Turn back the clock?
What is cell therapy and will it make a person immortal
A person begins to develop from a single cell. The mutations accumulated in the cells lead to aging, which means age-dependent diseases and death. What will happen if we tame this powerful mechanism and use it to treat people, or even turn back time? Biologist Alexander Tyshkovsky told post-science how cell therapy already rejuvenates mice today and makes it possible to improve the condition of patients with Parkinsonism and whether it will be possible in the near future to grow not only artificial meat, but also spare organs for humans.
What is aging and how does it occur at the cellular level?
Aging is a process of damage to the body that occurs at a variety of levels. There are molecular damages. The most famous of them are mutations in DNA that increase the risk of developing cancer, or, say, abnormal accumulations of proteins in brain tissues — one of the risk factors for Alzheimer's disease.
Alzheimer's disease is the most common form of dementia, a neurodegenerative disease that manifests itself in the accumulation of masses of beta—amyloid protein and tau protein in brain tissues, which leads to a violation of its function. As a result, in the early stages, the patient has short-term memory disorders, then the disease reaches long-term memory, speech and cognitive functions are disrupted, the patient loses the ability to take care of himself. The increasing loss of body functions leads to death. Alzheimer's disease mainly affects people over the age of 65. According to researchers, by 2050, the number of patients in the world may exceed
The next level of damage is cellular. When damage appears in the cell, in many cases it is able to cope with "breakdowns": there are repair mechanisms (repairs) DNA or, for example, proteolysis — the cleavage of damaged proteins. But the mechanisms of self-defense are not perfect, and when there are too many breakdowns in the cell, it has three possible outcomes. The first is the degeneration of a cell into a cancerous one: accumulated mutations lead to the fact that the cell gets out of control, begins to divide nonstop and cause harm to the body. The second option, perhaps the most humane for the body, is cell self—destruction (this mechanism is called apoptosis). The third outcome is intermediate: the cell does not die, but at the same time, under the yoke of breakdowns, it ceases to divide and perform its biological functions. Such cells are called senescent (from the English senescence — "senescence", "aging") or "zombie cells": after all, in a sense they are neither alive nor dead. Some studies show that these cells still have benefits: for example, they help to preserve tissue after acute injury. But in the long run, the harm from them, apparently, is still greater. In particular, senescent cells secrete inflammatory factors into the tissue, thereby causing new damage in other cells. Thus, the breakdowns of individual molecules eventually grow to the level of an entire organ, like a forest fire. This inevitably leads to serious pathologies in the body.
In parallel with the accumulation of senescent cells, the number of stem cells decreases with age. They are responsible for regeneration, replacement of dead cells with new ones. Over time, damage also occurs in stem cells, as a result of which they can become senescent or die. As a result, tissue regeneration is worse in the old organism, and it is easy to see this even with the naked eye: a cut on the arm of an elderly person heals more slowly than that of a young one.
This is an incomplete list of aging mechanisms, but it is already noticeable that there are many damages and each of them can cause subsequent ones. With age, this snowball becomes more and more, a person develops chronic diseases, and eventually he dies. Moreover, the occurrence of breakdowns with age is largely a random process. What will happen first: mutations will accumulate and cancer will arise, senescent cells will accumulate and myocardial infarction will occur or beta-amyloid aggregates will appear, and with them Alzheimer's disease — this is a kind of Russian roulette that each of us is forced to play. However, there is also a positive point in the fact that all the mechanisms of aging are interconnected: if we can significantly slow down the accumulation of the main types of damage from a young age, then the risk of cancer, the risk of Alzheimer's disease, and the risk of heart attack will simultaneously decrease in a person.
What cellular technologies help prevent or slow down diseases?
Since we already have special cells in our body whose task is to fight many diseases, it seems logical to use them for new medical purposes. Of course, we are talking about our immune system, and the treatment of diseases with its help is called immunotherapy. For example, you can take a sick person's own immune cells and in the laboratory "incite" them to a specific disease of this patient. The most striking example of such technology is CAR—T (Chimeric Antigen Receptor, or chimeric antigen receptor). This method works like this: let's say we have a patient with some type of blood cancer. Immune cells responsible for the search and destruction of "wrong" cells in the body, T—lymphocytes, are taken from this patient. In the laboratory, with the help of genetic engineering, a certain receptor is "sewn" to them, which allows them to accurately detect cancer cells of the patient. Then these cells are transplanted back to the patient, where they successfully fulfill their purpose and rid the person of the disease. In the USA, this method has already been approved for the treatment of several types of blood cancer.
By the way, the same approach can be used to combat the mechanisms of aging. To do this, it is enough to "incite" T-lymphocytes not to cancer, but to senescent cells. Scientists have confirmed the effectiveness of such therapy in mice, where they were able to help rodents suffering from liver fibrosis.
Is it possible to rejuvenate the cells themselves?
Can. Moreover, today scientists are able to bring an adult cell of the body to its embryonic state. The fact is that in the adult state we do not have cells capable of giving rise to any type of cells. Even stem cells are limited in their capabilities: a liver stem cell will not be able to give rise to a heart muscle cell, and vice versa. However, each person begins with cells that subsequently give rise to all adult cells of the body — with embryonic cells.
In 2006, Japanese researcher Shinya Yamanaka for the first time managed to turn an adult cell of the body into an embryonic-like one. In fact, he was able to reverse the process of cell maturation, for which he received the Nobel Prize in 2012. To do this, it was enough to introduce four genes into an adult cell, which were named Yamanaki factors in honor of the scientist. And the cells themselves are called induced pluripotent stem cells (iPS cells).
This technology has given scientists huge opportunities, including the ability to transform one type of cell into another. For example, we can take a skin cell (fibroblast) from an adult, roll it into an embryonic state, and then grow a liver cell, brain cell, and the like out of it. In this case, we no longer need to freeze the umbilical cord stem cells from childhood, because for any adult it is possible to get his "embryonic" cells within a month. But most importantly, these cells will also be biologically young, that is, they will have much less damage than in similar adult cells.
It is not surprising that this technology has already found application in clinical practice. For example, two years ago, scientists grew young corneal cells for one patient, thereby restoring her vision. Another striking example is the treatment of Parkinson's disease, a neurodegenerative disease.
Parkinson's disease is a neurodegenerative neurological disease of the motor system. It is caused by the progressive destruction and death of neurons that produce the neurotransmitter dopamine, which leads to disorders of motor function and brain function. It begins with a tremor (trembling) in one of the limbs, and ends with the patient being bedridden and unable to serve himself. Parkinson's disease often manifests itself in old age, but it can also develop in 30-40-year-olds.
Scientists take skin cells from the patient, after which, using iPS technology, they grow new young brain cells from them and transplant them back to the patient, but this time into the brain. As a result, such therapy can slow down the progression of the disease, and in some cases even improve the health indicators of patients. Of course, it has not yet been possible to completely cure the disease with this therapy, but the current result is already a big breakthrough. Especially considering that there are still no effective drugs that cure Parkinson's disease.
Is it possible to rejuvenate all cells of the body using iPS technology?
Theoretically, if we have learned to reverse aging at the level of each individual cell, we can do it for the whole organism. But in practice it is extremely difficult to do this: after all, a person has tens of trillions of cells. To get, rejuvenate and return each of them back is not the most promising idea. You can, of course, try to rejuvenate cells not in the laboratory, but directly in the body. To do this, you will need a virus that will deliver the same Yamanaki factors to the cells. However, this technology is still quite risky: if you overdo it and bring the cells to the "embryonic" state, they can be reborn into cancerous and lead to the formation of a tumor. Therefore, scientists are now looking for a middle ground, including Yamanaka factors for a limited, short time. In this way, scientists are trying to rejuvenate the cells, but not to allow them to turn into "embryonic".
These manipulations have a result: the temporary use of iPS technology in mice has led to the fact that their biological age has decreased in many physiological parameters, and the quality of health has increased. At the same time, they did not have cancer more often. Whether this will lead to the fact that the mouse will live longer is still unknown — it takes time to find out. But the prospects for the approach are certainly high.
As for human use, most likely, at first this technology will be tested for the treatment of certain diseases. To do this, it is possible to introduce genes not into all cells of the body, but only into the organ that we want to "fix". Harvard University professor David Sinclair has demonstrated the effectiveness of this approach for restoring vision in elderly mice and mice suffering from glaucoma.
How can this be done? Let's take some virus, for example, adenoassociated, and load Yamanaki factors into it. If we introduce such a virus into the blood, then most of the viral particles will settle in the liver. If you inject the virus into the eye, the viral particles will not be able to leave this isolated organ, and the entire therapeutic effect will be concentrated in it. Sinclair's group injected a virus with Yamanaki factors into the eye of elderly mice and mice with glaucoma. As a result, their eyesight really improved: elderly mice began to see no worse than young ones.
Is it possible to grow organs and replace old ones with them?
Another interesting application of iPS cell technology is to use it to grow a new young organ for the patient to replace the old one. To date, there are two ways to do this. The first is to print the organ on a 3D printer. It sounds a bit futuristic, but this is already a reality: in 2019, in Israel, a group of scientists printed a heart from the cells of the heart muscle and the walls of blood vessels on a 3D printer layer by layer. True, the heart was the size of a rabbit and did not contract as a whole, only at the level of individual muscles. However, these shortcomings are rather technical in nature and may be finalized in the future. In this case, such a technology will be truly revolutionary. Firstly, it will solve the problem of the shortage of organ donors, since now everyone will be able to grow their own organ "turnkey". And secondly, the transplantation of such an organ will not lead to immune rejection: after all, the new organ will be printed from the cells of the patient himself.
By the way, growing organs in the laboratory can keep us not only healthy, but also well-fed. A similar approach is used to create artificial meat. To do this, scientists first make a skeleton for muscle fibers from gelatin, after which they "spray" young muscle cells on it. These cells germinate into the framework and at some point replace gelatin. As a result, the most real muscle fibers are formed, repeating in their shape the original gelatin framework. Recently , large businesses have become actively interested in artificial meat cultivation technologies . For example, in 2020, KFC signed an agreement with the Russian 3D Bioprinting Solutions laboratory to develop 3D printing technology for chicken nuggets. It is quite possible that thanks to cellular technologies, killing animals for food will soon be a thing of the past: the same delicious and fresh meat steak can be easily printed on a 3D printer.
The second way to create a new organ for a person is to grow it in an animal, for example, in a pig. To do this, they take a pig embryo and introduce a certain mutation, as a result of which the animal cannot develop one specific organ, say the pancreas. A pig cannot survive without a pancreas, so such an embryo will simply die. But if you add human iPS cells to it, they can give rise to the pancreas. As a result, a pig will grow up, in which the entire pancreas will be built from human cells. It remains only to cut out this organ and transplant it to the patient.
With the help of this technology, it has already been possible to grow the pancreas of rats in mice, and the pancreas of mice in rats. Unfortunately, growing a human organ in a pig turned out to be a much more difficult task. The fact is that human cells do not take root well in a pig embryo: contrary to a well-known misconception, a pig is genetically quite different from a human. Monkeys are another matter. And indeed, in the macaque embryo, human cells took root much better.
Is it possible to restore nerves with the help of cellular technologies?
As part of Sinclair's already mentioned work, another interesting experiment was conducted: Yamanaki factors were injected into the eyes of mice that had previously cut the optic nerve directly connecting the eye to the brain. Thanks to iPS technology, the nerve began to grow, regeneration was observed. If it is possible to transfer this approach to a person, it will allow treating many neurological diseases — for example, restoring activity to paralyzed people. Currently, exoskeletons are being developed for such people so that they can move artificial limbs. The use of iPS technology could give patients the opportunity to control their hands and feet again.
When will such technologies become a real practice?
It is difficult to name the exact dates. Even when it comes to more or less simple technologies, say medicines, their clinical trials on humans usually take about 7-10 years. When we talk about such complex approaches as cell therapy and genetic engineering, it becomes extremely difficult to predict something.
On the other hand, we already see how these technologies are tightly integrated into our lives. The Sputnik V vaccine, which saves us from the SARS-CoV-2 coronavirus, is actually an example of gene therapy and, in a technological sense, does not differ much from the method of rejuvenation of the body with the help of a virus carrying Yamanaki factors — the difference is only in the ratio of benefit and risk.
The technology of growing young cells in the laboratory is not very risky, since the most difficult part of this process is carried out outside the patient's body. Clinical trials of this approach for the treatment of certain diseases are already underway, which means that it may well enter medical practice within the next 10 years. On the other hand, systemic rejuvenation of healthy people with the help of Yamanaka factors is associated with a much greater risk. I don't think we should expect widespread preventive use of this technology in the next 10-15 years. Although I'll be only too glad to be wrong.
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