Human germline engineering

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Human germline engineering is the process by which the genome of an individual is edited in such a way that the change is heritable. This is achieved through genetic alterations within the germinal cells, or the reproductive cells, such as the oocyte and spermatogonium. Human germline engineering should not be confused with gene therapy. Gene therapy consists of altering somatic cells, which are all cells in the body that are not involved in reproduction. While gene therapy does change the genome of the targeted cells, these cells are not within the germline, so the alterations are not heritable and cannot be passed on to the next generation.

The creation of genetically modified humans may have been performed in the mid-1990s, in which a 1997 study published in The Lancet claimed, “the first case of human germ-line genetic modification resulting in normal healthy children.”.

The first attempt to edit the human germline was reported in 2015, when a group of Chinese scientists used the gene editing technique CRISPR/Cas9 to edit single-celled, non-viable embryos to see the effectiveness of this technique. This attempt was rather unsuccessful; only a small fraction of the embryos successfully spliced the new genetic material and many of the embryos contained a large amount of random mutations. The non-viable embryos that were used contained an extra set of chromosomes, which may have been problematic. In 2016, another similar study was performed in China which also used non-viable embryos with extra sets of chromosomes. This study showed very similar results to the first; there were successful integrations of the desired gene, yet the majority of the attempts failed, or produced undesirable mutations.

The most recent, and arguably most successful, experiment in August 2017 attempted the correction of the heterozygous MYBPC3 mutation associated with Hypertrophic Cardiomyopathy in human embryos with precise CRISPR–Cas9 targeting. 52% of human embryos were successfully edited to retain only the wild type normal copy of MYBPC3 gene, the rest of the embryos were mosaic, where some cells in the zygote contained the normal gene copy and some contained the mutation.

In November 2018, researcher Jiankui He claimed that he had created the first human genetically edited babies, known by their pseudonyms, Lulu (Chinese: 露露) and Nana (Chinese: 娜娜).

Human genetic modification is the direct manipulation of the genome using molecular engineering. The two different types of gene modification is "somatic gene modification" and "germline genetic modification." Somatic gene modification adds, cuts, or changes the genes in cells of a living person. Germline gene modification changes the genes in sperm, eggs, and embryos. These modifications would appear in every cell of the human body. Germline modification is yet to be done to a human.

CRISPR/cas9

Human germline engineering is modifying the genes in the human sex cells that can be passed on to the future generations. This process is done by a complicated but an accurate technique that contains an enzyme complex called CRISPR/Cas9 “clustered regularly interspaced short palindromic repeats”, this enzyme can be found in many bacteria immune system, in which they use it to fight off any harmful infections.

CRISPR is a repeated, short sequence of RNA that match with the genetic sequence that the scientists are aiming to modify or engineer. CRISPR works in rhythm with Cas9, an enzyme that splices the DNA. First, the CRISPR/Cas9 complex searches through the cell's DNA until it finds and binds to a sequence that matches the CRISPR, then, the Cas9 splices the DNA. After that, the scientist inserts a piece of DNA before the cell starts repairing the spliced part, said John Reidhaar-Olson, a biochemist at Albert Einstein College of Medicine in New York. The main purpose of human germline engineering is to enable the scientists to discover the unknown functions of the genes by eliminating specific DNA fragments and observing the consequences in the targeted cell. Also, scientists use CRISPR technology to fix the gene mutations and to treat or eliminate some diseases that can be passed on to the offsprings.

CRISPR/cas9 is a genome editing tool that allows scientists to edit the genome by adding or removing sections of DNA. It contains an enzyme and RNA, the enzyme acting like scissors to alter the DNA while the RNA acts as a guide for those enzymes. This system is currently the fastest and cheapest way to genetically engineer on the market today and it's uses are endless. The RNA in the CRISPR/cas9 allows researchers to target specific sequences in the genome making it possible for them to alter one sequence and not the others surrounding them. This is a new technology for scientists in the genomic altering field.

Although the CRISPR/cas9 cannot yet be used in humans, it allows scientists to target genes more effectively in diploid cells of mammals in order to one day be used in human research. Clinical trials are being conducted on somatic cells, but CRISPR could make it possible to modify the DNA of spermatogonial stem cells. This could eliminate certain diseases in human, or at least significantly decrease a disease's frequency until it eventually disappears over generations. Cancer survivors theoretically would be able to have their genes modified by the CRISPR/cas9 so that certain diseases or mutations will not be passed down to their offspring. This could possibly eliminate cancer predispositions in humans. Researchers hope that they can use the system in the future to treat currently incurable diseases by altering the genome altogether.

Conceivable uses

The Berlin Patient has a genetic mutation in the CCR5 gene (which codes for a protein on the surface of white blood cells, targeted by the HIV virus) that deactivates the expression of CCR5, conferring innate resistance to HIV. HIV/AIDS carries a large disease burden and is incurable (see Epidemiology of HIV/AIDS). One proposal is to genetically modify human embryos to give the CCR5 Δ32 allele to people.

There are many prospective uses such as curing genetic diseases and disorders. If perfected, somatic gene editing can promise helping people who are sick. In the first study published regarding human germline engineering, the researchers attempted to edit the HBB gene which codes for the human β-globin protein. Mutations in the HBB gene result in the disorder β-thalassaemia, which can be fatal. Perfect editing of the genome in patients who have these HBB mutations would result in copies of the gene which do not possess any mutations, effectively curing the disease. The importance of editing the germline would be to pass on this normal copy of the HBB genes to future generations. 

Another possible use of human germline engineering would be eugenic modifications to humans which would result in what are known as "designer babies". The concept of a "designer baby" is that its entire genetic composition could be selected for. In an extreme case, people would be able to effectively create the offspring that they want, with a genotype of their choosing. Not only does human germline engineering allow for the selection of specific traits, but it also allows for enhancement of these traits. Using human germline editing for selection and enhancement is currently very heavily scrutinized, and the main driving force behind the movement of trying to ban human germline engineering.

The ability to germline engineer human genetic codes would be the beginning of eradicating incurable diseases such as HIV/AIDS, sickle-cell anemia and multiple forms of cancer that we cannot stop nor cure today. Scientists having the technology to not only eradicate those existing diseases but to prevent them altogether in fetuses would bring a whole new generation of medical technology. There are numerous disease that humans and other mammals obtain that are fatal because scientists have not found a methodized ways to treat them. With germline engineering, doctors and scientists would have the ability to prevent known and future diseases from becoming an epidemic.

State of research

The topic of human germline engineering is a widely debated topic. It is formally outlawed in more than 40 countries. Currently, 15 of 22 Western European nations have outlawed human germline engineering. Human germline modification has for many years has been heavily off limits. There is no current legislation in the United States that explicitly prohibits germline engineering, however, the Consolidated Appropriation Act of 2016 banned the use of U.S. Food and Drug Administration (FDA) funds to engage in research regarding human germline modifications. In recent years, as new founding is known as "gene editing" or "genome editing" has promoted speculation about their use in human embryos. In 2014, it has been said about researchers in the US and China working on human embryos. In April 2015, a research team published an experiment in which they used CRISPR to edit a gene that is associated with blood disease in non-living human embryos. All these experiments were highly unsuccessful, but gene editing tools are used in labs.

Scientists using the CRISPR/cas9 system to modify genetic materials have run into issues when it comes to mammalian alterations due to the complex diploid cells. Studies have been done in microorganisms regarding loss of function genetic screening and some studies using mice as a subject. RNA processes differ between bacteria and mammalian cells and scientists have had difficulties coding for mRNA's translated data without the interference of RNA. Studies have been done using the cas9 nuclease that uses a single guide RNA to allow for larger knockout regions in mice which was successful. Altering the genetic sequence of mammals has also been widely debated thus creating a difficult FDA regulation standard for these studies.

Ethical and moral debates

As it stands, there is much controversy surrounding human germline engineering. Editing the genes of human embryos is very different, and raises great social and ethical concerns. The scientific community, and global community, are quite divided regarding whether or not human germline engineering should be practiced or not. It is currently banned in many of the leading, developed countries, and highly regulated in the others due to ethical issues. The large debate lies in the possibility of eugenics if human germline engineering were to be practiced clinically. This topic is hotly debated because the side opposing human germline modification believes that it will be used to create humans with "perfect", or "desirable" traits. Those in favor of human germline modification see it as a potential medical tool, or a medical cure for certain diseases that lie within the genetic code. There is a debate as to if this is morally acceptable as well. Such debate ranges from the ethical obligation to use safe and efficient technology to prevent disease to seeing actual benefit in genetic disabilities. While typically there is a clash between religion and science, the topic of human germline engineering has shown some unity between the two fields. Several religious positions have been published with regards to human germline engineering. According to them, many see germline modification as being more moral than the alternative, which would be either discarding of the embryo, or birth of a diseased human. The main conditions when it comes to whether or not it is morally and ethically acceptable lie within the intent of the modification, and the conditions in which the engineering is done. 

The process of modifying the human genome has raised ethical questions. One of the issues is “off target effects”, large genomes may contain identical or homologous DNA sequences, and the enzyme complex CRISPR/Cas9 may unintentionally cleave these DNA sequences causing mutations that may lead to cell death.

Another very interesting point on the debate of whether or not it is ethical and moral to engineer the human germline is a perspective of looking at past technologies and how they have evolved. Dr. Gregory Stock discusses the use of several diagnostic tests used to monitor current pregnancies and several diagnostic tests that can be done to determine the health of embryos. Such tests include amniocentesis, ultrasounds, and other preimplantation genetic diagnostic tests. These tests are quite common, and reliable, as we talk about them today; however, in the past when they were first introduced, they too were scrutinized.

One of the main arguments against human germline engineering lies in the ethical feeling that it will dehumanize children. At an extreme, parents may be able to completely design their own child, and there is a fear that this will transform children into objects, rather than human beings. There is also a large opposition as people state that by engineering the human germline, there is an attempt at "playing God", and there is a strong opposition to this. One final, and very possible issue that causes a strong opposition of this technology is one that lies within the scientific community itself. Inevitably, this technology would be used for enhancements to the genome, which would likely cause many more to use these same enhancements. By doing this, the genetic diversity of the human race and the human gene pool as we know it would slowly and surely diminish. Despite the controversy surrounding the topic of human germline engineering, it is slowly and very carefully making its way into many labs around the world. These experiments are highly regulated, and they do not include the use of viable human embryos, which allows scientists to refine the techniques, without posing a threat to any real human beings.

Genetically modified humans

The creation of genetically modified humans may have been performed in the mid-1990s, in which a 1997 study published in The Lancet claimed, “the first case of human germ-line genetic modification resulting in normal healthy children.”. In November 2018, researcher Jiankui He claimed that he had created the first human genetically edited babies, known by their pseudonyms, Lulu (Chinese: 露露) and Nana (Chinese: 娜娜).