The future of genetics

Imagine a future in which you can choose the height and color of your children's eyes. You can even go further in your fantasies. Imagine that your pet is sized perfectly for apartment life. Dream of plants that bloom longer. Think about getting rid of diseases that are considered incurable. And these are only the most obvious perspectives that genetic editing opens before us. Believe me, you still don't know about the real benefits of gene adjustment.

The world scientific community has been studying how genetics works for nearly seventy years. Since 1953, it has been known that a DNA molecule is structurally similar to a double helix. Already in 1961, scientists experimentally proved that the DNA code is composed with the participation of the amino acid sequence of proteins. Codons, ternary base pairs, are directly associated with encryption of genetic information.

But these discoveries are just a starting platform for further discoveries. For example, Robert Plomin, a geneticist at King's College London, claims that DNA is the only stable and long-term source of knowledge about who we are. In his new book, Blueprint, he concludes that DNA is "a 100% reliable predictor of fate."

Research has already progressed from theory to practical use. The American company Genomic Prediction announced that it is ready to begin the selection of the "smartest" embryos from among those that are suitable for artificial insemination. Polygenic IQ-based dropouts are thought to guarantee the birth of a child with good intelligence. The Genomics Prediction colleagues from China have gone even further. The media leaked reports of human babies with CRISPR-edited genes. This suggests that genetic engineering can be used to create designer babies. Moreover, there is a great chance that soon changes can be made not only in appearance, but also in the intellectual inclinations of children.

All this seems to be a fiction that has penetrated into the real world from a Hollywood dystopian film. But some of this does exist. CRISPR technology continues to evolve, and in the future, genetic editing will no longer be a curiosity.

Modification of genes in the laboratory has been available to mankind for several decades. Why is interest in the topic peaking now? The fact is that technological progress has reached the point where gene changes are being made with tremendous speed and precision. Zinc Finger Nuclease, TALEN, CRISPR-Cas9 ... The sonorous and incomprehensible names from the world of gene editing frighten the public. So that you understand the essence of these technologies and not succumb to an empty panic, we will analyze them using the example of CRISPR.

CRISPR is an acronym. In English, it stands for Сlustered Regularly Interspaced Short Рalindromic Repeats. The complex name hides a series of short DNA sequences. These repeating sections are separated by so-called "spacers". They are not involved in coding.

Scientists became interested in the CRISPR function when studying the characteristics of the genetic code of bacteria and single-celled microorganisms. The researchers are interested in the structure of their immune system. It provided unusually good protection against virus attacks.

The CRISPR sequence was discovered in 1987. Two decades later, Luciano Marraffini and Erik Sontheimer published a groundbreaking scientific paper. In it, they called CRISPR "a universal gene editing tool." Scientists even tried to patent their discoveries. However, the application was rejected. The reason for the refusal was that in the documentation the researchers did not give examples, practical results of work.

Therefore, confirmation of the incredible potential of CRISPR had to wait until 2012. Jennifer Doudna and Emmanuelle Charpentier, Ph.Ds, have their hand in the new publication. The collaboration between the California Institute employee and the French microbiologist has become a milestone in the field of biotechnology.

Feng Zhang, an American genetic engineer from the PRC, also made an important contribution to research. In 2013, he reviewed CRISPR therapeutic applications in detail. The studies were carried out on laboratory mice and human cells. In the early stages, Zhang was assisted by Harvard geneticist George Church.

Dudna, Charpentier, Zhang and Church became central figures, real stars of genetic engineering. They formed 3 CRISPR therapeutic startups: Editas Medicine, CRISPR Therapeutics, and Intellia Therapeutics. In 2016, all three companies received public status. The companies are now at the stage of development or preclinical testing of new drugs. The whole world is waiting for the demonstration of their achievements.

It is safe to predict the high therapeutic value of CRISPR for humans. The results of studies carried out in mice clearly indicate the positive effects of CRISPR. But the genome of mice is 90% the same as the human genome. Therefore, these mammalian rodents are considered ideal candidates for preliminary testing.

Experiments on mice gave excellent results. With the help of CRISPR, it was possible to disable the defective gene that provokes the development of Duchenne muscular dystrophy (DMD). Also, the technology was able to extinguish the formation of deadly proteins that accompany the course of Huntington's disease. And, of course, the most striking achievement was the elimination of HIV infection.

Advances are also being observed in areas of biotechnology that are not directly related to medicine. In 2015, Chinese genetic engineers reported that they had managed to raise two super-muscular beagle hounds. The myostatin gene, which is responsible for maintaining normal muscle growth, was removed from the dog's DNA. Without it, the beagles developed muscle hypertrophy. Dogs with the edited gene turned out to be much more muscular than their relatives.

Other cases of experimental modification of animal genes are also known. For example, scientists have tweaked the hereditary information of long-haired goats to obtain improved wool for cashmere production.
So what is the CRISPR phenomenon? To understand this, you need to consider its structure and function in more detail. So CRISPR is short strips of repetitive DNA sequences that are connected by spacers. Bacteria use segments with genetic sequences as "memory cards". They record information about every virus that has ever attacked a microorganism.

Making such "notes" takes place in a rather original way. The bacterium incorporates the viral DNA into its genome as a spacer in the CRISPR sequence. This can be called a kind of vaccination. The bacterium that has admitted the DNA of the virus into its genome is protected from new attacks.

Upon activation, these genes begin to produce Cas enzyme proteins. The enzyme's mission is to cut DNA. The most convenient type of such "molecular scissors" for genetic engineering is the Cas9 protein. Therefore, the CRISPR-Cas9 technology is used to introduce modifications into organisms of animals and humans.

A simple analogy for CRISPR-Cas9 functionality is the Find and Replace option, familiar to any Microsoft Word user. In a text editor, you can remove the wrong word and put another in its place. Genetic engineers do the same. They replace gene material with third-party fragments that better meet the requirements. The nature and purpose of the new piece in the DNA puzzle can be very different. Jennifer Doudna, in her book The Crack in Creativity, compares this variation to a Swiss knife: we can choose from a bunch of tools that we need, depending on what we are going to use it for.

The effectiveness of CRISPR-Cas9 technology is based on three components. The first is Guide RN A, developed in the laboratory. It is a separate piece of RNA that indicates the location of the target gene. The second is CRISPR, the very "molecular scissors". The third is a piece of DNA that has been selected to replace the deleted one.

Schematically, the process of changing DNA looks like this: Guide RN A, like a navigator, looks for a segment on the DNA strand for replacement and marks the zero point for cutting. When Cas9 reaches the point indicated by the RNA, it performs a double-stranded DNA cut. A prepared DNA fragment is inserted into the vacated opening.

It's worth noting that CRISPR testing in animals has progressed faster. Attempts to make changes in the human genome were hampered by ethical disputes and an undeveloped legal framework. The US FDA has been very cautious about CRISPR projects. In May 2018, the agency blocked the first human trials. Experimenters at CRISPR Therapeutics had to give detailed answers about the specifics of research related to the development of a drug for sickle cell anemia. The ban was lifted in April of the same year.

At about the same time, experts at the University of Pennsylvania began assessing the safety of CRISPR for patients with multiple myeloma, melanoma, and sarcoma.

CRISPR Therapeutics is working in parallel with Boston-based Vertex Pharmaceuticals to treat beta thalassemia. This is a disease in which the number of red blood cells in the blood abnormally increases. Leadership in development is still with Therapeutics: the company has already begun formal clinical trials of its therapy.

CRISPR already has proven results. In August 2017, reproductive biologist Shukhrat Mitalipov from the University of Oregon performed a procedure to eliminate mutations that caused thickening of the heart muscle. Human embryos that underwent modification were 72% mutation-free. This reduced the risk of developing heart pathologies in embryos by almost a quarter. With natural inheritance, the probability of occurrence of deviations is estimated at 50%.

China officially began human trials of CRISPR technology in 2015. The main areas of application are the fight against HIV, HPV and various forms of cancer. There have been encouraging results of therapy for patients with advanced types of cancer. According to preliminary information, tumors in several observed patients decreased.

It is difficult to assess all the risks associated with CRISPR now. Nobody knows what side effects may appear in the long term. The transformation of genetic material remains a hope for a cure for patients who have not been helped by traditional medicine.

In November 2018, information was leaked to the media that Chinese scientist He Jiankui had created the world's first human babies with edited genes. Twin embryos Lulu and Nana, according to sources, have improved their resistance to HIV infection during IVF.

An indirect confirmation of this information was provided by the scientist himself. Speaking at the Second International Summit on Human Genome Editing, He Jiankui quite transparently hinted at his achievements. He also posted several videos on his work on YouTube.

In January 2019, the Chinese authorities officially recognized the fact of He Jiankui's interference in human DNA. Since the scientist did not receive permission to work with CRISPR, his activities were investigated by the regulatory authorities. In addition, the scientist lost his position at the Southern University of Science and Technology.

The possibilities of CRISPR can be used not only in medicine. Promising challenges are emerging in the food industry, agriculture, and industrial biotechnology. The gene modification system is relatively simple, and this allows researchers from a range of scientific disciplines to access CRISPR.

The introduction of CRISPR methods into pharmaceuticals has become a promising area. The goal is to improve the properties of existing drugs. It is successful to work with antibiotics, the effectiveness of which decreases due to the emergence of new resistant strains of viruses. Such pathogens infect more than 2 million people annually, 23 thousand of them die.

To correct this bleak picture, pharmaceutical science professor Jason Peters proposed a new way to analyze the antibiotic functions of pathogenic bacteria. This method became known as Mobile-CRISPRi. It does not involve making cuts on DNA strands. It simply reduces the amount of protein produced by specific genes. In this state, the material is easier to study: scientists get an accurate understanding of how antibiotics prevent the spread of bacterial pathogens. The information obtained helps to find the best ways to improve the effectiveness of medicinal antibiotics. Peters' method has already been tested on the bacteria listeria, salmonella, staphylococcus, and a number of other infections.

CRISPR capabilities are in demand in the agricultural and food industries. Climate change is hampering the cultivation of crops. For example, hot and dry weather makes it difficult to cultivate cocoa trees. Unusual temperature regimes increase the losses of producers, who are already losing part of the harvest due to pathogenic plant diseases.

To solve the problem, industrialists turned to genetic technologies. The University of California's Institute for Innovative Genomics is developing cocoa varieties that can resist pathogens. The project is supported by MARS Inc., the largest supplier of chocolate.

Gene editing can save humanity from the lack of basic food crops: potatoes, tomatoes, cereals. The technical capabilities are already at a level that will allow products with modified DNA to be brought to the market in the coming years. The breakthrough has been postponed due to the cautious stance of regulatory agencies such as the USDA.

Another promising application for CRISPR is in industrial biotechnology. By changing the nature of microbes, new strains can be produced. In terms of industry goals, they are useful for modifying and developing new chemical products. In particular, we are talking about biomaterials and highly efficient biofuels. CRISPR has an extremely wide range of possibilities in the creation of new chemicals: from active aromatic components for perfumery to compositions for industrial cleaning.

Summing up the overview of the opening possibilities, we can safely say: if we know the location of the desired gene, CRISPR gives us the tools to change it in almost any direction.

It turns out that in the future we will literally create an environment for ourselves according to our taste. Already now, pet lovers can hypothetically model a cat or dog with a given color, length and thickness of hair. Families who dream of children have the freedom to choose their baby's height and eye color. If we could isolate genes that affect intelligence, that too could be manipulated.

Critics continue to believe that CRISPR techniques should only be used for therapeutic purposes. But technology has long gone beyond it. It is hard to imagine that its development will slow down anytime soon.

CRISPR applications are as numerous and varied as life forms. Simultaneously with reforms in therapeutic medicine and the food industry, initiatives are emerging aimed at developing little-known but very real applications of CRISPR-Cas9.

Among them - xenotransplantation, that is, the transplantation of cells, tissues or organs of an animal into the human body.

The number of people in need of transplantation always exceeds the number of organs available to medical institutions. Xenotransplantation will shorten transplant queues.

The transplantation process can be simplified as three consecutive steps:

First, human stem cells are injected into a live pig.

Second: stem cells develop inside the pig's body, they are divided into groups according to their purpose;

Third: stem cells are modified through Cas9 and proceed to the stage of transformation into cells of the type that is provided for by the task: for the heart, liver, pancreas, and so on.

The reality of interspecies transplantation has been practically proven. Testing was carried out on mice in which rat stem cells were placed. Using CRISPR-Cas9, the gene responsible for the formation of the pancreas in mouse embryos was turned off. Its place was taken by rat stem cells. As programmed, the mice grew a rat pancreas.

In the wake of success, attempts were made to repeat the experiment, but with the introduction of human stem cells into pig embryos. However, 4 weeks after the start of work, the study was stopped, noticing the risk of a security breach. The decision to stop was also influenced by insufficiently convincing intermediate results. Although the researchers noted that some of the stem cells have begun to develop into embryos of human tissue.

Geneticist, molecular engineer and chemist George Church made notable progress in preparing for xenotransplantation. His company, eGenesis, is trying to grow organs in a pig that can be transplanted into a human body. In August 2017, Church and his collaborators modified over 60 genes in pig embryos. This colossal work was done in order to get rid of retroviruses - because of them, the transplanted organs are rejected.

So far, researchers are only looking for a way to grow human cells in a living animal. When this is possible, it will become possible to create organs that are individually designed for the patient. For the client, the risk of rejection of transplanted materials or organs will be minimal. After all, in order to grow them, they will take the patient's stem cells, which contain his own, unique DNA.

The situation with gene editing is changing dynamically. Only a daredevil or a clairvoyant will venture to predict the vector of its development by 100, 50 or even 10.
Perhaps, in the future, it will become normal practice to customize or design the genes of plants, animals, and even humans. And then the gene pool and the course of evolution await irreversible changes.

The issues of interaction of genes and environmental factors are of increasing interest to genetic scientists. Since August 2019, the British biobank has received samples and health information from 500,000 volunteers. The duration of this initiative is up to three decades. It is assumed that the base collected during this period will become the largest in the world. The information, estimated at £ 61 million, will help explore the multilevel links between genes, lifestyle, environmental conditions and disease.

There has also been a resurgence in attention to pharmacogenomics, which studies how the body's response to drugs is dependent on genes. The discipline was originally focused on analyzing the side effects of medication. However, after the advent of genetic engineering, an unintended fact was revealed: a change in DNA can lead to a drop in the effectiveness of drugs.

There are plenty of unexpected conclusions in the book "Darwin Hack". In it, futurist Jamie Metzel examines scientific and historical precedents associated with genetics. Moving along the chronological milestones, he reviews the path traveled by this science. The path from the shameful popularity of eugenics to the first test tube baby. This is an attempt to predict the consequences of the technical shifts that we are seeing.
This analysis is interesting, but how accurately can it predict the shape of future healthcare? Rapid progress and new applications that scientists are discovering with amazing frequency are fueling the explosive development of genetics. It is difficult to guess what will happen to medicine even in the coming years.

Medical Center "Medeus" offers to take advantage of the medicine of the future now and invites geneticists to cooperate.

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