26 August 2020

Designer kids

Should we expect a GMO generation?

Sergei Sobol, Naked Science

Many of us are born with qualities that help us compete better in society: beauty, intelligence, spectacular appearance or physical strength. Due to the success of genetics, it begins to seem that soon we will be able to do something that was previously beyond our control - to "design" people even before they were born. To set the necessary qualities, if they are not given by nature, predetermining the opportunities so necessary in life. This is what we do with machines and other inanimate objects, but now that the human genome has been decoded and we are already learning how to edit it, it seems that we are getting closer to the appearance of so-called "designer", "engineered" children. So "it seems" or will it soon become a reality?

Lulu and Nana from Pandora's Box

The birth of the first children with a modified genome at the end of 2019 caused a serious resonance in the scientific community and among the public. He Jiankui, a biologist from the Southern University of Science and Technology of China (SUSTech), announced the birth of the first ever children with an edited genome in an interview with the Associated Press on November 19, 2018, on the eve of the Second International Summit on Human Genome Editing in Hong Kong.

The twin girls were born in China. Their names, as well as the names of their parents, have not been disclosed: the first "GMO children" on the planet are known as Lulu and Nana. According to the scientist, the girls are healthy, and interference with their genome has made the twins immune to HIV.

The event, which may seem like a new step in the development of mankind or at least medicine, as already mentioned, did not cause positive emotions among the scientist's colleagues. On the contrary, he was condemned. Chinese government agencies have launched an investigation, and all experiments with the human genome in the country have been temporarily banned.

The experiment, which was not appreciated by the public, was as follows. The scientist took sperm and eggs from the future parents, performed in vitro fertilization with them, and edited the genomes of the resulting embryos using the CRISPR/Cas9 method. After that, the embryos were implanted into the mucous membrane of the woman's uterus, while the girls' future mother was not infected with HIV – unlike the father, who was a carrier of the virus.

The CCR5 gene encoding the membrane protein used by the human immunodeficiency virus to penetrate cells was edited. If it is modified, a person with such an artificial mutation will be resistant to infection with the virus.

The mutation that He Jiankui tried to create artificially is called CCR5Δ32: it also occurs in nature, but only in a few people, and has long attracted the attention of scientists. Experiments on mice in 2016 showed that CCR5Δ32 affects the work of the hippocampus, significantly improving memory. Its carriers are not only immune to HIV, but also recover faster after a stroke or traumatic brain injury, have better memory and learning abilities than "ordinary" people.

However, so far no scientist can guarantee that CCR5Δ32 does not carry any unknown risks and that such manipulations with the CCR5 gene will not cause negative consequences for the carrier of the mutation. Now the only negative consequence of such a mutation is known: the body of its owners is more susceptible to West Nile fever, but this disease is quite rare.

Meanwhile, the university where the Chinese scientist worked disowned his employee. The alma mater stated that He Jiankui's experiments, which were called a gross violation of ethical principles and scientific practice, were allegedly not known, and he was engaged in them outside the walls of the institution.

It is worth noting that the project itself has not received independent confirmation and has not been reviewed, and its results have not been published in scientific publications. All we have is only the statements of a scientist.

He Jiankui's work violated the international moratorium on conducting such experiments. The ban is established at the legislative level in almost all countries. The geneticist's colleagues agree that the use of CRISPR/Cas9 genomic editing technology in humans carries huge risks.

But the key point of criticism is that the work of a Chinese geneticist has nothing innovative: no one has previously taken up such experiments for fear of unpredictable consequences, because we do not know what problems modified genes can create for their carriers and descendants.
As the British geneticist Maryam Khosravi stated on her Twitter account: "If we can do something, it doesn't mean that we have to do it."

By the way, in October 2018, even before the shocking statement of the Chinese scientist, Russian geneticists from the Kulakov National Research Center of Obstetrics, Gynecology and Perinatology also announced the successful modification of the CCR5 gene with the help of the CRISPR/Cas9 genomic editor and obtaining embryos immune to HIV. Naturally, they were destroyed, so it did not come to the birth of children.

40 years before that

Fast forward to four decades ago. In July 1978, Louise Brown was born in the UK – the first child born as a result of in vitro fertilization. Then her birth caused a lot of noise and indignation, both the parents of the "test tube baby" and the scientists, who were nicknamed "Frankenstein's doctors."

But if that success scared some, it gave hope to others. So, today there are more than eight million people living on the planet who owe their birth to the IVF method, and many of the prejudices that were popular then have been dispelled.

However, there was another concern: since the IVF method assumes that a "ready" human embryo is placed in the uterus, it can be genetically modified before implantation. As we can see, a few decades later, this is exactly what happened.

So is it possible to draw a parallel between two events – the birth of Louise Brown and Chinese twins Lula and Nana? Is it worth saying that Pandora's box is open and very soon it will be possible to "order" a child created according to the project, that is, a designer one. And most importantly – will the attitude of society towards such children change, as it has practically changed towards children "from a test tube" today?

Embryo breeding or genetic modification?

However, it is not only genome editing that brings us closer to a future where children will have pre-planned qualities. Lulu and Nana owe their birth not only to the CRISPR/Cas9 gene editing technology and the IVF method, but also to the preimplantation genetic diagnosis of embryos (PGD). In the course of his experiment, He Jiankui resorted to PGD of edited embryos to identify chimerism and non-target errors.

And if editing of human embryos is prohibited, then preimplantation genetic diagnostics, which consists in sequencing the genome of embryos for certain hereditary genetic diseases, and subsequent selection of healthy embryos is not. PGD is a kind of alternative to prenatal diagnosis, only without the need to terminate pregnancy in case of detection of genetic abnormalities.

Experts note that the first "legitimate" designer children will be obtained precisely by embryo selection, and not as a result of genetic manipulation.

During PGD, embryos obtained by in vitro fertilization are subjected to genetic screening. The procedure involves extracting cells from embryos at a very early stage of development and "reading" their genomes. All or part of the DNA is read to determine which gene variants it carries. After that, future parents will be able to choose which embryos to implant in the hope of pregnancy.

Preimplantation genetic diagnosis is already being used by couples who believe they carry the genes of certain hereditary diseases to identify embryos that do not have these genes. In the USA, such testing is used in about 5% of IVF cases. It is usually performed on three- to five-day-old embryos. Such tests can detect genes carrying about 250 diseases, including thalassemia, early Alzheimer's disease and cystic fibrosis.

Only today PGD is not very attractive as a technology for designing children. The procedure for obtaining eggs is unpleasant, carries risks and does not provide the necessary number of cells for selection. But everything will change as soon as it becomes possible to obtain more eggs for fertilization (for example, from skin cells), and at the same time the speed and price of genome sequencing will increase.

Bioethicist Henry Greeley of Stanford University in California states: "Almost everything you can do with gene editing, you can do with embryo selection."

Is DNA destiny?

According to experts, in the coming decades in developed countries, progress in technologies for reading the genetic code recorded in our chromosomes will give more and more people the opportunity to sequence their genes. But using genetic data to predict what kind of person an embryo will become is more complicated than it seems.

Research on the genetic basis of human health is certainly important. But still, geneticists have done little to dispel simplistic ideas about how genes affect us.

Many people believe that there is a direct and unambiguous connection between their genes and traits. There is a widespread idea of the existence of genes directly responsible for intelligence, homosexuality or, for example, musical abilities. But even with the example of the aforementioned CCR5 gene, the change of which affects the brain, we saw that everything is not so simple.

There are many – mostly rare – genetic diseases that can be accurately recognized by a certain gene mutation. As a rule, there is indeed a direct link between such a gene breakdown and the disease.

The most common diseases or medical predispositions – diabetes, heart disease or certain types of cancer – are associated with several or even many genes, they cannot be predicted with any certainty. In addition, they depend on many environmental factors – for example, on a person's diet.

But when it comes to more complex things like personality and intelligence, here we don't know much about which genes are involved. However, scientists do not lose their positive attitude. As the number of people whose genomes have been sequenced increases, we will be able to learn more about this area.

Meanwhile, Euan Birney, director of the European Bioinformatics Institute in Cambridge, hinting that the decoding of the genome will not give answers to all questions, notes: "We have to get away from the idea that your DNA is your destiny."

Conductor and orchestra

However, this is not all. Not only genes are responsible for our intelligence, character, physique and appearance, but also epigens – specific labels that determine the activity of genes, but do not affect the primary structure of DNA.

If the genome is a set of genes of our body, then the epigenome is a set of labels that determine the activity of genes, a kind of regulatory layer located on top of the genome. In response to the action of external factors, he commands which genes should work and which ones should sleep. The epigenome is the conductor, the genome is the orchestra, in which each musician has his own part.

Such commands do not affect DNA sequences, they simply turn on (express) some genes and turn off (repress) others. Thus, not all the genes that are in our chromosomes work. The manifestation of a particular phenotypic trait, the ability to interact with the environment, and even the rate of aging depend on which gene is blocked or unblocked.

The most well–known and, as it is considered, the most important epigenetic mechanism is DNA methylation, the addition of DNA–methyltransferase enzymes of the CH3 group to cytosine– one of the four nitrogenous bases in DNA.

When a methyl group is attached to a cytosine that is part of a gene, the gene turns off. But, surprisingly, in such a "sleeping" state, the gene is passed on to the offspring. Such transmission of traits acquired by living beings during life is called epigenetic heredity, which persists for several generations.

Epigenetics, a science called the younger sister of genetics, studies how turning genes on and off affects our phenotypic traits. According to many experts, it is in the development of epigenetics that the future success of the technology of creating designer children lies.

By adding or removing epigenetic "tags", we will be able, without affecting the DNA sequence, to fight both diseases that have arisen under the influence of adverse factors, and to expand the "catalog" of design characteristics of the planned child.

Is the "Gattaca" scenario and other fears real

Many fear that from genome editing – in order to avoid serious genetic diseases – we will move on to improving people, and there it is not far from the appearance of a superman or the branching of humanity into biological castes, as predicted by Yuval Noah Harari.

Bioethicist Ronald Green of Dartmouth College in New Hampshire believes that technological advances can make "human design" more accessible. In the next 40-50 years, he says, "we will see the use of gene editing and reproductive technologies to improve a person; we will be able to choose the color of eyes and hair for our child, we will want improved athletic abilities, reading or counting skills, and so on."

However, the appearance of designer children is fraught not only with unpredictable medical consequences, but also with deepening social inequality.

As the bioethicist Henry Greeley points out, a fully achievable 10-20% improvement in health through PGD, complementing the benefits that wealth already brings, can lead to an increase in the gap in the health status of the rich and poor – both in society and between countries.

And here in the imagination there are terrible images of the genetic elite, similar to the one depicted in the dystopian thriller "Gattaca": the progress of technology has led to the fact that eugenics has ceased to be considered a violation of moral and ethical norms, and the production of ideal people is put on stream. In this world, humanity is divided into two social classes – "fit" (valid) and "unfit" (in-valid). The former, as a rule, are the result of parents going to the doctor, and the latter are natural fertilization. All doors are open to the "fit", and the "unfit", as a rule, are overboard.

Let's return to our reality. We noted that it is not yet possible to predict the consequences of interfering with the DNA sequence: genetics does not provide answers to many questions, and epigenetics is actually at the initial stage of development. Every experiment with the birth of children with a modified genome is a significant risk, which may in the long term turn into a problem for such children, their descendants and, possibly, the entire human species.

But the progress of technology in this area, having probably saved us from some problems, will add new ones. The appearance of designer children who are perfect in all respects, who, having matured, will become members of society, can create a serious problem in the form of deepening social inequality already at the genetic level.

There is another problem: we did not look at the topic under consideration through the eyes of a child. People sometimes tend to overestimate the possibilities of science, and the temptation to replace the need for painstaking care of their child, his upbringing and studies to pay the bill in a specialized clinic may be great. What if a designer child, in whom so much money has been invested and on whom so many expectations have been placed, does not justify these hopes? If, despite the intelligence programmed in the genes and the spectacular appearance, he does not become what they wanted to make him? After all, genes are not fate.

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