“This is not the medicine that will raise Lazarus”: the truth about the development “for all types of cancer. Heat shock Heat shock protein when will there be a cure

If the temperature rises, a living organism reacts to this by producing peculiar compounds called “heat shock proteins.” This is how a person reacts, this is how a cat will react, this is how any creature reacts, since it consists of living cells. However, not only an increase in temperature provokes the synthesis of the heat shock protein of chlamydia and other species. Severe stress situations are often triggered.

general information

Since heat shock proteins are produced by the body only in specific situations, they have a number of differences from normally produced compounds. The period of their formation is characterized by inhibition of the expression of the main protein pool, which plays an important role in metabolism.

HSP-70 of eukaryotes, DnaK of prokaryotes - this is a family into which scientists have combined heat shock proteins that are important for survival at the cellular level. This means that thanks to such connections, the cell can continue to function even in a situation where stress, heat, and an aggressive environment oppose it. However, proteins of this family can also participate in processes occurring under normal conditions.

Biology at the microscopic level

If the domains are 100% identical, then eukaryotes and prokaryotes are more than 50% homologous. Scientists have proven that in nature, among all protein groups, the 70 kDa HSP is one of the most conservative. Studies devoted to this were done in 1988 and 1993. Presumably, the phenomenon can be explained through the chaperone functionality inherent in heat shock proteins in intracellular mechanisms.

How it works?

If we consider eukaryotes, then under the influence of heat shock the HSP genes are induced. If a certain cell has escaped stressful conditions, then the factors are present in the nucleus and cytoplasm as monomers. This compound does not have DNA binding activity.

When experiencing stressful conditions, the cell behaves as follows: Hsp70 is cleaved off, which initiates the production of denatured proteins. HSP forms trimmers, the activity changes its character and affects DNA, which leads over time to the accumulation of components in the cell nucleus. The process is accompanied by a multiple increase in chaperone transcription. Of course, the situation that provoked this passes over time, and by the time this happens, Hsp70 can again be incorporated into the HSP. DNA-related activity fades away and the cell continues to function as if nothing had happened. This sequence of events was identified back in 1993 in studies on HSP conducted by Morimoto. If the body is affected by bacteria, then HSPs can concentrate on the synovium.

Why and why?

Scientists were able to reveal that HSPs are formed as a result of the influence of a variety of negative situations that are dangerous to the life of the cell. Stressful, damaging influences from the outside can be extremely diverse, but lead to the same option. Due to HSP, the cell survives the influence of aggressive factors.

It is known that HSPs are divided into three families. In addition, scientists have discovered that there are antibodies to heat shock protein. HSPs are divided into groups based on molecular weight. Three categories: 25, 70, 90 kDa. If there is a normally functioning cell in a living organism, then inside it there will probably be various proteins mixed together, quite similar. Thanks to HSP, denatured proteins, as well as those that have folded incorrectly, can become a solution again. However, besides this function, there are some others.

What we know and what we guess

Until now, the heat shock protein of chlamydia, as well as other HSPs, has not been fully studied. Of course, there are some groups of proteins about which scientists have a fairly large amount of data, and there are others that have yet to be mastered. But now science has reached the level where knowledge allows us to say that in oncology, heat shock protein can be a truly useful tool to defeat one of the most terrible diseases of our century - cancer.

Scientists have the largest amount of data on Hsp70 HSPs, which are capable of binding to various proteins, aggregates, complexes, even abnormal ones. Over time, release occurs, accompanied by the ATP compound. This means that a solution appears in the cell again, and proteins that have incorrectly undergone the coagulation process can be subjected to this operation again. Hydrolysis, ATP coupling are the mechanisms that made this possible.

Anomalies and norms

It is difficult to overestimate the role of heat shock proteins for living organisms. Any cell always contains abnormal proteins, whose concentration can increase if there are external prerequisites for this. The typical story is overheating or infection. This means that in order for the cell to continue to function, it is urgent to generate more HSPs. The transcription mechanism is activated, which initiates the production of proteins, the cell adapts to changing conditions and continues to function. However, along with already known mechanisms, much remains to be discovered. In particular, antibodies to the heat shock protein of chlamydia are such a fairly large field for the activity of scientists.

HSPs, when the polypeptide chain increases and they find themselves in conditions that make it possible to enter into contact with it, allow them to avoid nonspecific aggregation and degradation. Instead, folding occurs normally, with the necessary chaperones involved in the process. Hsp70 is additionally required for the unfolding of polypeptide chains with the participation of ATP. By means of HSP, it is possible to ensure that non-polar regions are also susceptible to the influence of enzymes.

HSP and medicine

In Russia, FMBA scientists were able to create a new drug using heat shock protein for its construction. The cancer cure presented by the researchers has already passed initial testing on experimental rodents affected by sarcomas and melanomas. These experiments made it possible to confidently say that a significant step forward has been made in the fight against oncology.

Scientists have suggested and were able to prove that heat shock protein is a medicine, or rather, can become the basis for an effective drug, largely due to the fact that these molecules are formed in stressful situations. Since they are initially produced by the body to ensure the survival of cells, it has been suggested that with proper combination with other agents, even tumors can be fought.

HSP helps the drug detect affected cells in a sick body and cope with incorrect DNA in them. It is assumed that the new drug will be equally effective for any subtype of malignant diseases. It sounds like a fairy tale, but doctors go even further - they assume that a cure will be available at absolutely any stage. Agree, such a heat shock protein for cancer, when it passes all the tests and confirms its reliability, will become an invaluable acquisition for human civilization.

Diagnose and treat

The most detailed information about the hope of modern medicine was provided by Dr. Simbirtsev, one of those who worked on the creation of the medicine. From his interview, you can understand by what logic scientists built the drug and how it should bring effectiveness. In addition, it can be concluded whether the heat shock protein has already passed clinical trials or is still to come.

As stated earlier, if the body does not experience stressful conditions, then the production of BS occurs in an extremely small volume, but it increases significantly with changes in external influences. At the same time, the normal human body is not able to produce such an amount of HSP that would help defeat the emerging malignant neoplasm. “What happens if you introduce BTS from the outside?” - the scientists thought and made this idea the basis for research.

How is this supposed to work?

To create a new drug, scientists in the laboratory recreated everything necessary for living cells to begin producing HSP. For this purpose, a human gene was obtained, which underwent cloning using the latest equipment. Bacteria studied in laboratories were modified until they began to independently produce the protein so desired by scientists.

Scientists, based on the information obtained during research, have drawn conclusions about the effect of HSP on the human body. To do this, we had to organize a squirrel. This is not at all easy to do: we had to send samples into the orbit of our planet. This is due to the fact that earthly conditions are not suitable for the correct, uniform development of crystals. But space conditions make it possible to obtain exactly those crystals that scientists needed. Upon returning to their home planet, the experimental samples were divided between Japanese and Russian scientists, who took up their analysis, as they say, without wasting a second.

And what did they find?

So far, work in this direction is still underway. A representative of the team of scientists said that it was possible to establish precisely that there is no exact connection between the HSP molecule and the organ or tissue of a living being. And this speaks of versatility. This means that if heat shock protein finds application in medicine, it will become a panacea for a huge number of diseases - no matter which organ is affected by a malignant neoplasm, it can be cured.

Initially, scientists prepared the drug in liquid form - it was injected into experimental subjects. Rats and mice were taken as the first specimens to test the product. It was possible to identify cases of cure both at the initial and late stages of the disease. The current stage is called preclinical testing. Scientists estimate the time frame for its completion to be at least a year. After this, it will be time for clinical trials. A new product, perhaps a panacea, will be available on the market in another 3-4 years. However, as scientists note, all this is realistic only if the project finds funding.

To wait or not to wait?

Of course, doctors' promises sound attractive, but at the same time they rightly cause mistrust. How long has humanity suffered from cancer, how many victims has this disease had in the last few decades, and here they promise not just an effective drug, but a real panacea - for any type, at any time. How can you believe this? And worse than that - to believe, but not wait, or wait, but it turns out that the remedy is not at all as good as expected, as promised.

Drug development is a technique of genetic engineering, that is, the most advanced field of medicine as a science. This means that if successful, the results should indeed be impressive. However, at the same time this means that the process is extremely expensive. As a rule, investors are willing to invest quite a lot of money in promising projects, but when the topic is so loud, the pressure is great, and the time frame is quite vague, the risks are assessed as enormous. Now these sound optimistic forecasts for 3-4 years, but all market experts know well how often the time frame extends to decades.

Amazing, incredible... or is it?

Biotechnology is an area that is closed to understanding for the average person. Therefore, we can only hope for the words “success of preclinical trials.” The working name of the drug was “Heat Shock Protein”. However, HSP is only the main component of the drug, which promises to be a breakthrough in the market of drugs against oncology. In addition to it, the composition is supposed to include a number of useful substances, which will guarantee the effectiveness of the product. And all this became possible due to the fact that the latest research on HSP has shown that the molecule not only helps protect living cells from damage, but also acts as a kind of “guiding finger” for the immune system, helping to identify which cells are affected by the tumor and which are not. Simply put, when HSP appears in the body in a sufficiently large concentration, scientists hope that the immune response itself will destroy the diseased elements.

Hope and wait

To summarize, we can say that the new anti-tumor product is based on the fact that the body itself has a remedy that could destroy the tumor, it’s just naturally quite weak. The concentration is so low that one cannot even dream of any therapeutic effect. At the same time, some of the HSPs are found in cells that are not affected by the tumor, and the molecule will not “go away” from them. Therefore, it is necessary to supply a useful substance from the outside - so that it can further directly influence the affected elements. By the way, so far scientists assume that the drug will not even have side effects - and this is with such high effectiveness! And they explain this “magic” by the fact that studies have shown that there is no toxicity. However, final conclusions will be made when preclinical trials come to an end, which will require at least a year.

Heat shock heat shock- heat shock.

Stressful state of the body after exposure to elevated temperature, in particular, T.sh. used to induce polyploidy<induced polyploidy> mainly for animals that reproduce in water (fish, shellfish): the water temperature is increased to 29-33 o C for 2-20 minutes. (normal incubation temperature is usually 15-20 o C) after 3-10 minutes. (induction of triploidy) or after 20-40 minutes. (induction of tetraploidy) after fertilization; also able T.sh. analyze the activity of specific heat shock proteins<heat-shock proteins>, pouf activity<puffing> in fruit flies (in this case T.sh. at 41-43 o C).

(Source: “English-Russian explanatory dictionary of genetic terms.” Arefiev V.A., Lisovenko L.A., Moscow: VNIRO Publishing House, 1995)

See what “heat shock” is in other dictionaries:

Heat shock- * ceplav shock * heat shock is a stressful state of the body due to exposure to elevated temperature. T. sh. used: a) to induce polyploidy (see) in fish, mollusks, incubation of individuals after fertilization at tо = 29-33 °C (instead of ... ... Genetics. encyclopedic Dictionary

heat shock- Stressful state of the body after exposure to elevated temperature, in particular, T.sh. used to induce polyploidy mainly in water-reproducing animals (fish, shellfish): the water temperature is increased to 29-33 oC for 2-20 minutes... ... Technical Translator's Guide

Thermal shock- Syn: Thermal exhaustion. Occurs when overheated due to an insufficient response of the heart vessels to extremely high temperatures, especially often developing in older people taking diuretics. Shows weakness... Encyclopedic Dictionary of Psychology and Pedagogy

OVERHEATING AND HEAT STROKE- honey Overheating (heat syncope, heat prostration, heat collapse) and heat stroke (hyperpyrexia, sunstroke, overheating of the body) are pathological reactions of the body to high environmental temperatures associated with... ... Directory of diseases

- (English HSP, Heat shock proteins) is a class of functionally similar proteins, the expression of which increases with increasing temperature or under other conditions that stress the cell. Increased expression of genes encoding thermal proteins... ... Wikipedia

A tetramer consisting of four identical p53 protein molecules. They are interconnected by domains responsible for oligomerization (see text). p53 (p53 protein) is a transcription factor that regulates the cell cycle. In a non-mutated state... ... Wikipedia

Patients can receive a genetically engineered drug for all types and stages of malignant tumors in three to four years

At the State Research Institute of Highly Pure Drugs of the Federal Medical and Biological Agency (FMBA) of Russia, preclinical trials of Heat Shock Protein, a drug that could revolutionize oncology, are being completed. This is a fundamentally new drug for the treatment of malignant tumors, obtained using biotechnology. Scientists suggest that it will help people with tumors that are currently incurable. Success in creating the drug was achieved with the help of a space experiment. Deputy Director of the Institute for Scientific Work, Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor Andrey Simbirtsev told Izvestia correspondent Valeria Nodelman about this.

- What is the main active ingredient of the new medicine for malignant tumors?

Our drug has the working name “Heat Shock Protein” - based on the main active ingredient. This is a molecule that is synthesized by any cells of the human body in response to various stressors. Scientists have known about its existence for a long time. It was initially assumed that the protein could only protect the cell from damage. Later it turned out that in addition to this, it has a unique property - it helps the cell show its tumor antigens to the immune system and thereby enhances the antitumor immune response.

- If the body produces such molecules, why can’t it cope with cancer itself?

Because the amount of this protein in the body is minimal. It is not enough to achieve a therapeutic effect. It is also impossible to simply take these molecules from healthy cells and introduce them into sick ones. Therefore, a special biotechnology was developed to synthesize protein in the amount necessary to create the drug. We isolated the human cell gene that is responsible for protein production and cloned it. Then a producer strain was created and the bacterial cell was forced to synthesize human protein. Such cells reproduce well, which allowed us to obtain an unlimited amount of protein.

- Your invention is to create a technology for producing “Heat Shock Protein”?

Not only. We were also able to study its structure and decipher the mechanism of antitumor action at the molecular level. FMBA has a unique opportunity to conduct medical research using space programs. The fact is that for X-ray diffraction analysis of the action of a protein, it is necessary to form an ultra-pure crystal from it. However, it is impossible to obtain it under gravity conditions - protein crystals grow unevenly. The idea was born to grow crystals in space. Such an experiment was carried out in 2015. We packaged ultra-pure protein into capillary tubes and sent them to the ISS. Over six months of flight, perfect crystals formed in the tubes. They were brought down to earth and analyzed in Russia and Japan (they have heavy-duty equipment for X-ray analysis).

- Has the effectiveness of the drug already been proven?

We conducted experiments on mice and rats that developed melanomas and sarcomas. A course of drug administration in most cases led to complete cure even in the later stages. That is, we can already say with confidence that the protein has the biological activity necessary for the treatment of cancer.

Why do you think that Heat Shock Protein will help not only with sarcoma, but also with other types of malignant tumors?

The new drug is based on a molecule that is synthesized by all types of cells. It has no specificity. The drug will work on other types of tumors due to this versatility.

- Will it be necessary to send a protein into space each time to create a drug?

No. Creating a crystal in zero gravity was required only for the scientific stage of drug development. The space experiment only confirmed that we are on the right track. And production will be exclusively earthly. In fact, we are already producing the drug at the production sites of the research institute. It is a protein solution that can be administered to patients. We inject it intravenously into mice. But perhaps during clinical trials we will find more effective approaches - for example, targeted delivery of the protein to the tumor may turn out to be optimal.

- Does the new drug have any side effects?

So far no problems have been identified. During testing, Heat Shock Protein showed no toxicity. But we will finally be able to draw a conclusion about the complete safety of the drug only after the completion of preclinical studies. This will take another year.

- And then you can start clinical trials?

It depends entirely on whether we can find a source of funding for them. For the preclinical stage, we received a grant from the Ministry of Education and Science. Clinical trials are very expensive - about 100 million rubles. Usually they are carried out on co-financing terms: there is a private investor who invests funds, and the state returns 50% in case of successful completion. We count on the support of the Ministry of Industry and Trade or the Ministry of Health.

-Has a private investor already been found?

No. We have a lot of work ahead of us to find him. It would be possible to invite the Japanese to act as investors, but I would like to start with Russia, since this is a domestic development. We will knock on all doors, because the drug is unique. We are on the verge of discovering a completely new cancer treatment. It will help people with incurable tumors.

- Are similar developments being carried out abroad?

We have heard about attempts to obtain the drug "Heat Shock Protein" in different countries. Such work is being carried out, for example, in the USA and Japan. But so far no one has published their results. I hope that we are now ahead of our foreign colleagues in this matter. The main thing is not to stop on this path. And this can only happen for one reason - due to lack of funding.

- When realistically, under all favorable circumstances, will humanity be able to get a cure for cancer?

Full clinical trials typically take two to three years. Unfortunately, it won’t work faster - this is a serious study. That is, taking into account the final stage of preclinical studies, patients will receive a new medicine in three to four years.

What does a molecular thermometer look like? This question is much more complicated than it might seem at first glance. Apparently, the “thermometer” used by the cell, which plays one of the most important roles in maintaining the stability of the cell proteome, is a system of transcription factors and specialized proteins - chaperones, incl. heat shock proteins, which respond not only to increased temperature (this is just the first of the discovered functions of this class of proteins), but also to other physiological influences that damage the cell.

Chaperones are a class of proteins whose main function is to restore the correct tertiary structure of damaged proteins, as well as the formation and dissociation of protein complexes.

The chaperone system responds to damage that occurs during the life of the cell and ensures the correct passage of folding - the folding of amino acid chains coming off the ribosomal “assembly line” into three-dimensional structures. Despite the obvious importance of this system, for a long time none of the specialists studying it even imagined that this molecular thermometer is also a kind of “fountain of youth” of the cell, and its study provides an opportunity to look at a number of diseases from a new, previously unknown side .

Proteins, which are the main product of the functioning of the genome, not only form the structure, but also ensure the functioning of all cells, tissues and organs. No disruptions in the synthesis of amino acid sequences; The formation, assembly and transport of protein molecules, as well as the removal of damaged proteins, is a critical aspect of maintaining the health of both individual cells and the entire body. Proteins are also the material necessary for the formation and effective functioning of “molecular machines” that provide biosynthesis processes, a process critical to ensuring the longevity of the body. Many problems are caused by disturbances in the fundamental process of protein folding. Disturbances in the functioning of the “OTK”, represented by heat shock proteins and chaperones, lead to the appearance and accumulation of errors. These errors disrupt the functioning of molecular mechanisms, which can lead to the development of various diseases. The occurrence of such errors in neurons is fraught with truly terrible consequences, manifested by the development of neurodegenerative diseases such as multiple sclerosis, as well as Huntington's, Parkinson's and Alzheimer's diseases.

Discovered in 1962 by Ferruccio Ritossa, the heat shock response is described as a temperature-induced change in the organization of tightly packed chromosomes in the salivary gland cells of Drosophila flies, leading to the formation of so-called “bulges.” Such swellings, which look like cotton balls under a microscope, sandwiched between tightly packed sections of chromosomes, also appear when exposed to dinitrophenol, ethanol and salicylic acid salts.

It turned out that chromosome swellings are new transcription regions that begin the synthesis of new messenger RNAs within a few minutes of their occurrence. The protein products of this process are now commonly known as heat shock proteins, the best studied of which are Hsp90 and Hsp70. Proteins of this family regulate the folding of amino acid chains and prevent the appearance of incorrectly formed protein molecules in the cells of all living organisms.

In the late 1970s and early 1980s, using an original technique of cellular biochemistry to increase the number of messenger RNAs encoding the sequences of the corresponding proteins, scientists were able to clone the first heat shock genes of the fruit fly. At that time, experts were of the opinion that the heat shock reaction was characteristic exclusively of the Drosophila organism. At this stage, Richard Morimoto made his first contribution to the study of heat shock proteins. He collected an extensive collection of DNA from multicellular organisms and, using Southern blotting, demonstrated that they all contained analogues of the Hsp70 gene that were almost identical in structure. Around the same time, Jim Bardwell and Betty Craig from the University of Wisconsin at Madison identified the dnaK gene, also an analogue of Hsp70, in the genome of Escherichia coli. The result of further detailed study of this issue was the understanding that heat shock genes, practically unchanged during evolution, are represented in the genomes of representatives of all five kingdoms of the living world.

The next advance in the chain of events that followed was the identification of a family of transcription factors that control the initiation of the first stage of the heat shock response. Several research groups from different universities took part in this work, including Morimoto's group. Scientists have demonstrated that increasing cell temperature causes a change in the shape of these transcription factors, which promotes their binding to the promoters of heat shock genes, which initiate the synthesis of heat shock proteins. Moreover, it turned out that unlike yeast, fruit flies and the nematode Caenorhabditis elegans, which have only one transcription factor for heat shock genes, human cells have as many as three such factors. Such a complex scheme for regulating the expression of the genes under study led scientists to think about their multifunctionality, which requires additional study.

Further studies showed that heat shock proteins themselves regulate the functioning of the transcription factor that initiates their production in cell nuclei. It has also become obvious that heat shock proteins perform the functions of molecular chaperones - they control the folding of amino acid chains, ensuring the formation of the correct spatial conformations of protein molecules, and also identify and eliminate failures in this process. Thus, it turned out that the cellular thermometer not only measures temperature, but also monitors the appearance of malformed and damaged proteins in the cell. Heat shock and other stressors flood the cell with abnormal proteins, to which chaperones respond by binding these proteins and releasing heat shock transcription factor 1 (Hsf1). Molecules of this factor spontaneously form trimers (complexes of three molecules) that bind to the corresponding regions of the genome, which in turn trigger the synthesis of heat shock proteins. The subsequent increase in the concentration of heat shock proteins to the required level, according to the feedback principle, suppresses the transcriptional activity of the Hsf1 transcription factor.

Studying the functioning of heat shock proteins on cell lines greatly limited the capabilities of researchers, since it did not provide information about the accompanying changes occurring throughout the body. So around 1999, Morimoto and his colleagues decided to switch to a new model: the roundworm C.elegans. They were particularly inspired by the work of Max Perutz, published in 1994, who found that the cause of the serious neurodegenerative disease Huntington's disease was a specific mutation of a gene called huntingtin. This mutation results in the synthesis of a variant protein containing an additional fragment from the long chain of the amino acid glutamine, apparently disrupting the normal folding process. The aggregation of such abnormal protein molecules in neurons leads to the development of Huntington's disease. The researchers suggested that studying proteins whose molecular formation is disrupted due to the expression of polyglutamine or similar reasons would help to understand the operation of the molecular thermometer.

While working to create animal models of the expression of proteins containing excess polyglutamine sequences in neurons and muscle cells, researchers found that the degree of aggregation and associated toxicity of such proteins is proportional to their length and the age of the organism. This led them to believe that suppression of the insulin-mediated signaling mechanism that regulates lifespan could affect the aggregation of polyglutamine-containing proteins. The results of further studies confirmed the existence of the proposed relationship and also demonstrated that the effect of the functioning of the Hsf1 transcription factor on the lifespan of the organism is mediated by an insulin-dependent signaling mechanism. These observations made it clear that the heat shock response is equally important both for the survival of the organism under conditions of acute stress and for the ongoing neutralization of the toxic effects of proteins that negatively affect the functioning and lifespan of cells.

The use of living organisms as an experimental model allowed scientists to take research to a qualitatively new level. They began to pay attention to the mechanisms by which the body perceives and integrates information coming from outside at the molecular level. If stress affects the aging process, it is logical to assume that heat shock proteins, which detect the appearance and prevent the accumulation of damaged proteins in the cell, are quite capable of slowing down the development of the effects of aging.

The fact that many diseases associated with the accumulation of proteins prone to aggregation are characterized by symptoms of aging, and all diseases based on disturbances in the formation of protein molecules are associated with aging, suggests that temperature-sensitive metastable proteins lose their functionality due to as the body ages. Indeed, experiments on C.elegans have shown that the functioning of the mechanism triggered by the Hsf1 transcription factor, as well as other cell defense systems, begins to fade almost immediately after the organism reaches maturity. However, it turned out that activation of the Hsf1 transcription factor in the early stages of development can prevent disruption of the stability of protein molecules (proteostasis).

This intriguing possibility may not apply to more complex multicellular organisms, but all living things are made of proteins, so the results obtained from experiments on roundworms are likely to help scientists understand the mechanisms of human aging.

However, this is not the end of the story. The results of work recently carried out under the direction of Professor Morimoto indicate the existence of mechanisms for adjusting proteostasis that do not require direct interference with the functioning of the Hsf1 transcription factor. The researchers decided to conduct a classical genetic screening of C.elegans mutants that demonstrate disturbances in the formation of protein molecules in muscle cells. As a result, they found that the mutation affecting this process is located in the gene for a transcription factor that controls the production of the neurotransmitter gamma-aminobutyric acid (GABA). GABA controls the functioning of excitatory neurotransmitters and regulates muscle tone. An interesting fact is that any disturbance in the stability of the GABA-mediated mechanisms leads to hyperstimulation, causing postsynaptic muscle cells to respond to non-existent stress, which leads to disruption of the formation of protein molecules. In other words, it turned out that the activity of neurons can influence the functioning of the molecular thermometers of other cells in the body, which further complicated the emerging picture.

If this mechanism extends to humans, then perhaps scientists will be able to develop a method of influencing neurons that leads to the activation of heat shock proteins in skeletal muscle cells and helps eliminate the symptoms of muscular dystrophy and other motor neuron diseases. Perhaps manipulation of these mechanisms will also make it possible to control the process of accumulation of damaged proteins associated with aging. However, unfortunately, not everything is as simple as we would like. In C.elegans, the development of the heat shock response in all adult somatic cells is controlled by a single pair of neurons. It appears that the activity of these neurons and the feedback mechanism allow cells and tissues to activate heat shock proteins according to their specific needs. The fact is that different tissues are characterized by different activity of protein biosynthesis, as well as different severity and nature of external influences. Therefore, a universal approach to managing the heat shock reaction is in principle impossible.

Armed with their work and promising ideas, Morimoto and several of his colleagues founded Proteostasis Therapeutics, which aims to identify therapeutic small molecules that can correct the pathological effects of the accumulation of misformed protein molecules. This approach is associated with a fairly large share of risk, since the level of heat shock proteins increases in many malignant diseases. However, Morimoto and his associates believe that the direction they are developing has too much potential to ignore.

about the author
Professor Richard Morimoto, after defending his doctoral dissertation, devoted his entire work to studying the functioning of heat shock proteins and their role in the aging of the body. Morimoto took his first steps in his chosen direction at Harvard University under the guidance of Dr. Matt Meselson. Richard Morimoto is currently the director of the Rice Institute for Biomedical Research at Northwestern University in Evanston, Illinois, and a co-founder of Proteostasis Therapeutics (Cambridge, Massachusetts).

Evgenia Ryabtseva
Portal “Eternal Youth” based on materials from The Scientist: Richard Morimoto,

“Heat shock proteins” (abbr. HSP or HSP from the English Heat shock proteins) are special compounds that the cells of living organisms produce during a sharp increase in temperature or as a result of other stress loads. The first HSPs were first discovered by scientists in the middle of the last century. Since then, the role of heat shock proteins in plants, animals and humans has been actively studied.

At first it was believed that they performed an exclusively protective role, preventing the occurrence of irreversible disorders. However, over time it became clear that these compounds can take an active part in the regeneration of damaged cell structures, as well as in the functioning of the immune system.

In particular, it was hypothesized that HSPs are involved in the binding of protein fragments that appear during the destruction of malignant tumor cells. In this case, conglomerates are formed that are recognized by the anticancer immune system as an “aggressor”, i.e. so-called “antigen presentation” occurs. In other words, the human immune system gets the opportunity to “see cancer”, which under normal conditions can quite successfully camouflage itself from it. As a result, the natural process of tumor destruction is launched.

Confirmation of this theory, as well as a thorough study of the structure of the heat shock protein and its action in tumor tissues at the molecular level, became possible only after this unique substance arrived at the international space station. It was sent into space by Russian specialists from the FMBA Research Institute of Highly Pure Biological Preparations, who synthesized HSP using exclusive genetic engineering technologies.

Thanks to weightlessness, ideally even protein crystals suitable for X-ray structural analysis grew from the starting material, “packed” into the thinnest molecular tubes. The space stage made it possible to successfully solve the main problem facing scientists: under the conditions of Earth's gravity, proteins grew unevenly, and it was impossible to obtain crystals with the correct geometry on Earth. Analysis of crystalline proteins grown in space was carried out by Russian and Japanese scientists using modern heavy-duty equipment.

The data obtained formed the basis for the creation of a unique drug, the effect of which was tested first in test tubes on cell cultures, and then on laboratory animals. Mice with sarcoma and melanoma, including animals with the fourth (terminal) stage of the disease, were treated with a drug based on the synthesized HSP.

The results were more than impressive:

• the vast majority of mice recovered completely;
• no side effects were reported.

How Russian scientists obtain heat shock protein

HSP is produced by bacterial cells into which a gene isolated from human cells and cloned has been introduced. This gene is responsible for the synthesis of heat shock protein. Currently, its production using this technology is carried out at the production sites of the Research Institute of PCB.

How the medicine “works” and what types of cancer can be treated with it

The use of a biological product is aimed at increasing the concentration of Hsp in the tumor tissues of cancer patients to levels that cause a therapeutic effect. This need exists because the “cancer-showing immune system” heat shock protein in the human body:

• produced in very small quantities;
• cannot be “collected” in healthy cells and “transferred” to atypical cancer cells.

The developers claim that the method they developed is universal, just as the protein itself, produced by all tissues of our body, is universal. Therefore, if further tests confirm the therapeutic effect of the drug and no side effects are identified, it can be used to treat absolutely all forms of cancer.

Other advantages of Russian development:

• Treatment is effective in terminal stages, i.e. precisely when it is extremely difficult, very often impossible, to cope with the tumor in any other way.
• Scientists are considering the possibility of targeted action of the drug. Until now, the drug was administered intravenously to laboratory animals and spread through the blood throughout the body. At the stage of clinical trials, experts plan to test, in parallel with intravenous administration, a method of targeted delivery of heat shock protein to tumor cells, hoping to further increase the effectiveness of treatment and reduce the risk of side effects. This opportunity fundamentally distinguishes Russian technology from the “CAR-T cell therapy” method, the official introduction of which into clinical practice is expected in the summer of 2017.

Money for the final stage of preclinical research of the new drug (about 100 million rubles) has already been found. It remains to find a sponsor who will share the funding of clinical trials with the state. For now, priorities are given to Russian business. If Russian sponsors cannot be found, partnership options with Japanese entrepreneurs or business structures from other countries will be considered. It may take another 3-4 years to complete the testing process. If their outcome is positive, oncologists will be able to obtain a highly effective tool in the fight against cancer.

What can hold back investors and reduce the level of optimism in forecasts?

Investments in any clinical trials carry quite large risks for business. After all, even with the modern development of science, it is impossible to predict with one hundred percent probability how a new medicine will behave, how effective and safe it will be, not in a test tube and in the body of a laboratory mouse, but in practice. However, the search for investment is just a matter of time.

Time will also tell how effective the new method will be. For example, it cannot be ruled out that if natural immunity is weakened, its capabilities to fight the tumor may simply not be enough.

And, of course, only after several years will it be possible to understand:

• whether cancer cells can mutate in search of protection from “loading doses” of HSPs;
• whether the effect of the drug will cause undesirable consequences in the long term.