Tesnostics = therapy + diagnosis

One of the main problems of modern medicine is that all people are different. The same diseases can occur in different people in different ways, and the same medicine can help someone, and someone to cause unpleasant side effects; To someone to save their lives, and to kill someone.

Until now, such issues have tried to resolve as universally as possible. The regulatory authorities allowed the use of drugs with dangerous side effects, only with the most severe diseases and adverse prognosis. The maximum of what a separate ordinary doctor could do in his practice was to ask the patient if he had unusual reactions to this or a similar medicine earlier.

For some drugs, for example, the anticoagulant of warfarin , the sensitivity to which can vary greatly depending on the allelet variants of two genes, the dose is selected individually, from time to time taking a blood test and evaluating the coagulation parameters. Patients with diabetes now often purchase a home glucometer, measure the blood sugar several times a day and adjust the doses of insulin based on the measurement results. There is even the opportunity to install an insulin pump - a device that will measure the blood sugar itself, to calculate the desired dose of insulin and introduce it itself.

For people who constantly take anticoagulants and insulin, it is very important not to exceed the dose, in fact, this is a matter of life and death. Exceeding an individual dose of anticoagulants threatens with bleeding, and an too large dose of insulin - a very dangerous hypoglycemic coma. The low level of glucose in the blood is momentarily a more dangerous thing than a high one. It is not surprising that it is in these situations, in which, on the one hand, the condition of the patients and their reaction to medicines can be very different, and, on the other hand, there is a threat to life, medicine began to become personalized.

The next step towards personalized medicine is to stop choosing the desired dose by trial and error, and do analyzes at the very beginning and determine what and at what dose to treat a particular patient. This approach is relatively easy to implement in cases where differences in the reaction to drugs come from already known genetic differences. So, for example, the P450 cytochrome is a protein group involved in the metabolism of many drugs. He has faster and more slow varieties. Some drugs are produced and taken not in the form in which they work in the body. To become active, they must pass the transformation in which the P450 cytochrome is involved. If the P450 works too slowly, the concentration of therapeutic substance is lower than necessary. And if too fast, an overdose may occur. Several deaths of such an overdose occurred in 2012 in the United States with children, who, after operations, gave an anesthetic - codeine. Kodein, with the participation of the P450 in the human body, gradually turns into morphine, and in three children with very quick P450 options, the transformation into morphine was not gradual enough, and the children died in fact from an overdose of morphine.

With the development of sequencing technologies, it became possible to quickly and cheaply find out what kind of protein a person has. Such analyzes, however, have not yet entered into routine practice. Probably, they could help in the situation with codeine. However, meta-analysis of attempts to choose a dose of warfarin by genetic tests showed that such tests have no advantages over assessing the blood coagulation directly: they are not faster, not cheaper and do not reduce the number of side effects. Over time, sequencing price will still decrease, and its speed will increase. In parallel with this, knowledge about the connection between genotypes and phenotypes in people will accumulate. Therefore, the century of personalized medicine is no longer around the corner. It can be assumed that the most popular area will be the reading of tumor genomes. There are always a lot of mutations in tumor cells and, having learned which genes work abnormally in the tumors of a particular patient, it will be possible to find out where the tumor has weaknesses, and choose the best treatment option.

But there are bad news: not all the variability of pathological conditions and reaction to treatment is explained genetically. And in some cases, it may be explained, but scientists know nothing about it yet. Or they know that the hereditary component exists, but cannot indicate specific genes.

In this case, you can analyze not genes, but the state of the body in real time. Actually, this is exactly what they do when determining the dose of warfarin, monitoring the coagulation of blood, or selecting the dose of insulin according to the indications of the glucometer. The question is whether it is possible to automate this process so that it delivers a minimum of inconvenience to the patient and does not require him to close attention and daily visit to the doctor and the laboratory.

Insulin in humans does not fall into the blood all the time with constant speed. If it were so, even now, when there is no food shortage, people would have had hypoglycemia from time to time. For example, if you sleep for a long time. Or stay at work in the evening. Or if a sluggish waiter came across. And all these situations would be dangerous or at least unpleasant. And our ancestors, whose share did not fall out of such abundance, who often had to walk hungry at all, would not have lived at all for a long time. Therefore, from the very beginning, insulin should have entered the blood only when there was a lot of glucose in the blood.

Glucose-dependent intake of insulin in the blood is provided by β-cells of the islets of Langerganes. And this, basically, does not happen due to the fact that insulin is glucose dependently synthesized, namely, due to glucose -dependent insulin release from cells. This is a very complex multi -stage process, and no other cells can do that. When, as it happens with diabetes of the first type, the immune system kills β-cells, patients have to take their work on themselves: to monitor the level of glucose and do insulin injections at the right moments. With the development of genetic and cell therapy, a new option has appeared: to introduce an active insulin gene, for example, into liver cells. But it turned out that such a strategy is bad: it does not provide glucose -dependent ingress of insulin into the blood. Only β cells know how. In theory, it is possible to get new β-cells from stem (for example, from induced pluripotent stem cells) or reprogramming a different type of cell (for example, hepatocytes). Then such cells can be transplanted back into the pancreas. It is only necessary to understand that this method of treatment is very expensive, and there is no guarantee that the immune system will not act with new β cells just as it did with the old ones.

The third, not such an obvious strategy is based more on genetic engineering. Even in the gene encoding insulin (in fact, the precursor of insulin, which should still ripen), there are areas sensitive to glucose in the regulatory region. Many other genes have them: liver pyruvatkinase , glucose protein , glucagon receptor-proteins involved in metabolism. When combining these regulatory areas, it was possible to obtain genetic structures that, working in patients with diabetes in the liver cells, support the normal level of glucose in the blood, both with enhanced nutrition and when starvation.

If we talk about genetic therapy of chronic diseases, it is useful to make the structures so that they themselves monitor the state of the body, and depending on it, regulate the synthesis of therapeutic proteins. In this regard, the term therapy (Theranostics) has been consumed recently, that is, therapy and diagnosis at the same time. The genetic structure determines the conditions and, if necessary, supplies the right substance. For example, the expression of some genes in the human body is activated with a lack of oxygen. Armed with such regulatory elements, you can make genetic structures for the treatment of coronary heart disease or diabetic foot.

In December, work was published, offering such a genetic design for the treatment of psoriasis. Psoriasis is a skin, presumably auto -immune disease, the exact causes of which are unknown. Psoriasis, of course, is not fatal, but significantly reduces the quality of life. As a rule, its course is uneven: exacerbations are replaced by remissions. Although it is believed that some factors (diseases, stress, etc.) can provoke exacerbation, in life there are often exacerbations out of the blue and the same spontaneous remission. At the early stage of the exacerbation, excess reproduction of lymphocytes, synthesizing pro-inflammatory cytokines, and skin cells-keratinocytes (because of this, the most characteristic symptom of psoriasis-scales on the skin occurs). The main pro -inflammatory cytokine is synthesized by two - interleukin 22 (IL22) and the factor of necrosis of tumors α (FNOα, TNFα). The name of FNOα reflects the history of its discovery, and not specialization - this is a universal inflammatory agent that calls for the cells of the immune system to combat enemies. Modern Targete drugs against psoriasis are antibodies to inflammation mediators or molecules that kill lymphocytes. These drugs are quite effective, but apparently not specific enough: their use increases the risk of infections. Opposing cytokines - IL4 and IL10 - turned out to be the best medicines, but too expensive. These are proteins with a fairly short lifestyle.

In addition, the rise in the concentration of pro -inflammatory molecules in the blood can be seen earlier than exacerbation on the skin. If you could start treatment at this moment, exacerbation could be prevented. A magically proposed design in the article may also.

The authors of the work developed cells that, in response to the simultaneous appearance in the environment of the pro -inflammatory cytokines of the FNOα and IL22, synthesize anti -inflammatory cytokines IL4 and IL10. To do this, it was necessary to introduce additional artificial receptors and structures into the cage, in which the synthesis of IL4 and IL10 is controlled by signals from these receptors.

Cells packed in polymer capsules and implanted mice. It turned out that such capsules work well. Being implanted in advance, they prevented the development of psoriasis in mice, and being implanted already during illness, softened its symptoms. In addition, the cells did not respond to other diseases that were not associated with psoriasis. This is probably due to the fact that the combination of FNOα+IL22 is specific specifically for psoriasis.