2017: The Genetic Year
Results of the year in the field of medical technologies
Daria Spasskaya, N+1
In mid-December, we asked our readers to choose the most important, in their opinion, scientific event of the year. According to the results of voting on the VKontakte social network, news about an experiment on editing the genes of a living person suffering from Hunter syndrome came forward with a large margin (900 votes out of 2500). The third place was also taken by genetic news – about the synthetic genome of the bacterium. The editorial board of N+1 invites you to recall these and other achievements of biologists and geneticists in the past year.
From the point of view of the development of medical technologies, the past year can be called the "year of genome editing". Although the development of tools that would help people correct hereditary diseases or change the genome of individual cells to combat malignant changes in the body has been underway since the 90s of the XX century, it was in 2017 that we heard about patients who were really cured with the help of DNA editing tools. Well, a technology based on the modification of the genome of patients' own leukocytes, called CAR-T, has finally been officially approved for the treatment of certain types of cancer and has already saved many patients who were considered hopeless. In addition, this year was a turning point for editing the genomes of human embryos – such experiments were conducted for the first time in the United States and Great Britain, where they were previously banned for ethical reasons.
Perhaps the most outstanding medical news of the year was the first attempt to "repair" the DNA of an adult suffering from a severe genetic disease right in his body. A patient with Hunter syndrome, a rare disease associated with the X chromosome, was injected with safe viral particles containing a working copy of the enzyme iduronate–2-sulfatase, which was supposed to be embedded in the DNA of liver cells and replace a broken gene. In addition to a copy of the gene, the particles contained a special nuclease with "zinc fingers" – a protein that recognizes a given sequence in DNA and cuts it so that the desired gene can be inserted there. It's too early to judge about the success in the treatment of the first patient named Brian Mado, but we hope to hear next year that gene therapy helped him.
Genome editing technologies using nucleases with "zinc fingers" are being developed by Sangamo Therapeutics. Compared to the more well-known and "fashionable" CRISPR/Cas9 technology, "zinc fingers" provide precise cutting of DNA only in the right place, therefore they are considered safe enough to use them directly on a living person.
The second famous patient this year was a "butterfly boy", to whom scientists have grown a new skin based on his own, but genetically modified cells. A child suffering from a hereditary disease called epidermolysis bullosa had lost almost the entire epidermis by the time treatment began, was fed through a tube and constantly needed morphine. The cause of the boy's disease was a breakdown in the LAMB3 gene, which is why one of the proteins that bind the skin layers to each other stopped being synthesized in the skin, and the upper layer of the skin began to separate from the lower layers.
The child, who had almost no chance of being cured, had an epidermis biopsy taken and a working copy of the LAMB3 gene was inserted into the DNA of his cells using a special virus. After that, the modified cells were grown in culture in the form of layers and "laid out" directly in this form on the lower layers of the boy's skin. The transplantation was carried out in three stages, and the total treatment took eight months. The new skin took root without any problems. Two years after the therapy, the scientists, together with the doctors who carried out the treatment, published the final article, in which they reported that the boy feels well, goes to school and even plays football.
The year also brought good news for cancer patients. Two drugs based on CAR-T technology have been approved in the United States for the treatment of patients with several types of blood cancer who have not been helped by any other therapy, including bone marrow transplantation. This technology is based on the genetic modification of the patient's own T-lymphocytes, that is, the immune cells of the patient. Lymphocytes are taken from the patient and the gene of a chimeric antigenic receptor – a protein that recognizes a certain marker on the surface of malignant cells - is embedded in their DNA. After that, the cells are returned to the patient's body. Thus, there is an effective "adjustment" of a person's own immunity against tumor cells, and after a single manipulation with the disease, he copes by himself.
In the same year, the U.S. Food and Drug Administration finally approved the use of Kumriah and Yescarta drugs for the treatment of blood cancer, and Kumriah therapy became the first approved gene therapy in the United States. The first drug is aimed at the treatment of acute lymphoblastic leukemia in patients under 25 years of age, and the second is for the treatment of a number of lymphomas in adult patients. Despite the high cost of therapy, it helped the patients who were considered hopeless to achieve stable remission, that is, after a certain time, the disease did not return.
Several scientific publications in 2017 informed readers that editing the genome of human embryos will soon become commonplace in laboratories. Editing using the CRISPR/Cas9 system was first applied to human embryos by Chinese scientists in 2015, but the first really successful experiment was reported this year by Shukhrat Mitalipov from the University of Oregon in the USA. The research group under his leadership managed to edit a pathogenic mutation in the MYBPC3 gene using CRISPR/Cas9 technology and at the same time avoid side effects. A mutation in this gene leads to the development of heart pathology.
A little later, scientists from the UK edited the embryos "for purely scientific purposes", turning off the OCT4 factor in them in order to study its functions at the initial stages of development. Finally, Chinese researchers reported that they were able to successfully correct a mutation in the beta-globin gene of human embryos that leads to the development of anemia. As a tool for genome editing, scientists used a "base editor" developed on the basis of the CRISPR/Cas9 system. Such a protein does not cut DNA, but only introduces a single nucleotide replacement into its sequence, which means that theoretically it should be more predictable and safe.
By "embryos" in such works, we mean the stages of development from the zygote, that is, the cell that was formed as a result of fertilization of an egg by a sperm, to the blastocyst stage. After the experiment, the material is destroyed, and people from such embryos, of course, are not grown, so it is difficult to determine the real proportion of successful experiments. However, this approach has been successfully tested on laboratory animals in the last few years, for example, using the technology of editing zygotes with CRISPR/Cas9, transgenic mice are obtained, which serve as models of various diseases.
Finally, let's remember about the work that has nothing to do with medicine and humans, but it affects the fundamental principles of the structure of all living things. The DNA of all living organisms on Earth contains only four building blocks that form two base pairs – A-T and G-C. With this limited "alphabet", 20 amino acids are encoded, which are used to build all proteins. Each amino acid corresponds to a position from the table of the genetic code, which includes three bases, and in total the table contains 64 positions.
Scientists from the Floyd Romesberg group from the Scripps Research Institute in California managed to embed a third pair of X-Y bases in the DNA of bacteria and, thus, create the first semi-synthetic living organism. A DNA molecule containing a non-canonical base pair has been successfully copied and maintained in the cell for many generations. In the new work, scientists were able to encode a new "exotic" amino acid in DNA using an artificial third base pair, which is not usually found in organisms, and thereby expand the genetic code. By introducing additional genes encoding components of the translation apparatus into the Escherichia coli genome, bacteria were "taught" to decipher the artificial codons AXC and GXC and, in accordance with them, substitute the amino acid pyrrolysin into the protein.
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