” One of the most striking aspects of physics is the simplicity of its laws. The Maxwell equations, the Schrödinger equation, and the Hamiltonian mechanics can be expressed in several lines. The ideas that form the basis of our worldview are also very simple: the world obeys the laws, and all the basic laws are observed everywhere. Everything is simple, accurate and expressive from the point of view of everyday mathematics, or partial differential equations, or ordinary differential equations. Everything is simple and neat – except, of course, the world. Everywhere you look, of course, outside the walls of the class of physics – a person sees a world of surprising complexity ”  .
Kadanov and Goldenfeld  give some recommendations on how to explore a complex world. These recommendations are as simple as physical laws: ” To extract physical knowledge from a complex system, you need to focus on the correct level of description … Use the right level of description to catch phenomena of interest. Do not model bulldozers with quarks … you need to realize that complexity requires attitudes that are completely different from those that have so far been common in physics. So far, physicists have been looking for fundamental laws that are valid for all times and in all places. But each complex system is different from the other. Apparently, there are no general laws for complexity. Instead, it is necessary to extract “lessons” that, with insight and understanding, can be studied in one system and applied to another. ”
Such an outstanding physicist as Niels Bohr formulated the unknowability of life, for ” we would undoubtedly kill the animal if we tried to bring the investigation of its organs to the point that it was possible to say what role individual atoms play in its vital functions … The minimal freedom that we are forced to provide to the body is just enough to allow him, so to speak, to hide his last secrets from us ”  . This is the principle of uncertainty in biology, which is similar to the principle of uncertainty in physics.
If we do not even kill the living, then by interfering with the instrument for the investigation inside the living system, we distort its properties so that we investigate not its product but the product of its interaction with the device at the site of this interaction. Since it is in principle impossible to exclude the interaction of an electron with an instrument by means of which we investigate the properties of an electron, we can not determine its velocity and coordinate simultaneously. (The interaction of the device with an object that distorts the properties of this object is called the observer effect .)
But the principle of uncertainty is one of the fundamental laws of physics. Perhaps not being able to formulate such positive fundamental laws as Schrödinger’s equation or Newton’s laws, we can still formulate prohibitive laws for biology.
The remarkable Soviet astrophysicist Shklovsky expressed this view: ” Science is the sum of prohibitions. You can not create a perpetual motion machine. You can not transmit a signal at a speed greater than the speed of light in a vacuum, you can not simultaneously measure the coordinate and velocity of an electron ”  . This very elegant definition provides a possible way of defining some basic fundamental laws not only for physics. The laws of prohibitive. Laws “You can not.”
And then you can ask: are there any prohibitions on biology? Awareness of such prohibitions would not allow carrying out studies that fall within the scope of the ban. On fundamentally unresolved problems, one should not waste time and money. Just like creating a perpetual motion machine.
I tried to answer this question in my review “Fundamental prohibitions of biology”, published in the journal “Biochemistry” in 2009  .
Part of the provisions expressed here I published earlier  ,  . The full version of this review was published in Biochemistry in 2018  .
Categories of unsolvable problems
I. Unsolvable problems due to stochastic mutations in DNA replication
- You can not create two identical individuals. Including two identical complex cells  .
- You can not defeat cancer.
I would also like very much to formulate such a ban: you can not defeat old age and natural death, but I can not stop on this issue due to the limited volume of the article and the complexity of the problem, and I refer readers to recent reviews [8-10] , leaving the problem for their trial.
II. Unsolvable problems due to interactions in complex systems, leading to unpredictable “emergent” properties
- It is impossible on the basis of properties of a sign to establish its reasons (the inverse problem ).
- It is impossible on the basis of known reasons, if they interact with each other, to establish unambiguously the properties of the attribute, due to the emerging properties ( direct problem ).
- It is impossible to predict with certainty the reaction of a complex system to an external effect.
III. Unsolvable problems due to the existence of the uncertainty principle and observer effect in biology
- It is impossible to obtain adequate information about the cells in their tissue microenvironment by isolating and analyzing a single cell – transcriptome, proteome, etc. In particular, it is impossible to draw conclusions on the properties of stem cells in their niches on the basis of stem cell cultures.
- It must be remembered that the probe introduced into the system for observation changes its properties, at least at the position of the probe ( observer effect ).
I mentioned this problem in the introduction. Her, apparently, was first formulated by Niels Bohr. I also can not discuss it and also refer the reader to the reviews  ,  .
This system of prohibitions, in particular the prohibition of the identity of organisms due to unavoidable stochastic mutations, leading to extreme intraorganism and interorganizational heterogeneity, calls for caution, more precisely puts limits to the hopes for personalized medicine  ,  .
On the problems that I have already discussed in recent reviews, I will dwell very briefly, mainly using the most recent data and referring readers to them and to the literature cited therein. The main focus of this article will focus on problem II “Cancer can not be defeated”. It fully illustrates all the complexities that the biological sciences have to deal with, and all the inadequacy of the research apparatus they are now using.
I will consider other problems concisely.
1. You can not create two identical individuals, including two identical complex cells
These prohibitions are associated with the constantly occurring DNA replication of various kinds of mutations – in different tissues of different speeds, but on average about three mutations per cell division.
The adult human body consists of approximately 10 14 cells. Ignoring that different tissues can achieve complete differentiation at different times and that cells can die, an estimate of the number of cell divisions N resulting in the formation of a finite differentiated cell yields a value of N?46. If we take, based on the available data, the mutation rate of 10 -9 and the genome length of 3 × 10 9nucleotides, the final somatic cell as a result will receive about 120 mutations that differentiate it from the original one. The neighboring cell will receive the same number, but they will be located in other places (stochastic!). So, every two cells of an adult organism will distinguish from each other more than 200 mutational substitutions. The probability that there are two cells in which the positions of all 100 mutations will coincide is very low. Thus, the individual is a mosaic of different cells.
“Biomolecule” has recently published a review on genetic mosaicism: ” Genomic puzzle: open a mosaic ”  . – Ed.
Such a theoretical conclusion with the advent of the era of full genomic sequencing has practical confirmation [16-18] . We add to this stochastics of epigenetic changes  , and we come to the conclusion that there are no two genetically and epigenetically identical individuals. Each person in terms of the structure of the genome and the epigenome is unique. Even identical (homozygous) twins are not identical [20-22] .
2. You can not defeat cancer. While genes continue to mutate spontaneously, the cancer will never be eradicated completely. He will constantly arise. Cancer treatment is problematic
There are two sides to this problem: the inevitability of cancer in the population and the problems with its prognostic diagnosis and treatment.
A bit of history. In the victory over cancer invested a lot of money
In December 2016, the US Congress passed the Cures Act of the 21st century, allocating $ 1.8 billion for 7 years to fund a cancer shot of cancer ( Cancer Moonshot ). Vice President of the United States Joe Biden expressed his hope that by 2030 we will live in a world where cancer as such will not exist .
When John F. Kennedy promised in the presidential speech of 1961 to put a man on the moon and safely return it to Earth, he created a metaphor for “a shot on the moon.” Today this metaphor is used to characterize the beginning of ambitious ambitious projects designed to raise society to a new stage of development.
The promise to cure the cancer that President Nixon gave in 1971, declaring war on cancer and investing $ 100 million in this project is an example of such a shot. He ended with a formal failure. Cancer was not defeated.
The second cancer war, albeit a less ambitious one, announced in 2005 by Andrew von Eschenbach , then head of the National Institute of Oncology , ended in failure . Her goal was to defeat cancer by 2015.
The idea that one billion dollars can eliminate cancer, misleads society. Each year of new research increasingly reveals how much the problem of cancer is complex, and makes the idea of its complete elimination less and less real. Undoubtedly, the breakthrough in cancer immunotherapy, when new fundamental knowledge about the mechanisms of the immune organization of the body led to the development of a technique that gives a small number of patients such long-term remissions that it may even be a cure. Cancer research is in the middle of the revolution, and may be on the verge of even greater success. Nevertheless, in general, we are very far from victory over cancer.
“Biomolecule” repeatedly wrote about the interaction of the immune system with cancer cells and about the success of cancer immunotherapy: ” Good, bad, evil, or How to anger lymphocytes and destroy a tumor ”  , ” Immunostimulating vaccines ”  , ” T cells – puppets, or how to reprogram T-lymphocytes to cure cancer ”  . – Ed.
A scientific lunar shot is a grandiose, optimistic and worthy enterprise. But the project should not mislead the public and damage its trust in science. In this respect, the ultimate goal of the project, as former Vice President Biden formulated it, is unrealistic.
The inevitability of cancer in the population
In 1996, a widely publicized interview with prominent oncologist Alfred G. Knudson was published , where he said: ” As genes continue to mutate spontaneously, the cancer will never be eradicated completely. To think otherwise is unrealistic … But we can hope that in a quarter of a century we minimize the death rate from cancer ”  .
On what did Knudson base his statement?
The human body plays with the fire of evolution. Evolutionary inevitability of cancer
Cancer is the result of the evolutionary process of the development of the organism, which requires the renewal of tissues in the process of vital activity of the multicellular organism  .
In evolution, a mechanism has evolved that consists in the withering away of old cells and replacing them with new ones. This process requires a constant division of cells throughout the life of the body. But not all cells are divided. After the completion of the development of the multicellular animal (man is no exception), in almost every tissue there remain fissionable and not fully differentiated cells – the so-called adult stem cells ( VSC )  . When old tissue cells die, VSCs are divided and differentiated, becoming final adult cells. So in place of the deceased come fresh, and so it lasts a lifetime. But each cell division leads to the appearance of mutations in daughter cells . Some of the mutations in VSC can initiate intraorganism evolutionary events leading to fatal malignancy. Thus, cancer is a payment for multicellularity [29-31] . One might think that the likelihood of developing cancer increases with the number of cells in the body. In turn, it follows that with the increase in life expectancy increases the likelihood of cancer. Here is how the Norwegian scientist Jarle Breivik formulated this : ” Cancer is a natural consequence of aging, and the better the medical science helps to prolong the life of people, the higher the number of cancer patients in the population ”  .
Now axiomatically, the root cause of cancer is the damage to genes, which further lead to the subsequent evolution of a complex system that is a cancer tumor  . A number of experimental facts reliably substantiate this conclusion. Most recently, the brilliant works of Christian Thomasetti and Bert Vogelstein have shown that the probability of cancer of a certain tissue is almost proportional to the frequency of stem cell division ( see below ), that is, the frequency of mutations in it  .
Thomasetti and Vogelstein came to the conclusion that DNA copy errors are responsible for 66% of the mutations, while 29% are related to environmental factors and 5% to heredity. In these 66%, cancer is a stochastic failure of an individual. Bad luck. It’s not his fault. He behaved well, did not drink, did not smoke. Just cells mutated, and by chance he received an unsuccessful mutation.
Hence the most important strategic conclusion is that the main strategy of the struggle should be early diagnosis. In the early stages, cancer is much easier to cure, it does not yet have time to build up protective mechanisms.
The incidence can be reduced due to external factors. But changes in environmental conditions reduce the incidence only to a level determined by stochastic mutations. In 2008, the cost of cancer treatment in the United States was $ 93 billion. Less than 15% of research funding goes to early detection, although early intervention is much more effective than late treatment. The greatest success can be achieved by reorienting research for prevention and early detection.
About molecular biomarkers for early diagnosis of cancer, their search and significance for medicine, Sergei Moshkovsky told in a recent article on Biomolecule – ” Omiks biomarkers and early diagnosis: when happiness is possible”  . He also commented on this review, which you can see at the very end. – Ed.
Cancer treatment is problematic
A tumor cell in its genome can contain 10,000 mutations at the time of tumor detection (10 9 cells, 1 g.). Doctor Gleyzir ( Glazier ) ( see. Quotation in  ) evaluated the possible number of different cells with the number of mutations randomly distributed as a 10 ~ 68000 ! Thus, there are no two identical cells in one tumor, there are no two identical cells in different tumors. In addition, tumors of the same type differ in genetically different patients  . The tumor is heterogeneous genetically and epigenetically  . All cells in it are different in genetic structure. Among them are resistant to almost any impact . With the therapeutic effect, sensitive cells die, stable remain and give rise to a new tumor – resistant to the used therapeutic effect. The so-called molecular targeted therapy, based on the use as targets of individual molecules or groups of molecules, altered in cancer cells compared to normal, is inadequate multilayered complexity of cancer.
The impression is that the deeper we penetrate intimate molecular details, the more we focus on specific targets, the more the methods of treatment become inadequate to the complexity of the problem. Exhaustive genomic genotyping is likely to help only a small proportion of patients  .
The development of intra-tumor heterogeneity also creates serious limitations for the detection of mutated molecules or signaling pathways based on molecular analysis of tumor biopsy. The result of the molecular analysis of a single biopsy specimen from a tumor is not required to be reproduced in its other parts. Therefore, treatment based on this analysis is unlikely to be of much use, since other cells with other molecular characteristics that are not susceptible to this effect are active in other parts  .
To understand the further presentation, it seems to me useful to give a brief description of the complex systems that I have already mentioned and to which any living organism and most of its pathologies belong.
A short excursion into unsolvable problems caused by the complexity of systems
Problems of complex systems in recent reviews  ,  ,  are considered in detail . Here I give only a very brief summary of the main points.
A complex system – a multi-component system consisting of interacting subunits, the interaction of which there are so-called emerging ( emergent ) properties inherent in the whole system and are not predictable based on the properties of the starting subunits ( see below. ). Emerging properties are the most important quality of complex systems. They can not be attributed to individual interacting components, these are properties of the whole system. In this case, the system can consist of hierarchical levels, each of which has its own emerging properties [41-45] .
Complex systems are nonlinear and extremely sensitive to initial conditions  . This means that the trajectory of the system  , defined as the change in its state, for example, in time, is unpredictable. Two systems, whose states are very close in the initial period, and which function according to the same rules, will have different trajectories over time. The immune system, for example, consists of various elements (macrophages, T- and B-cells, etc.), which interact with each other by the exchange of signals (in particular cytokines ). Even under the influence of absolutely identical stimuli, the immune system, like other complex systems, including a cancer tumor, can respond absolutely differently.
Small changes in the impact on complex systems do not necessarily give a small response to the system. Often, a large unexpected effect occurs in response to a small impact.
In complex systems, it is impossible to accurately predict the effect of environmental factors. In the body it (as well as the influence of stochastic factors) begin in utero and continue throughout the life of the individual  .
Finally, complex systems, as a whole, do not lend themselves to computer simulation  ,  .
The editorial board will take the liberty to note that, although absolutely accurate modeling of complex systems is really impossible, in many practical cases such “simulations” are not only feasible, but can also be very useful: ” Spatial-temporal modeling in biology ”  , ” 12 methods in pictures:” dry “biology ”  . – Ed.
1. Cancer is a complex system with a large number of interactions with the environment that generates unpredictable emerging properties
The cancer tumor combines a complex, varying in time and space a variety of cells, each of which has its own signal cascades, replication, transcription, etc. and undergoes numerous changes in the way of transformation into a cancer cell. It is inherent in the complexity of a growing evolving system with all its characteristics and properties that enable it to withstand anticancer agents and induce that intracellular cellular heterogeneity that makes the tumor unique to each patient  . In this respect, cancer differs from all other diseases  .
However, the complexity of the tumor is far from being limited to sets of cancerous genes and cells, which to some extent influence the progression of the tumor. In its latest version of the distinctive features ( hallmarks of ) cancer, Douglas Hanahan and Robert Weinberg  indicate that tumors showing still another dimension of complexity ( Tumors not exhibit another dimension of complexity ): tumor, attracted to its evolution with a wide repertoire of normal cells, they adapt to their needs, and which contribute to the acquisition of distinctive criteria, creating what is called a tumor microenvironment ( tumor microenvironment), its ecological niche, and that plays an important role both in the evolution of the primary tumor itself and in its metastasis  ,  . Today, it can be safely assumed that, perhaps, the main complexity of the tumor is the enormous amount of interactions between the cancer cells themselves (usually epithelial cells) and the various stromal cells that make up the tumor microenvironment  . A cancer tumor carries a symbiosis with its environment.
Therapeutic approaches can be directed not at cancer cells, but at destroying interactions within an evolving cancerous tumor
In recent years, a fundamentally new approach has received a great response. Instead of treating mutations in cancer cells, the new therapy focuses on destroying the complex interactions of cancer cells with the immune components of the stroma that determine the success of the evolution of cancer in the body. These interactions allow cancer cells to inhibit immune cells in their environment and thus avoid destruction by the immune system.
The successful use of inhibitors of these interactions in the clinic over the past five years [55-57]have demonstrated that cancer can be recognized by the immune system, and the immune system can regulate and even eliminate tumors  .
Although these methods of treatment immeasurably increased the life expectancy of many cancer patients, a large number of patients with malignant diseases do not respond to therapy [58-60] . In addition, successes are accompanied by numerous adverse autoimmune effects  ,  . In general, the effect of therapy on a particular patient is unpredictable. Future studies are likely to open new promising immunological targets or old targets in combination with other immunotherapeutic approaches, chemo- and radiotherapy, oncolytic viruses and small molecule therapy.
The obtained results once again demonstrate that complexity remains a challenge. Its response to impacts is unpredictable.
2. Unsolvable problems in the study of genotype relationships with the phenotype and decoding of the functional architecture of the genome
Now I would like to consider the problem of the inability to determine the exact map of genomic elements that determine the phenotypes of the organism, in particular, the definition of the functionality of non-coding and non-regulating genomic elements (the so-called junk )  .
The community of researchers of the functional elements of the genome was divided into two almost equal irreconcilable camps, like the Jonathan Swift lilliputians in the debate between “spiked” and “stupidly” on the correct practice of breaking eggs. Many believe that, for example, very low-level transcripts represent a huge world of functional RNAs only because they exist. Their opponents think that there is reason to question this view. Undoubtedly, many functional coding and non-coding RNAs can be found among such transcripts, but it is even more likely that the overwhelming majority of these transcripts are simply junk.
So who is right? To answer this question, we need, first of all, to define the meaning of the term “function”.
In 2012, the authors of the consortium ENCODE  attributed the “biochemical functions” of 80% of the human genome  on the grounds that they are transcribed.
The figure of 80% contradicted the notion that up to 90% of the genome is a junk. But it was enthusiastically accepted by “determinists” (and believers in intelligent design of the genome ( Intelligent design )), because it seemed to indicate the absence of non-functional elements in the genome.
But this interpretation was sharply criticized by proponents of the evolutionary origin of organisms and their genomes: if an element has some kind of biochemical activity, it does not necessarily mean that it has any significance for the functioning of the cell and, especially, of the whole multicellular organism. According to  and other authors, the functional element must differ in that it is selected in the process of evolution and therefore remains in the genome. In my comment in BioEssays I defined it this way: a transcribed junk remains junk if it does not acquire a function that is selected in evolution  .
Such functionality is protected by natural selection; If this protection ceases to work, the functional element will accumulate harmful mutations and eventually lose its functional activity  .
Graur Dan ( Dan of Graur )  suggested that only the functionality of the genome can be damaged by harmful mutations, while mutations in the non-functional parts must be neutral. Due to harmful mutations, each couple of each generation must produce more than two children in order to maintain a constant population size. The larger the proportion of the functionally important part of the genome, the more descendants should be born by each pair in order to maintain the size of the population. Graur found that if 80% of the genome were to function, an unacceptably high birth rate would be required. According to his calculations, the maximum proportion of functional elements in the human genome does not exceed 25%. His conclusions are confirmed by recent data, that 8.2% (7.1-9.2%) of the human genome are currently subject to negative selection and, therefore, are likely to be functional  .
Graur speculates : ” There is no need to sequester everything under the sun. We need to sequester only those parts that, as we know, are functional . ”
The determination of the position and functions of all functional elements of the genome is problematic
Graur’s assessments are extremely valuable, especially from an evolutionary point of view, but they do not give an indication of specific elements of the genome that are functional, and the specific functions that they perform.
The answer to this question can not be given on the basis of the analysis of phenotypes, as it would require solving the so-called inverse problems ( to inverse problem ), which in general can not be solved  . In the case of complex systems, especially complex ones such as the organism, it is impossible to solve a direct problem – the derivation of the phenotype properties from the genome structures and other molecular components involved in the formation of the phenotype. This inability is due to the interactions of these components, generating unpredictable emerging properties.
The simplest paradigmatic example is a direct problem: from the properties of hydrogen and oxygen molecules it is impossible to predict all the properties of water – its boiling point, surface tension, properties as a solvent, specific gravity, the ability to freeze, giving snowflakes of various forms, etc. This is the “phenotype” of water. It arises from the interactions of hydrogen and oxygen. The inverse problem: simply from the properties (the “phenotype”) of water it is impossible to deduce which components make up it, and to predict their properties.
To go to the links of the genome and the body, I will quote [the text in square brackets – approx. author] of one of the most respected modern scientists and philosophers of science Sidney Brenner, a Nobel laureate who introduced into science a remarkable model – the nematode.
” The sequence of the human genome was once likened to sending man to the moon. The comparison turns out to be literally correct, because it’s easy to send a person to the moon; his return, that’s what is difficult and expensive. Today the sequence of the human genome, so to speak, is stuck on the metaphorical moon, and our task is to bring it back to Earth and give it the life it deserves. Everyone understood that getting the sequence would be very simple, this is the problem of 3M Science – sufficiency of money, machines and management (Money, Machines and Management). Interpreting the sequence to identify the functions it encodes and the regulatory elements and understanding how they are integrated into the complex physiology of a person has always been considered a difficult task, but since it is easier to continue collecting data, this task[interpretation] were in fact not seriously engaged ”  .
” There is no simple way to” map “organisms to their genomes if they have reached a certain level of complexity. … The proposals to base everything on the sequence of the genome, annotating it with additional data [direct problem] , will only lead to an increase in its incomprehensibility ”  .
Thus, we fall into the “scissors of impossibility.” I suggest that the reader draw conclusions by reading a very interesting article by Brenner  .
To convince the skeptics, I decided to give such an illustration. Look at the picture. Can anyone imagine how the Einstein chromosomes look when they look at this person? This is the reverse problem. And on the other hand – is it possible, looking at the chromosomes of Einstein, to imagine his appearance or mental abilities?
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