Category Archives: Human Genetic Engineering

Melissa Nolan

By the end of this chapter, students should be able to:

Those beautiful blue eyes you inherited from your mother are actually a result of a complex science known as Genetics. The scientific field of genetics studies genes in our DNA. Genes are units of heredity transferred from a parent to offspring and determine some characteristic of offspring. Your genes are responsible for coding all of your traits- including hair color, eye color, and so on. In recent years, scientists began exploring the concept of gene editing, which is the deliberate manipulation of genetic material to achieve desired results. Gene editing can potentially alter any given trait in an organism- from height to hair texture to susceptibility for certain diseases.

Gene editing applied to humans is referred to as Human Genetic Engineering, or HGE. There is extensive debate in and out of the scientific community regarding the ethics of HGE. Much of this debate stems from how this technology will affect society, and vice versa. Individuals may harbor concerns about the rise of designer babies or scientists playing God by determining the traits of an individual. On the contrary, HGE presents potential cures to diseases caused by genetic mutations. Human Genetic Engineering (HGE) is a novel technology which presents various ethical concerns and potential consequences. HGE should be approached cautiously and with extensive governmental regulation given its history, its current state, and the potential it has to change the world in the future.

Genetic Encoding of Proteins by MIT OpenCourseWare is licensed under CC BY-NC-SA 2.0

HGE utilizes CRISPR/Cas9 gene editing tools to cut out specific genes and replace them with a newly designed gene.

HGE encompasses a variety of methods which all work to produce a deliberate change in the human genome. The most common and prevalent way to edit the human genome is via CRISPR/Cas9. CRISPR stands for clustered regularly interspaced short palindromic repeats, and Cas9 is a protein that functions as scissors to cut DNA/genes. The CRISPR/Cas9 system originally developed as a part of a bacterias immune system, which can recognize repeats in DNA of invading viruses, then cut them out. Since then, scientists have harnessed the CRISPR/Cas9 system to cut DNA sequences of their choice and then insert new DNA sequences in their place.

The CRISPR/Cas9 system allows for designer genomes, and rapid engineering of any cells programming. With the use of CRISPR/Cas9, scientists can cut out certain traits from an individuals cells and insert new traits into those same cells.

CRISPR Cas9 System by Marius Walter is licensed under CC-BY-SA-4.0

Gene therapy is a recently-developed technology which can be applied to both somatic and germline genome editing.

Gene therapy concepts were initially introduced in the 1960s, utilizing outdated methods, such as recombinant DNA technology and viral vectors, to edit microorganisms genomes. Recombinant DNA consists of genetic material from multiple sources. The first experiments involved transferring a genome from one bacteria to another via a viral vector. Soon after was the first successful transformation of human cells with foreign DNA. The success of the experiment prompted public concern over the ethics of gene therapy, and led to political regulation. In the gene therapy report of the Presidents Commission in the United States, germline genome editing was deemed problematic over somatic genome editing. Also, non-medical genome editing was deemed problematic over medical genome editing. Germline genome editing occurs when scientists alter the genome of an embryo, so that the entire organism has altered genes and the traits can be passed to offspring. Somatic genome editing involves editing only a few cells in the entire organism so that traits can not be passed down to offspring. In response to the report, the rDNA Advisory Committee of the National Institutes of Health was formed and proposed the first guidelines for the gene therapy clinical trials. This is an example of technological determinism, in which technology determines the development of its social structure and cultural values or regulations.

In the past few decades, gene editing has advanced exponentially, introducing state-of-the-art technologies such as the CRISPR/Cas9 system, which was developed to induce gene modifications at very specific target sites. Thus, gene editing became a major focus for medical research (Tamura, 2020). Gene editing has led to the potential for development of treatment strategies for a variety of diseases and cancers. So far, somatic genome editing has shown promise in treating leukemia, melanoma, and a variety of other diseases. In this way, HGE may be demonstrative of cultural determinism, in which the culture we are raised presents certain issues which necessitate the development of a specific technology.

DNA CRISPR Scissors by Max Pixel is licensed under CC0 1.0

CRISPR/Cas9 is the primary technology proposed for use in HGE. HGE presents a variety of pros and cons to society.

Somatic genome editing in HGE via the CRISPR/Cas9 system has proven to be effective at editing specific genome sites. Since 2015, genome editing technologies have been used in over 30 human clinical trials and have shown positive patient outcomes. The treatment of disease may be a positive benefit of HGE, but there are also various potential risks. Various forms of deliberative democracies formed in recent years to address scientific and ethical concerns in HGE. Deliberative democracies afrm the need to justify technological decisions made by citizens and their representatives with experts in the field via deliberation. Overall, the consensus remains that the pros and cons of HGE are not equivalent enough to justify widespread use of the technology.

Current human clinical trials show successful transformation of human immune cells to HIV-resistant cells. This implies that HGE may be the cure for HIV(Hu, 2019). Other successful somatic genome editing trials treated myeloma, leukemia, sickle cell disease, various forms of epithelial cancers, and hemophilia. Thus, gene editing has provided novel treatment options for congenital diseases and cancers (Tamaura, 2020). Congenital diseases are those present from birth, and typically have a genetic cause. For these reasons, scientific summits concluded HGE is ethical for research regarding somatic genome editing in congenital diseases and cancers.

There are many safety concerns regarding CRISPR applications, mainly in germline genome editing. As a result of technological determinism, a leading group of CRISPR/Cas9 scientists and ethicists met for the international Summit on Human Gene Editing. The summit determined that heritable genome research trials may be permitted only following extensive research on risks and benefits of HGE. However, the summit concluded that federal funding cannot be used to support research involving human embryos with germline editing techniques. These decisions were made to avoid potential risks such as the following.

The major concerns regarding germline genome editing in HGE include: serious injury or disability, a blurry line between therapeutic applications of HGE and medical applications, misapplications, potential for eugenics ( the study of how to arrange reproduction within a human population to increase the occurrence of heritable characteristics regarded as desirable), and inequitable access to the technology.

HGE is a complex technology which presents a variety of risk factors for the coming decades. Deliberative democracy is necessary to keep this technology in check, ethically.

The future of HGE is uncertain and requires immense forethought. The American Society of Human Genetics workgroup developed a position statement on human germline engineering. The statement argues that it is inappropriate to perform germline gene editing that culminates in human pregnancy; and that in vitro(outside of an organism) germline editing should be permitted with appropriate oversight. It also states future clinical human germline editing requires ethical justification, compelling medical rationale, and evidence that supports its clinical usage. Many of these decisions were made based on the potential concerts over the future possibilities of the technology.

At the societal level, there may be concerns related to eugenics, social justice, and accessibility to technology. Eugenics could potentially reinforce prejudice and enforce exclusivity in certain physical traits. Traits can be preselected for, thus labeling some as good and others as unfavorable. This may perpetuate existing racist ideals, for example.

Moreover, germline genome editing may also increase the amount of inequality in a society. Human germline editing is likely to be very expensive and access may be limited to certain geographic regions, health systems, or socioeconomic statuses. Even if human genetic engineering is only used for medical purposes, genetic disease could become an artifact of class, location, or ethnic group. Therefore, preclinical trials are necessary to establish validity, safety, and efficacy before any wide scale studies are initiated.

Others argue that HGE may lessen genetic diversity in a human population, creating a biological monoculture that could lead to disease susceptibility and eventual extinction. Analyses have predicted that there will be negligible effect on diversity and will more likely ensure the health and longevity of humans (Russel, 2010). Legacy thinking may be responsible for the hesitations towards continuing forward with HGE, as there are also many potential pros for genetic engineering. Legacy thinking is using outdated thinking strategies and actions which may not be useful anymore.

In an alternative modernity, we can imagine HGE as an end-all for most congenital diseases and cancers. Moreover, it may be used in germline gene editing to prevent certain birth defects or heritable diseases. So, although HGE has a variety of potential risk factors, there is also great promise for novel medical therapies in the coming decades. The continued use of this technology should be approached cautiously and with extensive governmental regulation, allowing for research regarding its medical applications only.

In 2016, germline gene editing was proven feasible and effective in chickens by leading researchers in genetic engineering, Dimitrov and colleagues. In this study, scientists used CRISPR/Cas9 to target the gene for an antibody/ immunoglobulin commonly produced in chickens. Antibodies are proteins produced in immune response. In the resulting population, the chickens grew normally and healthily with modified antibodies which conferred drug resistance. This study was the first to prove that germline editing is both feasible and effective.

HGE is a rapidly expanding field of research which presents novel possibilities for the coming decades. HGE utilizes CRISPR/Cas9 gene editing tools to cut out specific genes and replace them with a newly designed gene. As important as this technology is, it is also important to recognize how new it is. Gene therapy research began in the 1960s, with somatic cell editing only commencing in the past two decades. This has presented many advantages for the potential treatment of congenital diseases, but also presents various risks. Those risks stem from germline gene editing and include eugenics and inequitable access to the technology creating large socio economic divides. In the future, more regulation should be placed on the advancement of HGE research before larger-scale studies take place.

1. What is the primary technology proposed for use in HGE?

A. Recombinant DNA technology

B. CRISPR/Cas9

C. Bacterial Transformation

D. Immunoglobulin

2. When was gene therapy concepts first introduced?

A. 1920s

B. 1940s

C. 1960s

D. 1980s

3. What is a major ethical concern regarding HGE addressed in this chapter?

A. Potential for ageism

B. Gene editing is only 50% effective

C. HGE can only be used in Caucasians

D. Potential for eugenics

Answers:

Baltimore, D. et. al.(2015). A prudent path forward for genomic engineering and germline gene modification. Science. https://doi.org/10.1126/science.aab1028

Brokowski, C., & Adli, M. (2019). CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2018.05.044

Cong, L., Ran, F., & Zhang, F. (2013). Multiplex Genome Engineering Using CRISPR/Cas9 Systems. Science. https://doi.org/10.1126/science.1231143

Dimitrov, L., et. al. (2016). Germline Gene Editing in Chickens by Efficient CRISPR-Mediated Homologous Recombination in Primordial Germ Cells. Plos One. https://doi.org/10.1371/journal.pone.0154303

Hu, C. (2019). Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-Infected Subjects with Hematological Malignancies. U.S National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT03164135

Ormond, K., et. al.(2017). Human Germline Genome Editing. AJHG. https://doi.org/10.1016/j.ajhg.2017.06.012

Russell P.(2010) The Evolutionary Biological Implications of Human Genetic Engineering, The Journal of Medicine and Philosophy: A Forum for Bioethics and Philosophy of Medicine. https://doi.org/10.1093/jmp/jhq004

Tamura, R., & Toda, M. (2020). Historic Overview of Genetic Engineering Technologies for Human Gene Therapy. Neurologia medico-chirurgica. https://doi.org/10.2176/nmc.ra.2020-0049

Thomas, C. (2020). CRISPR-Edited Allogeneic Anti-CD19 CAR-T Cell Therapy for Relapsed/Refractory B Cell Non-Hodgkin Lymphoma. ClinicalTrials. https://clinicaltrials.gov/show/NCT04637763

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18 Human Genetic Engineering - Clemson University

Gene therapy involves inserting a gene into a patients cells to treat or prevent disease instead of using drugs or surgery. Although still experimental, gene therapy aims to target the root cause of a disease, such as gene transfer into the individual cell types of the complex lung structure in cystic fibrosis patients, and has the potential to save a patient from a lifetime of complicated treatments all the while suffering the condition.

Research into using gene therapy to prevent diseases such as cancer and diabetes is showing some potential. However, it is the power of gene therapy to enhance humans that is causing the greatest concern. In September 2015, scientists at Londons Francis Crick Institute applied for a licence to use technology based on the CRISPR/Cas9 system a recently developed technique for precisely editing genomes to study early human development to edit genes in human embryos.

By Robert Sparrow, professor of philosophy, Monash University, Australia

Scientists, philosophers and science fiction authors have been discussing designer babies since the 1930s. However, the issues they have been discussing have remained theoretical because of the difficulty in getting genes to do what they want. The new technology of genome editing, known as CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats), which makes possible precise modifications of the genetics of organisms, changes things dramatically. Genetic modification of humans now looks all too possible.

Researchers and corporations are rushing to investigate and hopefully exploit the potential of this new technology to modify human beings genetically.

Many of the proposed applications would involve modifying patients somatic cells (any cell of the body except sperm and egg cells) in the hope of curing, or at least ameliorating, particular diseases and genetic disorders, thus eliminating the need for a lifetime of medical and drug treatment. Such uses of CRISPR/Cas9 would hold tremendous promise. However, they are not my concern here.

Some scientists have been quick to tout the potential of this new technology as a possible cure for some forms of infertility and to prevent various genetic diseases affecting future individuals[1]. These hypothetical techniques would entail editing the genome of human embryos or of stem cells a practice currently outlawed in the UK that might then be coaxed into developing into sperm and eggs. What makes such hypothetical uses of genome editing especially controversial is that the genetic modification would or at least could affect the germline of the individuals who were brought into existence. Should something go wrong, multiple generations would be at risk.

Yet, discussion of the therapeutic potential of germline modification is in many ways a distraction. The real potential of CRISPR/Cas9 lies elsewhere.

There are already means to allow affected individuals to have healthy children[1],[2]. In particular, preimplantation genetic diagnosis (PGD) allows doctors to choose which of a number of embryos created outside the human body to implant into a womans womb in order to ensure that a child is born without particular undesirable genes. Only when a couple is unable to produce viable embryos that do not carry genes for a disorder using their own gametes would there be any grounds for attempting to cure affected embryos by editing their genomes. Even in such cases, couples could always have children using donor sperm and/or donor ova. Similarly, individuals who are unable to produce viable gametes are able to use donor gametes to create embryos and secure a pregnancy.

Rather than a cure for a disease, then, genome editing would function solely as a means to satisfy the preferences of couples to raise children who were their genetic offspring. One cannot help but marvel at the success of the marketing of reproductive medicine, which has brought us to the point where it could seem reasonable to prefer a child who had been genetically modified rather than a child who was related to someone other than his or her social parents.

What germline modification could do that existing technologies cannot is produce embryos with particular genes associated with desirable traits[1]. If scientists can find genes that are associated with above-species-typical traits for example, higher intelligence, longevity, concentration or memory CRISPR/Cas9 will allow them to insert these genes into embryos. In theory, at least, the CRISPR/Cas9 system would allow parents to insert genes for as many desirable traits as they liked into the genome of their child.

No matter how many animal trials we perform, there will be no way to be sure how the modification will affect a human child as they mature. It is also worth admitting the limits of our ability to bend living things to our designs even with this incredible new tool.

The more we learn about genetics, the more complicated the interactions between genes and the environment which produces the phenotype of the organism appear. It is one thing to be able to cut and paste DNA but it is another to know what the result will be, especially because modifications to one part of the genome can have unexpected effects elsewhere. Of course, concerns about risks to health are arguably as much of a barrier to therapeutic use of CRISPR/Cas9 as they are to its use for human enhancement.

Cynically, it seems that references to risk often serve as a smokescreen to defuse public anxiety about potential applications of new reproductive technologies, while research on them continues. While scientists cannot do something, it would be too risky to try. The moment they can do it, the potential benefits mean that it would be irresponsible not to.

Let us not be deluded, then, that the renewed debate about germline genetic engineering, prompted by CRISPR/Cas9, is about rescuing a small number of individuals from the burden of genetic disease. It is nothing less than a debate about what it will mean to be human in the future. Will our grandchildren or perhaps even children be born all equally subject to the vicissitudes and the joys of the genetic lottery?[3]Or will they be made? Stronger, better perhaps children of the wealthy more so than others but are created by designers and so are vulnerable to obsolescence[4].

There is a choice to be confronted here but it is a difficult one. To make a decision wisely we will need to draw on all our resources and, in particular, our deepest values about what sort of world we want to live in, with what sorts of human flourishing. It would be a dreadful mistake to allow enthusiasm for impressive science and the vague promise of therapeutic benefits to distract us from the vital importance of this debate.

By Glenn Cohen,faculty director, Petrie-Flom Center for Health Law Policy, Biotechnology & Bioethics, Harvard Law School, Cambridge, Massachusetts

CRISPR-Cas9 allows DNA sequence changes in pluripotent embryonic stem cells that can then be cultured to produce specific tissues, such as cardiomyocytes or neurons[5]. The hope is that it will lead to much more refined approaches to a range of human diseases, but there are also concerns that it can be used to change the DNA in the nuclei of reproductive cells that transmit information from one generation to the next (an organisms germline), prompting a group of prominent scientists and ethicists to recommend a temporary (at least) moratorium on any human clinical uses.[5]

Gene editing is but one of a series of forms of human enhancement. And while it perhaps poses the most safety risks in its germline form, the fear is we will make changes that pose risks that may not manifest until many generations downstream when the cat will be out of the proverbial bag.

Genetic engineering is not a single phenomenon. It represents a series of different subcategories and they have to be examined individually. By seeing the full panoply of cases, we can see that sometimes we may be engaged in a kind of biological exceptionalism that what strikes us as scary in the biological context is something we do in the non-biological context routinely, and we need to examine whether the biological versus non-biological, as well as other lines, are morally significant ones.

When discussing the issue of gene therapy and, ultimately, genetic engineering, it is useful to make a distinction between biological and non-biological enhancement[6]. For example, a hypothetical pill or surgery to raise ones performance on standardised testing versus tutoring to improve ones performance on standardised testing. The first seems to concern us, while the second is common place. Some might also distinguish genetic from non-genetic biological enhancement. We should also consider the concept of choosing for ourselves as opposed to choosing for others. For example, an adult using anabolic steroids versus providing human growth hormone for a child.

Some enhancements are like swiss army knives in that they can improve the prospects for a child, whatever the child chooses to do with his or her life, for example, improvements in intelligence or disease resistance. On the other hand, some enhancements will serve to close off certain life plans while they improve the chances in others. To give a trivial example, enhancing height may increase a persons chance of becoming a professional basketball player, but decrease their chance of riding a racehorse to glory. The same is true regarding non-biological enhancements. Ethicists are usually more worried about the latter category.

Some would draw distinctions between treatment to correct disease or disability as opposed to enhancement to make people better than well. For example, a colleague of mine defines the distinction in relation to species typical functioning[7]. Others, including myself, are sceptical and think this falls prey to a classic baseline problem and treats our status quo states of health or other goods as morally significant.

Some would also draw a finer sub-distinction between enhancements to the upper bounds of what people already have versus enhancements that add beyond human nature as it now stands but, again, one might wonder why give moral pride of place to our own current status quo.

Finally, some goods, such as being tall, are beneficial primarily in a positional sense they are desirable to have only because others lack them. By contrast, other goods, such as immunity to disease, are primarily absolute goods, in the sense that one would want to have the enhancement even if everyone were to have it.

Using enhancement for positional goods may particularly exacerbate inequalities of access and also impose costs (to our health, for example) that create a kind of evolutionary rat race where people must enhance merely not to fall behind.

Most traits, though, are mixes of positional and absolute goods, in that they are sought to confer positional advantage and because they have absolute benefit. Indeed, determining just how much a particular trait is valued for positional as opposed to absolute value may be difficult or costly to determine.

To evaluate whether the law should permit or prohibit or otherwise regulate any particular form of human enhancement, it is useful to first situate it within this taxonomy. When enhancements impose costs on the enhancer, or especially externalised costs, that is more problematic when the good sought is more positional than absolutely beneficial. The less reversible an enhancement, the more the concerns about safety but also its effects on social change loom large. And so on.

Some enhancements have the potential to improve the human condition as we know it and some have the potential to wreak havoc on our lives and social structure. Anyone who has a position on enhancement has not thought deeply enough on the question. The right answer to the regulatory, legal, and ethical questions can only be answered on a category-by-category basis.

Either way, pharmacogenetics, gene therapy and, ultimately, genetic engineering will continue to progress. We have already seen this earlier this year, when Chinese scientists reported editing the genomes of human embryos[8]. The results were published in the journalProtein & Cell[9]and sparked widespread debate about the ethical implications of such work.

No doubt, this debate will continue.

Originally posted here:
Genetically engineering humans: a step too far?

Written by Audrey Eaves

Advancements in science and technology have enabled the possibility of human genetic cloning and engineering. In contemporary society, these biological technologies are controversial. Many governmental, scientific, and religious organizations are fervently opposing genetic engineering due to controversy in the context of safety and moral outcomes. Nevertheless, advocates and supporters argue that these technologies are fundamental to providing remedies via regenerative medicine through genetically identical human cells, organs, or tissues. Other health areas such as cosmetic and reconstructive surgeries, infertility, burn treatments, heart disease, cancer, and diabetes can benefit from the new technologies available through gene therapies. Gene therapy can help millions suffering from disease and disorders. Biomedical researchers are working on effective solutions regarding some major genetic disorders such as sickle-cell and hemophilia, but there are always risks.

Genetic engineering certainly has its dilemmas, but it also has a moral and ethical value in contemporary society, therefore, a new branch of ethics is born: bioethics. Bioethics refers to the application of medical and biological sciences in appropriate, humane, and responsible ways. Supporters see genetic engineering and cloning as a viable way to duplicate organs and tissues for patients who otherwise would not be able to find transplants and could escape lifetimes of medications with undesirable side effects. Yet, some are concerned that if done incorrectly, genetic engineering could actually introduce new disorders that would subsequently circulate in the population and thus become a permanent aspect of the worlds population.

The majority of biomedical researchers view genetic engineering as a crucial tool for medicine, especially in the provision of solutions for diverse terminal health issues. Consider these daunting statistics from Kidney.org: the average wait time for a needed kidney is three to five years, and some patients cannot wait that long. According to another source, Donate Life America, 8,000 people die every year waiting for an organ, 80% of which are kidneys. However, in a world where slavery, human organ harvesting, and black markets continue to be a problem, genetic engineering and cloning could provide even darker opportunities for these human rights crimes. A realistic approach in the context of humanitys place in the world and a code of ethics to form the foundation of human genetic engineering practices is needed.

Religious factions are by no means the only moral compass of society, but they tend to be the loudest sounding alarms of anything that is morally questionable. While their objections sometimes (but not always) deviate from science and can frustrate progressive efforts, they provide a necessary role in a symbiotic system of checks and balances within the scientific communities they oppose. It is constructively beneficial that science should always be questioned and forced to prove itself before diving headfirst into the deep waters of the latest and greatest technological discoveries.

Embryonic engineering and cloning in particular draws criticism from people of various faiths who argue that the creation of embryos for the purposes of research does not respect life. A number of religious faiths assert that embryos should be assigned personhood. This particular characterization disarms objectification practices that are currently in place regarding human embryos. During the process of embryonic research, excess embryos are created and destined for destruction, which is another challenge for bioethics. However, this is nothing new, as the process of IVF does similarly for couples who struggle with infertility. Matters of human wastefulness always arise in these waters. Even with natural pregnancies, research shows that half of the embryos fail to implant or are lost. While embryonic loss does occur in natural pregnancies, most people do not equate laboratory embryonic loss with infant mortality, which implies they have a different moral value to most of society. Does regarding human embryos as mere objects that can be used in any desirable way make them lack the nascent aspect of human life and significance? Whatever side one falls on the argument, it is vital to encourage the cultivation of a society that views life as having great intrinsic value. This understanding and respect for life creates the difference between barbarism and civilization.

There are yet other faiths who place great spiritual importance on what goes inside their bodies. This can apply both to what is in their food as well as medical treatments. For these groups, there could be a moral dilemma posed by significant genetic modification of food and medicine. For example, various genes are being injected into peppers and tomatoes to make them grow faster and more hearty. Animal and human cells are also used in the production of some vaccines. This raises the question of how many human and animal genes can be present in vegetables or medicine without it being considered unsuitable for vegans or the millions of religious adherents who abstain from certain animal and human by-products, such as with Islam, Jehovahs Witnesses, and Judaism. While these unique groups of people are ultimately responsible for their own decisions, sensitivity to diverse belief systems must be a consideration of the scientific community as well.

Despite all the current ethical concerns regarding genetic engineering and human cloning, the practice still has tremendous potential in light of more conclusive scientific research studies on this particular subject. However, the challenges experienced in past genetic experiments should be a major factor in discouraging a rushed start of biogenetics. More research should be developed to review the ethical and moral considerations in genetic engineering practices. A full understanding of what we are doing and its consequences needs some time to catch up with the technology. Most important is the conviction and cultivation of a society that protects and enhances life in all of its scientific endeavors.

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Genetic Engineering and Ethics: Are We Ready? | The Voice

By Zachary Rom|Considering Another Side Essays

Scientists have been trying to create synthetic life, life created in lab, for many years. The first breakthrough in this process happened about thirty years ago when genetic engineers began to genetically modify organisms (Savulescu). These engineers physically move genes across species in order to improve an organism or to cause an organism to function differently. Even though this process sounds as if it happens only in fantasy games, genetically modified organisms are common. For example, genetically modified crops are used every day in the worlds food supply and genetically modified bacteria have been used in medicine, chemical manufacturing, and bio warfare (Pickrell). Slowly, genetic engineering has become a powerful tool in many different fields. Recently, genetic engineerings potential power increased when Craig Venter, a famous geneticist and entrepreneurs, recreated a living organism out of synthetic chemicals. His success proved to genetic engineers that functioning genomes can be made purely of synthetic chemicals. This power would allow genetic engineers to build new artificial genomes instead of having to modify naturally existing genomes. Genetic engineers now have the chance to broaden their fields applications. However, genetic engineering is unpredictable and dangerous, and broadening the application of genetic engineering only furthers the risks. Genetically engineered organisms pose lethal and economic risks to human society.

The availability of genomic information and genetic engineering technology creates a lethal threat to humanity because terrorists can use both the information and technology to recreate deadly pathogens, such as the poliovirus. The naturally occurring poliovirus killed and paralyzed millions of people for many years. In 1988, a worldwide vaccination campaign against the virus nearly exterminated it from the environment, and this solved the poliovirus epidemic. However, in 2002, well intentioned scientists decided to recreate the poliovirus for research means. Using the genomic sequence of the poliovirus found on a public database and commercially available machines, these scientists synthesized fragments of viral genomes into a functional poliovirus (Avise 7). These scientists proved that deadly pathogens can be recreated from genetic engineering techniques. Also, the information and technology used in genetic engineering is readily available and relativity cheap (Kuzma and Tanji 3). Mixing the power to recreate a deadly pathogen with the public availability of genetic engineering information and technology creates a lethal risk to humanity when terrorist exist in society. Terrorist could use genetic engineering to reinstate the poliovirus into the environment, and the virus would kill and paralyze more people. Luckily, these scientists were filled with good intent; however, there is nothing to prevent terrorists from harming innocent lives. Recreating deadly pathogens makes genetic engineering dangerous enough; however, genetic engineers also have the potential to improve the effectiveness of deadly pathogens, such as Y. pestis.

Genetic engineers can make deadly pathogens, such as Y. pestis, resistant to modern antibiotics, and these pathogens could kill innocent people if used as a weapon. Y. pestis, also known as the black plague, wreaked havoc on humanity during the Middle Ages by killing millions of people. In response to a Y. pestis threat during the 20th century, scientists developed an effective vaccine for the pathogen. However, genetic engineers at Biopreparat, a Russian biological warfare agency, engineered a new Y. pestis strain with genetic resistance to modern antibiotics and natural human immunity (Avise 6). The genetically engineered Y. pestis was more deadly and effective than the natural Y. pestis that killed millions of people during the Middle Ages. Biopreparats research proved that deadly pathogens can be genetically engineered into superior forms that are resistant to modern medicine. If this strain of Y. pestis was released, a black plague would devastate current human society. Militaries could use the same genetic engineering techniques that Biopreparat used to create deadly biological weapons. With this ability to make deadly pathogens resistant to modern medicine, genetically engineered organisms become lethal weapons that cannot be stopped. Other than lethal weapons, genetically engineered organisms can produce lethal chemical compounds when they are used as a manufacturing tool in the chemical industry.

Showa Denkos genetically modified bacteria produced a lethal L-tryptophan amino acid that killed and disabled people who took the companys food supplements. In 1989, an epidemic of eosinophilia myalgia syndrome, a syndrome that is characterized by a high eosinophil count and severe muscle pain, struck the United States (Genetic Engineering: Too Good to Go Wrong 9). This epidemic killed a hundred people and physically disabled ten thousand patients, some of which were paralyzed. Doctors eventually discovered that L-tryptophan, an amino acid used as a food supplement, was causing the epidemic. In 1990, the Journal of the American Medical Association reported that only people who took the L-tryptophan supplement made by Showa Denko, a Japanese biotech company, came down with EMS. Showa Denkos genetically engineered organisms produced corrupted forms of L-tryptophan that were dangerous to human health (Smith 4).

Many chemical companies want to use genetically engineered organisms to produce chemicals because it is cheaper than normal manufacturing methods. If chemical companies begin to rely on genetically engineered organisms to produce food and medical chemicals, the public could be at risk for another dangerous outbreak of lethal chemicals. Using genetically engineered organisms to cutting down manufacturing costs seems as if it will help the economy; however, genetically engineered organisms, specifically anti-material organisms, can hurt economies more than help them.

Genetic engineers possess the ability to create anti-material organisms that can degrade infrastructure and man-made materials, and malicious people can use these organisms to tear down societys infrastructures and economies. In nature, there are many organisms with the ability to degrade infrastructure and man-made materials. These microbes cost governments and industries millions of dollars in biodeterioration and biodegradation damages. For instance, bacteria are the leading cause of road and runway deterioration. In Houston, Texas, microbes have been known to degrade the concrete in the citys sewage systems, and the city has spent millions of dollars trying to contain the problem. High-tech companies, such as airlines and fuel companies, constantly have their facilities and machinery being degraded away by anti-material organisms. These natural organisms cause enough damage to infrastructure, and fixing the damage is expensive and time consuming (Sunshine Project 2). Similarly to the artificially made poliovirus, genetic engineers have the potential to recreate or improve these naturally occurring anti-material organisms. In theory, malicious people could unleash genetically engineered anti-material organisms on infrastructures worldwide, and this would create an expensive cleanup project for governments and companies. With these expensive damages, genetically engineered organisms can destroy economies. The same economic and environmental dangers of anti-material organisms can also be seen in genetically modified crops.

Genetically modified crops will negatively impact the economy and environment because engineered genetic resistance is ineffective at stopping natural parasites in the long term. Farmers use genetically modified crops because these crops contain a genetic resistance to parasites, such as insect pests and microbes. In evolution, two organisms that are in a parasitic relationship evolve in a balance with each other. When genetically modified plants are placed into a natural environment, parasites will evolve in a direction that allows them to bypass the genetic resistance engineered into the crops. Since the majority of crop parasites go through successive generations at a fast pace, these parasites will quickly evolve into a population that can surpass the genetic resistance. This evolutionary process makes the benefits of genetically modified crops short lived. Farmers, who pay more for genetically modified seed than natural seed, then have to pay for harmful and expensive pesticides to protect their crops. In the end, farmers will lose money due to the increased costs of buying genetically modified crops and dangerous pesticides. Also, dangerous chemicals, such as DDT, will be reintroduced into the environment (Avise 73). The ineffectiveness of genetically modified crops creates an economic and environmental risk to human society in the long run since farmers will be losing more money and introducing dangerous chemicals into the environment.

Genetically engineered organisms pose an enormous risk to human society on a lethal and economic front. Natural lethal pathogens, such as the poliovirus and Y. pestis, can be recreated or improved, and malicious people could use these genetically engineered pathogens to kill millions of people. Chemicals manufactured by genetically modified bacteria have proven to be harmful to human health, which was the case during the EMS epidemic in the United States. On an economic front, genetically engineered organisms increase costs instead of minimizing them, and they harm the environment. Anti-material organisms can be created to deteriorate infrastructures, and this would cost governments and industries millions of dollars in repair costs. Also, genetically modified crops in the long term will cost farmers more money than they save because the advantages of the genetically modified crops will be nullified by evolving parasites. Genetically engineered organisms have a huge potential to harm society. However, researching new methods and applications of genetic engineering will not stop because scientists believe in the vast opportunities of the field. In order to keep human society safe, scientists must exhaust all options before turning to the power of genetic engineering. It is an unwise idea to rely on genetic engineering since it is unpredictable and imprecise form of engineering.

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Genetic Engineering: A Serious Threat to Human Society

Scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard Medical School (HMS), and Duke University, in collaboration with Gameto, report that they have created a living, fully human ovarian organoid that supports egg cell maturation, develops follicles, and secretes sex hormones. This ovaroid model enables the study of human ovarian biology without the need to take tissue from patients and could enable the development of new treatments for conditions like infertility, ovarian cancer, and more, according to the researchers.

Through an agreement with Harvards Office of Technology Development (OTD), the technology has been licensed to Gameto, which is using it to develop therapeutics for diseases of the female reproductive system. The ovaroids are described in detail Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression in eLife.

An in vitro model of human ovarian follicles would greatly benefit the study of female reproduction. Ovarian development requires the combination of germ cells and several types of somatic cells. Among these, granulosa cells play a key role in follicle formation and support for oogenesis. Whereas efficient protocols exist for generating human primordial germ cell-like cells (hPGCLCs) from human induced pluripotent stem cells (hiPSCs), a method of generating granulosa cells has been elusive, write the investigators.

Here, we report that simultaneous overexpression of two transcription factors (TFs) can direct the differentiation of hiPSCs to granulosa-like cells. We elucidate the regulatory effects of several granulosa-related TFs and establish that overexpression of NR5A1 and either RUNX1 or RUNX2 is sufficient to generate granulosa-like cells. Our granulosa-like cells have transcriptomes similar to human fetal ovarian cells and recapitulate key ovarian phenotypes including follicle formation and steroidogenesis.

When aggregated with hPGCLCs, our cells form ovary-like organoids (ovaroids) and support hPGCLC development from the premigratory to the gonadal stage as measured by induction of DAZL expression. This model system will provide unique opportunities for studying human ovarian biology and may enable the development of therapies for female reproductive health.

Our new method of fully human ovaroid production is several times faster than existing human/mouse hybrid methods, and replicates many of the critical functions of these organs, marking a significant step forward in our ability to study female reproductive health in the lab. In the future, similar technology could also treat infertility by growing egg cells from peoplewhose own eggs arent viable, said co-first author Merrick Pierson Smela, a graduate student in the lab of George Church, PhD, at the Wyss Institute and HMS.

Creating the granulosa cells on their own was a significant accomplishment, but making an ovaroid out of only granulosa cells wouldnt tell us anything about their ability to support the maturation of germ cells, which was what we wanted to be able to studyin vitro, said co-first author Christian Kramme, PhD, the vice president of cell engineering at Gameto and a former graduate student in Churchs group at the Wyss Institute and HMS. This process had been replicated previously using hPGCLCs and mouse somatic cells, but with this new technology, we now have the ability to do it with a fully human model.

The Wyss team is continuing to develop its human ovaroid model and plans to integrate additional ovarian cell types, including hormone-producing theca cells, to more fully replicate the complex functions of the human ovary. They also hope to improve their culture system to allow their germ cells to fully develop into egg cells, and determine the optimal dosage of the different TFs. Gameto, meanwhile, has conducted preclinical studies of a derived co-culture system for egg maturation in humans with leading national fertility clinics.

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Fully Human Ovarian Organoid That Supports Egg Cell Maturation Created ...

Abstract

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 [13]. 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 [68].

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 [1416], 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 [2022] 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 CC 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 organisms 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 [2628]. 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.

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 geneor its absencecan 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, its 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.

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 neutralin the sense of not progressiveprocess. 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 [2022]. 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 employedas part of our domestication/selective breeding of other animalstechniques 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 healthyas domesticated dogsbut be less biologically fit according to Darwins 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 [4244]. 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 levelse.g. genetic, cellular, among individuals and among different taxaplay 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 Fundao para a Cincia e a Tecnologia (FCT) of Portugal [CFCUL/FIL/00678/2019 to M.A.].

Conflict of interest: None declared.

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