, cloning is prohibited in 46 countries [link at the bottom]. Reproductive cloning is illegal in 32 countries. Therefore, those countries use clones for therapeutic purposes. For instance, they clone human cells for organs or medical research.

A specific application of genetics and biotechnology is chimeras. A chimera is a cross between two organisms. This hybrid is different from crossing organisms, such as:

• A mule (a baby of a donkey stallion and a horse mare)
• Another mule (a baby of a horse stallion and a mare).

In a cross, all cells contain the same DNA. However, a chimera has the DNA of one organism and the other.

The chimera also appeared in  Greek mythology , although it was written slightly differently (as Chimaera). It was an animal that was put together by humans. They pictured the chimera with a lion’s head, a goat’s body, and a snake’s tail.

Human monkey embryo

Although chimeras with human elements still seem far-fetched, significant developments are taking place in scientific research. For example, the Japanese government broadened the rules in 2019 [link at the bottom].

The idea is once again strictly for medical research. For example, it is to cultivate human brain cells in an animal’s brain or human organs placement in an animal.

Fundamentally, scientists are curious about molecular biology and the interaction between various organisms’ cells. For example, they announced in 2019 that scientists in China had created an embryo made up of cells from a human and a monkey [link at the bottom].

Xenotransplantation

Under the term xenotransplantation, they investigate whether it is possible to grow a liver, kidney, heart, or even lungs in sheep or  pigs  [link at the bottom]. Pigs are certainly an excellent candidate for such interventions since this species is genetically almost identical to humans [link at the bottom].

When the technology is ready, the same moral and social questions play a role here, as I have outlined earlier. What if companies can make livers that can break down alcohol even better? How about lungs with extra capacity and a heart that can effectively spread this extra oxygen to the muscles?

Bonus: what are the best documentaries about this topic?

Best documentaries

What are the best documentaries about human genetic engineering? I made a video: top 3 documentary tips about genetic engineering. Take a look at the video below, or visit my YouTube-channel .

Like you could see in the video above, I like  Human Nature  and the series  Unnatural Selection . You can find both on Netflix.

The documentary  Human Nature  is about the discovery and applications of CRISPR/cas9.

The documentary series  Unnatural Selection  is about biohackers applying genetic modification on themselves:

If you have another documentary or film tip, please leave a comment down below!

Do you want to know more about human enhancement?

Please contact me if you have any questions! Like if you want to invite me to give a  lecture , presentation, or  webinar  at your company, at your congress, symposium, or meeting.

Or if you want to book a session with me as an expert consultant in this area.

Reading list

I previously wrote these related articles about  human enhancement :

• What is Human enhancement ?
• Which are  human enhancement technologies ?
• Which are  human enhancement drugs ?
• What is  human enhancement research ?
• What are the  ethics  of human enhancement?

These are the external links:

• Book The Mutant Project
• List  by George Church
• Article  about Emily Whitehead
• Research  about Retinal Gene therapy
• Article  about Elizabeth Parrish
• An Article  about Josiah Zayner
• Article  about chimera rules
• An Article  about human-monkey chimera
• Article  about human and pig DNA

How do you view the genetic engineering of humans? Leave a comment!

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Related posts.

Genetic Engineering in Humans. 5 Examples

What are Cyborgs? Definition, Movies & 8 Examples

Cyberpunk: Edgerunners (Netflix): a Tender Series

What is Human Augmentation?

Biohackers Netflix series review

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The Case of the Designer Baby

I have recently been working on a bioethics textbook. Bioethics is a discipline largely driven by case studies – short narratives intended to make the ethical issues under discussion clear, real and urgent. Consequently, many bioethics textbooks include case studies. I want to do something different in this month’s column, namely, present one of the case studies on which I have been working. Attentive readers will notice that the case study presented below gets at the same issues I considered in last month’s column (CRISPR and the genetic revolution). I would like readers to think not only about the issues raised by the case itself, but also about whether or not the case study helps to make the ethical issues raised by these technologies clearer and more accessible.

The development of new technologies like CRISPR are likely to make it possible to alter the human genome in ways that will affect future generations – that is to say, genetic alterations that are made in particular individuals will then be passed on to their descendants. Moreover, while these changes are likely to occur as a result of particular parents making changes in the genomes of their children rather than as a result of government interventions, the long-term consequences may alter not only individual genomes but the human genome as well. This case study is set at a time in the future in which this technology has become both commonplace and commercialized.

J oe and Susan desperately want to have a family, and they both want children who are genetically related to both of them. Unfortunately, they are both carriers of undesirable genetic conditions that are likely to affect the health of their children. They do not want any potential children to suffer, so they have, so far, chosen not to reproduce.

Joe and Susan have been inundated with ads from CRISPR Services lately, and they are intrigued by their promise. ‘Do you have a family history of Huntington’s Disease or cystic fibrosis? Tay -Sachs or sickle cell anemia? Dementia or cancer? Come and see us, and we’ll make sure that your children are born disease-free, and that your descendants will not be afflicted by the family curse!’ The clinic offers IVF treatments, and then uses gene editing technology on the resulting embryos to ensure that any that are implanted will produce healthy offspring.

Joe and Susan feel that this is the answer to their prayers: they both really want a family, but were afraid to have children who were sick and suffering. Now, they feel that their dreams have come true. They quickly make an appointment with the clinic director, who assures them that the gene editing necessary to ensure that their future children will be healthy is safe, simple, and accurate. He also hands them a pamphlet detailing the clinic’s services. The bronze package will ensure that their children are disease-free; the silver package will allow these disease-eliminating alterations to be passed on to their descendants; the gold package offers additional changes, such as the elimination of undesirable traits (like a tendency to be obese or shy) and the addition of desirable ones (such as athletic ability and enhanced intelligence); the platinum package allows future generations to also receive the enhancements chosen for the child. The gold and platinum packages have a check list of traits to eliminate and enhance, and the cost, of course, goes up the more options the customer chooses.

‘I’ve always wanted a kid that I could play basketball with,’ says Joe. ‘And could you imagine if we had a child who is both athletic and mathematically brilliant? We’d never have to pay for university!’ ‘It would be such a relief to have kids who are disease-free,’ notes Susan. ‘No worries about dementia, no risk of Huntington’s.’

‘We could have healthy kids who are geniuses as well as empathetic and kind,’ adds Joe. ‘I didn’t know that was even possible, but look at all these options! Who wouldn’t want all these things for their kids?’

Joe and Susan spend a few minutes perusing the list of desirable traits that they could select, and undesirable traits that they could eliminate. Finally, though, they have to come to a decision.

Should they add these desirable traits to their future children, as well as ensuring that they are born healthy? Should they delete traits that are undesirable, but not health-related? If they decide to go ahead with these design modifications, should they stop at the Gold package, or go all out, and choose the Platinum one?”

Readers, I encourage you to think about how you would answer these questions.

Featured image: Designer Baby store, Hackney, London, sludgegulper , CC BY-SA 2.0 , via Wikimedia Commons.

Wolfville native Rachel Haliburton teaches philosophy at the University of Sudbury. Her latest book, The Ethical Detective: Moral Philosophy and Detective Fiction , was published in February by Lexington Books.

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• Published: March 2008

The ethics of human gene transfer

• Jonathan Kimmelman 1  

Nature Reviews Genetics volume  9 ,  pages 239–244 ( 2008 ) Cite this article

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Almost 20 years since the first gene-transfer trial was carried out in humans, the field has made significant advances towards clinical application. Nevertheless, it continues to face numerous unresolved ethical challenges — among them are the question of when to initiate human testing, the acceptability of germline modification and whether the technique should be applied to the enhancement of traits. Although such issues have precedents in other medical contexts, they take on a different character in gene transfer, in part because of the scientific uncertainty and the social context of innovation.

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Acknowledgements

I regret that, owing to the brevity of this Perspective, many important contributions to the literature on gene-transfer ethics went unmentioned. The work of the author is funded by a Canadian Institutes of Health Research Maud Menten New Principal Investigator Award.

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Jonathan Kimmelman is at the Department of Social Studies of Medicine, Biomedical Ethics Unit, McGill University, 3647 Peel Street, Montreal, QB H3A 1X1, Canada. [email protected],

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