Is it time to change the paradigm?

Make friends with tumors

Natalia Leskova, "Scientific Russia"

Andrey Petrovich Kozlov – Doctor of Biological Sciences, Professor, Head of the laboratory of the N.I. Vavilov Institute of General Genetics of the Russian Academy of Sciences, Professor of St. Petersburg Polytechnic University, has developed a fundamentally new biological theory of evolution, in which a significant role is assigned to the evolution of tumors. According to him, research in this area will take humanity to a new level in understanding the nature of tumors and will allow us to fight them more successfully.

– So, Andrey Petrovich, is your theory about cancer?

– It is devoted to evolution – and the evolutionary role of tumors, not only in oncology, but also in biology in general. In recent years, a new direction in biological sciences has emerged, related to health sciences. These are Darwinian medicine, evolutionary epidemiology and evolutionary oncology. Working in the field of evolutionary oncology, we propose to solve some biological problems. Thus, depending on the tasks set, we can talk about a new oncological theory or a new biological theory. This does not contradict one another, but mutually complements each other.

– Andrey Petrovich, was oncopathology laid down evolutionarily?

– This is an interesting question. After graduating from St. Petersburg University, I joined the graduate school of the N.N. Petrov Institute of Oncology in St. Petersburg. This is the first Russian and Soviet Institute of Oncology, which was founded by the outstanding oncologist Nikolai Nikolaevich Petrov. And after university, we passed the candidate's minimum according to Petrov's book "General Oncology". There I read for the first time and was very surprised that tumors are peculiar not only to humans, but also to animals and plants. It was a revelation.

– I knew about animals – but plants?

– Yes, and plants. But this is still a revelation for many. I remember doing a report at the National Cancer Institute in the USA, where, by the way, I also studied as a postdoc. And there, one senior researcher, a geneticist, says to me: "What, are tumors not only in humans?" You understand, an outstanding institute – and they do not yet know that tumors have an evolutionary character peculiar to all living things. Biology is a very big, very complex science, it diverges, already deals with the tips of branches and the tips of leaves on these branches. She is following the path of specialization. But we need to cover all the foliage. That's what new theories are for.

– After all, Andrey Petrovich, when did the malignant neoplasms appear? Were they originally laid down in the nature of the same person or did they appear over time, evolutionarily?

– Evolutionarily, tumors appeared a long time ago. Comparative oncology began in the XlX century, and after humans, tumors were first found in domestic animals, and then in fish that we eat. Comparative oncology has accumulated so much material over the entire XX century that it can now be argued that tumors are spread throughout the phylogenetic tree. This is the first.

Second. It turns out that oncogenes and tumor suppressors are the oldest classes of genes after household genes. It means that someone needed it, and from the earliest stages of the evolution of multicellularity. It is interesting that we did this specifically and published an article in a good magazine in 2019. There were great responses to it. We found out that the evolution of oncogenes and suppressor genes goes in parallel with differentiation genes. This was predicted by our theory and proved with good statistics that the evolution curves practically coincide. This is the second part of the answer to your question: tumors are an ancient phenomenon.

– And not just ancient, but also necessary for evolution.

"That's right. If we move in line with modern biological theories, then none of them solves the problem of cancer. Of course, science does not stand still, many successes have been achieved, but there are also many cancers. There are not fewer of them – rather the opposite. Nature encourages the creation of new hypotheses and theories. They do not arise from scratch. There are questions that need to be answered. And the number of these questions is increasing.

– Humanity perceives cancer as a terrible enemy that we must defeat. It turns out that this approach is wrong?

– Not quite right. The fact is that the concept of a tumor is broader than the concept of cancer. Cancer is only some consequence of a tumor. But we know that there are benign and malignant tumors. And it is clear that doctors are interested in malignant, and benign – well, why be interested in them if there is no problem?

When they began to deal with the problem of early diagnosis, they found a huge number of tumors of unknown kind. The clinicians did not understand where to take them. It turns out that early diagnosis gave the growth of the problem, and not vice versa. And the mortality rate did not grow. And this difference between the number of detected cases and the number of deaths began to be called "pseudo-diseases". There is something that defies explanation. It turns out that the problem is much broader than just malignant tumors, and we need to understand why not all tumors kill. If we understand this, then we will cope with malignant tumors. For many years, it was believed that tumor tissue was not needed. But this is not the case. Tumors are by no means useless tissue, it is important and can participate in a variety of processes.

– Well, for example?

– First of all, it is, of course, excess cell mass. We see that progressive evolution has always been associated with the generation of additional cell masses. At the expense of what? We know that there are stem cells, and they divide and regulate all the time depending on functional needs. If they violate this regulation and this feedback, it is already an autonomous process, and it is already a tumor. That is, it turns out that wherever you throw, we come to tumors all the time.

Now look: in tumors, it turns out, a significant number of genes are activated and expressed, which otherwise do not work anywhere. According to our theory, which we have confirmed experimentally, evolutionarily new genes are activated in tumors. Especially genes associated with morphological innovations and with new functions, such as, for example, the immunoglobulin locus.

– I heard that, according to your theory, it was tumor cells that became the precursors of many organs of the human body.

– Yes, and we confirmed it. If evolutionarily new organs originate from some tumor structures, then they must have signs of tumors. Such evolutionarily new organs are the placenta, mammary gland and prostate, and there are many signs of tumors. They all invade in the process of their development. We observe regulated invasiveness in the placenta, breast and prostate.

– And all these are reproductive organs, which is interesting.

– In my book, I analyzed an example of a placenta. I even came up with a name – "tumor-like organ". The placenta has a lot of tumor signs. After the book was published, a conference was held in Europe on the similarity of the placenta to tumors. People who study the placenta have arrived. They asked – it is clear that there are many similarities, but are there any differences? There is one difference – regulation. It turns out that the placenta is a regulated tumor, that is, it is a tumor that has acquired a function, and it is regulated.

– And the mammary gland and prostate?

– The same thing. The youngest organs, the most affected by cancer. It turns out that they pull tumor signs behind them. They originated from tumors. Therefore, they are more affected by cancer than other organs. Back in my student years, I noticed some signs of fatty tissues, which indicate that this is an organ. We mammals have three or four adipose tissues: white, brown, beige and bone marrow. And it turns out that they function as a single body. Many people say that adipose tissue is an endocrine organ. But not only endocrine – it is an organ that provides and regulates energy metabolism and glucose metabolism. That is, it is an organ. It is dissected anatomically, consists of several depots, which are innervated by separate bundles and supplied with blood vessels.

Now on. It turns out that despite the fact that fat metabolism is an ancient sign, because energy is stored in the form of fat droplets, the organ is evolutionarily new for mammals. It also happens that way. Brown adipose tissue is generally found only in mammals. It turns out that the number of characteristic signs of a fatty organ reaches a maximum in mammals.

– If it is a young organ, then it must have tumor signs?

– Yes, and I started looking for them. And I found all the main tumor signs. Theory is like a lamp. Everything works in theory coverage. We turned on another flashlight, which tells us what follows from where.

– What follows from this?

– The fact that obesity is an oncological problem. This is our very recent discovery. The N.N. Petrov Institute of Oncology held an All-Russian webinar on the topic "Tumor signs of human adipose tissues" last month. Oncologists are very interested in this. It turns out that we will be able to potentially combine different categories of technologies that have been developed to combat obesity and to fight cancer.

– Andrey Petrovich, any theory can be formulated. How do you formulate your theory?

– All theories have a well-established structure. Every theory should have a basic hypothesis. Our main hypothesis is that inherited tumors in the early stages of progression in the process of evolution provide an evolving multicellular organism with additional cell masses for the expression of evolutionarily new genes that arise in the germ plasma, and not in tumors. That is, a tumor is a polygon of expression, and thus tumors contribute to the emergence of new types of cells, tissues and organs.

In addition, the structure of the theory includes non-trivial explanations, non-trivial predictions, analysis of connections with other theories. One of the signs that the theory was born is the publication of a book, a monograph on this topic. In our publications, we have cited fifteen hundred links. We have made a number of non-trivial predictions, confirmed experimentally, and given a number of non-trivial explanations.

In particular, we explain what is a transitional form in the step of complication of progressive evolution. In our opinion, these are populations of tumor-bearing organisms. They can be invisible in the paleontological chronicle even when, apparently, there was a jump. A tumor in this sense is a search engine. It turns out that for transitions, evolutionary leaps, we need an intermediate state, metastable, not very stable, maybe pathological, but it provides this transition.

– I know that your students are already doing experiments according to your theory. And what do these experiments demonstrate?

– Yes, they are eager to fight. The most nontrivial prediction is that evolutionarily new genes should work, activate and express themselves in tumors. And these genes were discovered by us. It turned out that this group of genes are potential targets for antitumor technologies. And another prediction is that tumors can acquire functions in the body. Using the example of goldfish caps, we proved this experimentally. This cap, which was selected for beauty by breeders, is actually a benign tumor. On the one hand, she has all the signs of a normal organ – symmetry, localization, anatomical development at certain stages. And, on the other hand, she has signs of a tumor. It grows so huge that the fish swims up with its fins.

– That is, this hat hinders her.

– It covers the eyes, the gill slits. This cap is an evolutionarily young organ. Like the prostate in men. This is a benign tumor that grows throughout life, and almost all elderly men have prostate adenoma. That is, it is an organ that has not yet completed its formation. And understanding this is very important to us. If this is the case, we must learn to live with tumors.

– That's exactly what I wanted to ask you. It turns out that not in all cases we need to fight the tumor. Do we need to learn to live with it so that we don't harm each other?

– It is necessary to fight, but the struggle for complete destruction is the paradigm of the XlX century, the paradigm of the "magic bullet" of Ehrlich.

– Yes, and now it is.

– But it's time to change the paradigm. The "magic bullet" paradigm is an outdated ideology of the late XIX – mid XX century. It turns out that chemotherapy kills the immune system and much more.

– Often it's not cancer, but chemotherapy that kills a person.

– Increasingly, clinicians say that it is not necessary to kill the immune system, let's somehow control the tumor. This leads to the concept of adaptive, suboptimal, and immunological therapy, which is now making huge strides. And we are trying to understand this mystery evolutionarily.

– How do your colleagues and doctors perceive your theory?

– The best listener is a clinician. It would seem that a person who heals every day and sees death every day is not the most grateful listener to evolutionary texts, but it turns out that this is exactly the case, because theory opens his eyes, he sees new ways, and it is only necessary to find them somehow. That's what we're trying to do.

– What exactly have your predictions already come true?

– Many years ago I predicted that if the theory is correct, the number of oncogenes should correspond to the number of types of differentiated cells. If there is an evolution with the help of tumors – and oncogenes are associated with tumors – then how many types of cells are differentiated, there should be about as many oncogenes. When we started the study, 12 oncogenes and about 200 types of differentiated cells were known. Now there are about 400 cell types and about 300 oncogenes. And oncogenes evolve in parallel with differentiation genes. Here's an example of a prediction that worked.

There are a number of other predictions. For example, we say that there are evolutionarily new genes that work in tumors. Students immediately say: "And let's calculate in the computer how they evolve, these genes?" And we do it – we look at evolutionarily new fish genes. Some of them are expressed in the tumor. According to the theory, they should acquire progressive functions. All right. We discovered that orthologs of evolutionary genes of fish that worked in fish tumors give progressive signs in humans. They are never found in fish – this is the placenta, mammary gland, prostate, lungs, cerebral cortex, cardiac septum. That's what these genes give.

And then we became interested in the fat organ – that it is an evolutionarily new organ in humans and all mammals. I say, "Stop! And how do our genes behave there?" We described 23 genes in the article. Five of them work in the fat organ. And these same genes work in the prostate. This means that we have discovered some kind of network of evolutionarily new genes in fish, which in evolution led to the development of several progressive traits in humans. It's fantastic, and it's very interesting. Now we are going to create an experimental model for studying these genes at the Institute of General Genetics.

– Andrey Petrovich, how do you imagine the model of medicine of the future, where your theory has already been implemented? For example, a person comes for a preventive examination to a doctor, and they carry out some kind of genetic analysis, look at what his predispositions are, give specific recommendations. What might it look like in your opinion?

– I think it will be connected with computer analysis. We have a supercomputer center at the Polytechnic University, where they can calculate anything, but it's not always clear what. We must set clear objectives. We come to the conclusion that progressive evolution is a search very similar to computer search – calculation and search in the space of unrealized possibilities. There is a space of realized opportunities, and there is a space of unrealized opportunities. Moreover, entities from the space of unrealized possibilities are Popper's teachings, which are called "entities in the process of becoming". And it turns out that they can be counted. An evolutionarily new gene that has not acquired a function is an entity in the process of birth, becoming. It turns out that all of nature in general, and biological nature in particular, is some kind of giant supercomputer that is constantly calculating something. The evolution of the genome, the origin of evolutionarily new genes is nothing but a calculation in the space of unrealized possibilities. This is the coding of proteins that have not yet occurred. This is a calculation.

And then the search begins. One of the predictions of the theory is that the tumor is such a search engine. There is a selection for gene compatibility, and what is combined is frozen by selection. This is internal causality, or Berg's nomogenesis. When we include external entities, Darwin selection begins. This giant supercomputer calculates the universes where the largest number of compatible entities are realized. That's the amazing thing.

And so the answer to your question is we will turn on the computer. A person comes, we turn on the computer and conduct a genetic analysis, predicting his capabilities and his risks. And we help to avoid some risks, and live with some. This is the model of preventive medicine of the future.

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