25 December 2012

Medicine of the future

From tadpole to cyborg

About the paradigm of preventive medicine, cyborgization of people and medicine in the distant future in his lecture in "Gazeta.Ru" says Roman Deev, Candidate of Medical Sciences, lecturer of the RNIMU Department, Candidate of Medical Sciences, employee of the Institute of Human Stem Cells.

Cellular technologies: is there an unambiguous future?The question of what medicine will be like in the future is both very interesting and very provocative.

The prognosis of the development of medicine can be dictated, on the one hand, by the evolutionary way in which our ability to know the surrounding reality develops – from the planetary to the nanoscale. On the other hand, the emergence of researchers who are able to unexpectedly refract the totality of knowledge and give out an "asymmetric" offer, rather than make a qualitative leap (Craig Venter alone is worth something!).

Looking from our country, it may seem that the future has already come beyond its borders. Robotic surgical installations exist and are used, pushing the surgeon out of the operating room into the gaming room. After the first tissue–engineered organ, the bladder of Antonio Atala, Paolo Macchiarini's replicated technology appeared – tissue–engineered organs became the event of today, not tomorrow. Positive fantasies about bioartificial organs in district pharmacies in general have ceased to be a pipe dream, it remains only to silently optimize the technology of cultivation and bioprinting of tissues and organs. Black fantasies about human cloning and growing homunculi "for organs" have not come true: it is technically impossible and expensive – it grows slowly, eats a lot ... The technology of humanized organs in this sense is much more promising.

In the first decade of the XXI century, we experienced a romantic wave of flourishing hopes for cellular technologies (regenerative medicine), since then the phrase has been fixed in our minds that they are the future of medicine, and they are all very promising. We hoped that the cells extracted from the body and specially prepared in the laboratory conditions would be able to fight after transplantation with what people in white coats, alas, cannot cope with yet – with the fatal consequences of a heart attack, with malignant tumors, with genetic diseases, etc.

However, years passed, and it became clear that, in fact, humanity, despite the rich accumulated experience, remained at the same technological point of medical cellular technologies – at the level of the second half of the twentieth century.

Transplantation of hematopoietic bone marrow cells, performed by Donal Thomas in 1968, opened an era of effective fight against malignant diseases of the hematopoietic system (leukemia, lymphoma, multiple myeloma, etc.), now there is a tool to combat this deadly disease. Since then, more than 60,000 bone marrow transplants have been performed, and in some diseases, the effectiveness of its use has reached 90 percent. For the development of this method, D. Thomas was awarded the Nobel Prize in 1990.

Another "working" rather than auxiliary cellular technology – in vitro fertilization – was performed in 1977-1978 by Robert Edwards, and also the Nobel year in history is 2010. Otherwise, global victories of regenerative medicine have not yet happened.

And whether there will be breakthroughs here is a big historical question, the answer to which may be related to a change in the research worldview: to develop not only and not so much means of "repairing" the body, but to anticipate the possibilities of the development of a particular pathological process and prevent it.

However, in order for preventive medicine as a culture of consumption and provision of medical services or medical care to work, researchers and developers, as well as health care organizers, will have to penetrate even deeper from the cellular level – to the molecular and genetic levels.

Some time ago it became obvious that the harbingers of diseases – specific proteins or their fragments, which are the products of the decay or perverted synthesis of single diseased cells – can be detected in the blood, as well as antibodies to them. This discovery has breathed life into the emerging paradigm of preventive medicine.

Indeed, as Professor Alexander Borisovich Poletaev has shown, this phenomenon can be adopted and several diagnostic panels can be developed – for early detection of gastrointestinal cancer, monitoring of pregnancy, the state of the cardiovascular system and many others. All of them are already actively used in the relevant medical research center. Moreover, more advanced test systems have already appeared, when the patient's breathing can detect cancer at the earliest stage.

Things are much more complicated when a researcher penetrates even deeper into the world of genetic information, but it is with him that the future of preventive medicine is connected.

Nobel laureate and discoverer of the double-stranded structure of DNA James Watson once said a phrase that immediately became a catch phrase: "It was assumed that our fate is hidden in the stars. However, now we know for sure that it is written in our genes." Sir Francis Collins, the head of the Human Genome program, echoes him: "Indeed, it can be argued that almost any disease (possibly with the exception of injuries) has genetically determined components." Professor Sergey Lvovich Kiselyov (Institute of General Genetics of the Russian Academy of Sciences) likes to quote them in his lectures. He develops the following idea: "The idea of correcting the work of genes appeared two decades ago, a whole scientific and practical direction arose - gene therapy. Today, its practical achievements are not very great, although there are already some successes – these are four gene therapy drugs used in the world (including one Russian one). The newest of these drugs can be safely attributed not only to the category of "repair" of damaged genes, but also to the prevention (in a group of patients) of the development of atherosclerosis and its severe complications.

But perhaps the most important thing that this direction has given is the improvement of technologies for the genetic correction of cellular specialization.

Back in 1987, it was shown that it was possible to change cellular specialization with the help of genes, to turn skin cells into muscle cells. Today, 25 years later, we know much more about human genes, their structure and functions. In the near future, we can expect that genetic correction of a hereditary disease will become possible at the earliest stages, if it turns out to be possible to combine it with cellular technologies of in vitro fertilization."

It was the work with stem cell genes that opened the way to reprogramming. The Nobel Prize recently awarded to Shinya Yamanaka has made familiar to a large number of interested people the secret of turning any cell of an adult organism into cells of the earliest embryo, which gives them special properties for further development into a wide variety of working elements of body tissues – neurons, cardiomyocytes, pigment cells, etc., this makes them almost identical in their properties and meaning embryonic stem cells, also awarded by the Nobel Committee (Martin Evans, 2007). Shinyi Yamanaki technology is implemented in laboratory conditions, in special nutrient media and is still far from clinical practice.

However, there were also some scientists who thought that if reprogramming is possible in artificial laboratory conditions, then is it possible to reprogram cells of "undesirable" tissues directly into "necessary" inside the body: for example, in case of a heart attack, scar fibroblasts into workable cardiomyocytes.

Immediately, several scientific groups from Boston, Tokyo and Texas managed to obtain the first positive results in laboratory animals: after local injection of genetic constructs or a special type of RNA into a post-infarction scar, some fibroblasts were reprogrammed and "turned" into heart muscle cells. It is quite obvious that if the technology becomes reproducible in more complexly organized and large animals, it will potentially displace the need for laboratory work with reprogramming, all manipulations to correct an emergency situation can be performed directly in tissues.

Repair of a genetically damaged organismCompletely different technologies are needed to "repair" the body not in the case of an acquired disease, but in the case of a congenital disorder of the genetic apparatus.

Even in such a delicate matter, several technologies are developing that differ from each other in the levels of filigree of problem solving. The most gross interference in the holy of holies of the body is the use of viruses that can be embedded in the structure of our DNA. Although such interventions are highly effective, they carry a high risk of developing malignant tumors. Therefore, new ways of "operating the genome" are being developed – as highly effective as they are safe.

Not so long ago, in 2005, Fyodor Urnov and his co-authors developed a method for correcting the mutant genome using the technology of so–called zinc-finger endonucleases - specialized enzymes that cut out the damaged section of DNA. This approach has already begun to be worked out in studies involving patients with HIV (to create immunity of lymphocytes to the virus).

However, perhaps one of the most audacious approaches is the creation of an artificial chromosome in the laboratory.

Yes, it turns out that you can take an ordinary chromosome, remove all the "unnecessary" sections from it, leaving only those responsible for its doubling before cell division - the centromere and telomere, and integrate the necessary full–fledged serviceable gene between them. And it is possible, as our compatriot from the National Institutes of Health (USA) Vladimir Larionov has shown, even to assemble, like beads, an absolutely functional artificial chromosome from fragments-beads of artificially synthesized DNA sections, including the necessary therapeutic gene or a huge piece of another chromosome. During the "assembly", regulatory sections can be provided and inserted, through which it will later become possible to control the process of its removal from the cell, if necessary.

After placing an artificial chromosome in the cells of a sick organism, the missing proteins begin to be produced in it, and gradually the organism with the genome strengthened in this way recovers.

It has not yet been found that this manipulation leads to the development of tumors or other adverse consequences. Julio Kossu (King's College London) and Mitsuo Oshimura (Tottori University, Tokyo) have advanced the furthest in this direction. In a large experiment on animals with a damaged dystrophin protein gene (in humans, such damage leads to a fatal disease – Duchenne myopathy), they managed to embed artificial chromosomes into muscle cells and the production of high-grade protein by the latter, which positively affected the life expectancy and motor activity of animals. Now scientists are busy creating the same artificial chromosome, but fully optimized for cells and the human body.

According to Alexey Nikolaevich Tomilin, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Molecular Biology of Stem Cells of the Institute of Cytology of the Russian Academy of Sciences: "Artificial human chromosomes can be of great practical importance for the treatment of a wide range of diseases, including hereditary ones. The main advantages of artificial chromosomes over viral and other vector systems are practically unlimited capacity, mitotic stability, the absence of any modifications of the host genome, as well as the possibility of controlled removal of these chromosomes from cells. The most convenient means of transferring artificial chromosomes into the patient's body are stem cells."

Find and fix in the budThe most interesting thing is that you can detect the disease even before a person is born – while he is in the womb.

The phenomenon of fetal microchimerism, i.e. the preservation in maternal tissues of some fetal cells that have penetrated into the parental bloodstream through the placental barrier, has been known for a long time.

Recently, it was possible to calculate that fetal cells appear in the mother's blood starting from the 7th week of pregnancy. Such "traveling" cells of a child can become an important diagnostic object characterizing the state of a child's health, which means that, if necessary, doctors will be able to take measures for urgent treatment, even if the fetus is still in the womb. In particular, this includes intrauterine (fetal) surgery; allogeneic transplantation of hematopoietic or other stem cells to an unborn child in order to cure a congenital disease: after all, the intrauterine period is the most convenient time when the immune system is immature and the risk of incompatibility of donor material is extremely low. Several dozen such operations have already been performed in the world. Isn't this the real preventive medicine?

This is how Artur Isaev, director of the Institute of Human Stem Cells, draws the image of medicine of the future:

The idea of preventive and preventive medicine from the point of view of understanding has long been accepted and understood by almost everyone. No one objects to this concept, because it is obvious that the prevention of diseases is cheaper than their treatment; the implementation of this concept will lead to an increase in the duration and quality of life.

However, so far only part of this concept is being implemented by the healthcare system: these are vaccinations and the fight against viral diseases, these are preventive examinations, dispensary registration, etc. Unfortunately, a number of measures that could be implemented are not being carried out: after all, technologies for them exist, are not being implemented yet.

This is what is meant: firstly, it is pre–conception medicine (aimed at treating an unborn child) and hereditary diseases - more than 10,000 children are born every year with hereditary monogenic diseases associated with death at an early age. And this happens despite the fact that there are inexpensive technologies for checking parents for the carriage of such diseases, as well as technologies that ensure the birth of their own healthy children (preimplantation diagnostics).

Secondly, it is the identification of hereditary predispositions, the prediction of their realization during the life of the organism and their management. Technologies of such screening are available, and medical approaches for the prevention and prevention of the realization of predispositions to diseases in terms of cases are also clear.

The third component of preventive medicine is bio–insurance. By storing their cells or the cells of their children in various cell banks – a hemabank, a fibroblast bank, a bank of reproductive (germ) cells – a person takes care in advance of possible problems that, if they arise, can be solved. According to these positions, society and professionals have a common understanding, it remains to form a culture of implementation."

It is quite obvious that by the XXI century medical science has achieved impressive results, severe infectious diseases have been defeated, the quality of life has improved. The average person has added several decades of life. However, as knowledge accumulates, it becomes clear that the next qualitative leap is possible only with a radical change in the medical worldview and the health care system, which should anticipate and anticipate the disease.

The world's research centers are working in this direction. Major companies that do not seem to have a direct relationship to medicine (for example, Google) invest a lot in new branches of medicine.

Over the past year, for example, more than 50,000 scientific articles have been published in the USA on cellular technologies alone, a comparable number in Europe is a huge, incomparable flow of knowledge with other sciences.

The opportunities opening up to humanity amaze the imagination and inspire optimism to many incurable patients. Some of these possibilities are like a fantasy novel. A year ago, the Russian neuroscientist Dmitry Kuzmin, who now works at University College London, gave a popular science lecture on "People and medicine of the Future", where he touched on the possible cyborgization of people who want to live for more than 120 years.

And the first steps in this direction have already been taken: the development of such ailments as Alzheimer's disease or Parkinson's disease can be slowed down or even stopped with the help of an implant implanted in the brain of the patient. The corresponding developments were presented in 2012 by researchers from the American Johns Hopkins University.

As a postscriptIt was 1906, when Ross Garrison at Johns Hopkins University for the first time was able to create conditions for maintaining the viability of a section of the central nervous system of a tadpole.

He placed a fragment of the spinal cord in a nutrient medium and watched for several days how life was maintained in artificial conditions and the growth of nerve processes took place. More than 100 years have passed since then; by the standards of the development of civilization, not so much. Perhaps the moment will come when the whole brain – both the brain and the spinal cord – can be placed in a nutrient medium, and this will be the date of the coming of the "future of medicine" – the state when both "repair" medicine and prevention medicine are not needed.

If there is no body, there are no diseases.
Perhaps humanity will learn to live without the need for a physical body, supporting ageless consciousness in artificial conditions, learn to find a common information language with technical devices. Diseases that affect cells and tissues, diseases that age the body, will become a thing of the past. But this is just one of the options for the future of medicine.

Portal "Eternal youth" http://vechnayamolodost.ru25.12.2012

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