Cancer: The Cruel Cost of Biological Evolution

2019-12-30 | Back to Park original |

The genome has undergone profound changes not only in the evolution of millions of years, but also in the life cycle of individual organisms. Regarding the latter, the most extreme example is the world's second largest killer-cancer.Fear, but it opens a fascinating window for us to understand the evolution of the past.

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Writing | Paul Davies

Translator | Wang Pei

Cancer: The Cruel Cost of Multicellular Organisms

The genome has undergone profound changes not only in the evolution of millions of years, but also in the life cycle of individual organisms. Regarding the latter, the most extreme example is the world's second largest killer-cancer.Fear, but it opens a fascinating window for us to understand the evolution of the past.

Cancer is not strictly defined. On the contrary, it has about 12 signature characteristics. Human advanced cancer may show all or some of its characteristics. These characteristics include: a rapidly increasing mutation rate,Unrestricted cell proliferation, ineffective mechanisms of apoptosis programmed cell death, immune escape, angiogenesis formation of a new blood supply system, changes in metabolism, and metastasis that is, cancer cells tend to spread throughout the body and invade awayOrgans of primary tumors, a medical problem that is now widely known.

In the field of biology, cancer is the most researched topic. In the past 50 years, more than 1 million related papers have been published. Therefore, you may be surprised that we have not yet defined the cancer, cancerThe cause and the story of how cancer is embedded in the life of the planet have been reached. People rarely understand cancer as a biological phenomenon, but instead treat it as a disease that must be eradicated anyway. Most of the huge scientific research in the worldResources are used to destroy cancer, however, standard cancer therapies—a mix of surgery, radiation, and chemical toxins—have remained almost unchanged for decades. [1] With the exception of a few cancers, cancer survival rates are only marginalIncreased, or no improvement at all. After all, chemotherapy is often the last stroke that can only extend lives for weeks or months instead of years. We can't blame this frustrating fact on the lack of scientific research funding. Since Nixon took office in the United StatesSince the president declared war on cancer in 1971, the US government alone has spent $ 100 billion on cancer research, and charities and pharmaceutical companies have also investedBillions of dollars.

Research has made little progress. Could the reason be that scientists are wrong about the way cancer is treated? There are two common misconceptions about cancer, namely that cancer is a "modern disease" and it is mainly harmful to humans. These are bothNot the truth. Cancer or cancerous phenomena can be found in almost all mammals, birds, reptiles, insects and even plants. Research by Athena Aktipis and his collaborators suggests that cancer or cancerous phenomenaIt is found in all multicellular organisms, including fungi and corals see Figure 1. Examples of cancers can even be found in lower animal leeches.

Figure 1 Cancers spreading throughout the tree of life

The fact that cancer is so widely distributed among species points to its ancient evolutionary origins. For example, the common ancestor of humans and flies can be traced back 600 million years ago, and the convergence point of the broader category of cancer-susceptible organismsIt goes back to 1 billion years ago. This means that cancer has always been accompanied by multicellular organisms metaplastic animals, and this is reasonable. It goes without saying that cancer is a physical disease, so it is said that a single bacterium has cancer.Meaningless. However, the "body" does not always exist. For up to 2 billion years, life on the earth was only a single-celled organism; about 1.5 billion years ago, the first multicellular organism appeared, this geological age is calledProterozoic It means "earlier life" in Greek. [2]

The conversion of life from a single-cell form to a multi-cell form is bound to bring a fundamental change in the logic of life. In the world of single-celled organisms, there is only one order: copy, copy, copy! In this sense,Unicellular organisms are immortal. However, multicellular organisms are completely different. Immortality has been "outsourced" to specialized reproductive cells such as sperm and eggs, and their job is to pass the organism's genes to offspring. At the same time, asThe carriers of these germ cells, the bodies of multicellular organisms also behave completely differently from single-celled organisms, and they will eventually die. The cells of the body somatic cells retain the weak echo of their past immortal state, that is, limited replication capacity. For example, A typical skin cell can divide 50 to 70 times.

When a somatic cell reaches the end of its useful life, [3] it either sleeps a so-called aging state or commits suicide apoptosis. But this does not mean the end of the organ, because the same type of replacement cellsWill be made from stem cells. But eventually the replacement process will be exhausted, and the entire body will die, leaving only the germline offspring if any to pass on the genetic heritage.

Since it will die after a brief explosive replication, why do any "normal" cells participate in the survival of multicellular organisms? In the great evolutionary survival game, this approach is likely to obtainWhat are the advantages? There is always a trade-off in biology. By adding a population of cells with similar genes, a particular cell will contribute to the spread of most genes through germ cells. If a single population of cells as a whole does not haveSurvival function, the genetic heritage algorithm will be biased towards groups rather than single cells. When the algorithm seems correct, an agreement will be reached between individual cells and organisms. Single cells join the "collective project" and die in return,Organisms assume the responsibility of transmitting the genes of cells. Therefore, in multicellular organisms, there is a “contract” between the organism as a whole and its cell members, which was signed as early as 1 billion years ago in the Proterozoic.

Multicellular organisms are a good idea, they are the basis for human beings; but they also have disadvantages. When individuals join groups and work together, it is easy to deceive. This is a common phenomenon in human society, and people from organizedThe government receives subsistence benefits such as defense, health, and infrastructure, but also needs to pay taxes. As everyone knows, there are always people who intend to swindle benefits to avoid paying taxes. This phenomenon exists around the world. To solve this problem, the government has formulated a number ofRules eg, Australia ’s tax law is one million words long; in the United States, tax regulations are almost beyond imagination. The government and law enforcement agencies then monitor the implementation of these regulations. Despite careful design, the tax system is still incompleteThere is an "arms race" between scammers and law enforcement-Internet scams and identity theft are the main examples of the moment. Similar arms races will be staged in multicellular organisms. In order for individual cells to comply with the contract, layers must be carried outLayers, and are supervised by the organism as a whole, thus deterring the crooksTherefore, a particular somatic cell skin cell, liver cell, lung cell, etc. usually only divides if allowed by the rules. When more cells of this type are needed, the "replication" inside the cellThe "program" will handle it by itself. But if the division is not correct, the regulatory mechanism will intervene to prevent it from dividing; if the cell is disobedient, the regulatory mechanism will sentence the cell to death-apoptosis. One of the cases about strict law enforcementOccurs when a cell is found to be in the wrong tissue environment. For example, if a liver cell is accidentally transported to or intentionally transplanted to the lung, the cell will not pass well in the lung. From the lung tissueThe chemical signals realized that they had an intruder here "It's not one of us!" And could have sentenced this intruder to death.

In multicellular organisms, what does deceptive behavior mean to a cell? It means that this cell defaults to the self-serving strategy of single-cell life: replication, replication, replication. In other words, uncontrolled cellsProliferation or cancer. In simple terms, cancer is the destruction of an ancient contract between somatic cells and organisms, and each cell returns to a more primitive, selfish living state.

Why did the law enforcement operation fail? There are many reasons. One of them is obvious. The "police" gene is damaged by radiation or carcinogenic chemicals. There is a group of genes that can suppress tumors. The most widely known is the p53 gene. If p53 is affectedOnce destroyed, the tumor may not be suppressed. Another trigger is immunosuppression. The role of the adaptive immune system includes cancer monitoring. If the system works properly, it can detect early cancer cells and before they cause troubleKill or imprison and suppress them. But cancer cells can chemically hide themselves to avoid immune surveillance. They can also recruit "scouts" macrophages to make these "scouts" look like captive spiesIt also works for them, thereby destroying the immune system. Tumor-associated macrophages TAM shelter the tumor and prevent the immune system from attacking.

The occurrence of cancer has two indispensable conditions: one is that the normal cells adopt a deception strategy, and the other is that the regulatory system in the body fails somewhere. The conventional explanation is the somatic mutation theory. According to this theory, because of aging,Radiation or carcinogenic chemicals cause cell misbehavior and rogue. Gene damage accumulates in somatic cells and begins to act on their own. As a result, neoplasms—new cell populations—will develop rapidly this is the orthodox theoryThe salient features I mentioned in the previous article include uncontrolled cell proliferation and the tendency of cancer cells to spread throughout the body and invade distant organs. Somatic mutation theory assumes that in each host, only through a certain type of rapidDarwin's natural selection process can recreate the same cancer characteristics from scratch. In this process, the most adaptive and most dangerous cancer cells will defeat their competitors by quickly replicating, eventually killing the host and themselves.Despite its solid position, somatic mutation theory has little predictive power, and its explanation and case-basedThe story of "what it is" is almost the same. What's more serious, it can't explain why the mutation can be in such a short period of time yes, emphasize this point again, giving a single neoplasm so much to improve its adaptability.Obtained. Increasing genetic damage and defects have given a neoplasm such powerful new features and so many predictable features, which also seem to contradict itself.

Tracking the Deep Evolutionary Roots of Cancer

In the past few years, my colleagues and I have traced the origin of cancer in the distant past, and proposed a slightly different interpretation. We were surprised at the fact that cancer is almost nothing new. InsteadIt just misappropriates the existing functions of the host organism, many of which are very basic and ancient. For example, unlimited proliferation is the basic characteristic of single-cell life for billions of years. After all, the continuation of life requires replication, and cellsYou can learn how to continuously face various threats and challenges for billions of years. Cancer cell metastasis is the process by which normally fixed cells become mobile, leave the tumor and spread throughout the body. This is similar to the early stage of embryogenesis:Mature cells are not usually anchored in one place, but appear in large numbers in various locations in an ordered pattern. Circulating cancer cells tend to invade other organs, which occurs almost simultaneously with the immune system's inability to heal wounds. TheseThe facts well understood by oncologists, coupled with the predictable and efficient way of cancer's progression at different stages, lead us to believe thatCancer does not refer to the situation where damaged cells randomly kill normal cells, but an ancient, well-organized and effective response to the stress of survival. [4] It is important that we consider the various distinctive characteristics of cancer andNot evolved independently with the emergence of neoplasms meaning that these features occur by chance, but are intentionally turned on and used systematically as part of an orderly response strategy for neoplasms.

In short, our view on cancer is: it is not the product of damage, but a systemic response to the damaging environment-a primitive cellular defense mechanism. Cancer is a way for cells to respond to harsh environments. It may be affected byThe mutation triggered, but its root cause was the self-activation of an ancient deep-embedded toolbox for emergency survival procedures. [5] The key difference between the two theories can be illustrated by an analogy. One is bullied on the playgroundFor his child, his survival strategy is to escape. This behavior is self-driven. The attacker's push and fist will trigger the escape behavior of the victim, but this is not the root cause for the victim to escape-heNot being pushed away, but spontaneously running away. Let's look at another analogy. If a computer is attacked possibly due to software damage or mechanical shock, it will start safe mode see Figure 2.This is a default program that enables the computer to run its core functions even if it is damaged. Similarly, cancer is also a default state, threatened by detailsWill run its ancient core functions, thereby preserving its important functions, of which proliferation is the oldest, most important and most protected function. The threat that triggers cancer is not necessarily radiation or chemicals, it may also be caused by aging tissues,Hypoxic tension or various mechanical stresses, including injuries even electrical interference. There are many factors that alone or collectively cause cells to adopt its built-in "cancer safety model."

Figure 2 Interface for selecting safe mode When encountering a startup problem, a similar message may appear on your computer screen. It indicates that there is some kind of damage that causes the computer operating system to run only its core functions until the problem is solvedSolve. Cancer can do something similar, running the default core cell functions—a function that evolved from more than a billion years ago—while ignoring or disabling certain newly evolved additional biological functions.

Although the elements of the cancer's default procedure are very old and can be traced back to the origin of life, some more delicate features appeared later in the evolution process, especially during the period from 600 million to 1.5 billion years ago.At that time, primitive metazoans had just emerged. In our opinion, cancer is a phenomenon of ancestral reversion or the default ancestral form; expressed in technical terms, it is a ancestral phenotype. Because cancer is deeply implanted in multiple cellsIn the logic of life, its ancient mechanism has been well preserved and desperately protected, and fighting it is bound to be a difficult challenge.

Our theory makes a lot of specific predictions. For example, we expected that those genes that are causally related to cancer commonly referred to as oncogenes accumulated in large numbers during the emergence of multicellular organisms. We have no evidence for this.Yes? By comparing the number of genetic differences in many species, it is possible to estimate the age of a gene based on genetic sequence data. This tried-and-tested technique is called "phylostratigraphy," which scientists can use toReconstructed the life tree, deduced from today's common characteristics, and deduced their convergence points in the past see Figure 3.

Figure 3 Tracing the history of the tree of life Since Darwin first drew a tree of life to represent species differentiation over time, biologists have begun to try to reconstruct life history using fossil records. Now they are alsoUse a technique called "evolutionary ageing" to determine the common ancestors of ancient times based on the genetic sequences of multiple species. The tree of life in the picture shows the three major life domains derived from a common ancient origin.. The length of the line segment represents the genetic distance. The last common ancestor of this tree of life lived 3.5 billion years ago.

A study in Germany used 4 different cancer gene datasets, and the results showed that the peaks in the markers of these genes appeared at the time when metazoans began to evolve. Recently, David Good and Anna Te from Melbourne, AustraliaRiggs led an analysis of seven tumor types with a focus on gene expression. They divided genes into 16 groups based on age and then compared the expression levels of each group of genes in cancer tissues and normal tissues. ResultsIt's amazing, as we predicted, over-expressed oncogenes belong to two older groups, while under-expressed genes belong to younger groups. In addition, they found that as cancer progressed toIn the more aggressive danger phase, older genes will be expressed at higher levels. This confirms our view that the development of cancer in the host organism can quickly reverse the goal of evolution, allowing cells toOr return to its original ancestral form within a few months. In a more general sense, the Australian research team found thatEvolutionary genes, genes related to single-celled organisms are more active in cancer cells.

In a related study we conducted at Arizona State University, we examined the mutation rate of genes. The ancestral theory predicts that older genes have a lower probability of mutating in cancer cells after all, their role is to run "safe modeProgram, and younger genes are more likely to be mutated in cancer cells. My colleagues Kimberly Percy and Luis Sisneros examined a total of 19,576 human genes and used the British Sanger StudyThe institute compiled a database called "COSMIC" Cancer Somatic Mutation Catalogue. They combined this data with a gene sequence database containing about 18,000 species, including a gene sequence database covering all taxonomic groups that can be age-evolved.Analysis. This allowed my colleagues to predict the evolutionary age of genes in the human genome. They found that genes that were created 500 million years ago are indeed more likely to mutate this is true in normal tissues, especially in cancer cells; And as we expected, genes that were mutated 1 billion years agoThe rate is lower than the average. They also confirmed the German study that the onset of the oncogene [6] dates back to the emergence of multicellular organisms. The results of this research support our view that cancer is driven by functional disruptionIt is these functional evolutions that have produced multicellular organisms. The COSMIC database divides genes into dominant and recessive. My colleagues found that recessive oncogenes are significantly older than most human genes.

The most powerful research result comes from a completely different question: What are the benefits of oncogenes to organisms? A genetic annotation tool called "DAVID" annotation, visualization, and integrated discovery database organizes genes by function.When Sisneros and Percy input COSMIC data into DAVID, the results showed that recessive oncogenes produced 950 million years ago were enhanced in two core functions: cell cycle control and DNA double-strand break damage DNAThe most severe damage suffered repair. By investigating the evolutionary history of genes, researchers have made important discoveries. In the same DNA repair pathway, non-mutated genes [7] are equivalent to those in bacteria that drive response to stress.Adaptively mutated genes. Just like in bacteria, these genes' role is to survive by evolving a way out of the predicament, trying to increase the mutation rate of the cell, and thus survive. I explained Susan Law in the previous articleSunberg's discovery is that when bacteria sense a double-strand break in DNA, it switches to a hasty messy repair mechanism.Which one created a series of errors mutations. We would like to know if the cancer cells will also switch to destruction mode during double-strand repair? The answer is yes. My colleagues studied 7 different cancers pancreatic cancer, Prostate cancer, bone cancer, ovarian cancer, skin cancer, leukemia, and brain cancer of 764 tumor samples, of which 668 tumor samples showed the accumulation of mutant oncogenes around DNA breaks. This is completely consistent with our theory.Consistent, that is, stressed cells will re-awaken the ancestral gene network and generate high mutation rates, which will cause cancer. Therefore, one of the most well-known characteristics of cancer this is why it often allows chemotherapy by evolving resistant variantsFailure is self-harm. This research result also well supports the theory of ancestral return: cancer just misappropriates the ancient stress response mechanism. Today, bacteria still use this mechanism, and its evolutionary origin can be traced back to single-cell life.

Just like the bacteria facing the pressure of survival, the mutation of cancer cells is not random, but there are certain mutation "hot spots" and "cold spots" regions with a low mutation rate. This makes sense. Multicellular organismsEfforts should be made to protect key parts of their genomes, such as those responsible for the core functions of cells; and, at the same time, invest less resources in additional functions related to newly evolved and less important traits.A project led by Robert Austin and Amy Wu to put cancer cells in a therapeutic toxin doxorubicin and study the evolution of their resistance to the drug. TheyFound that cold spot genes are significantly older than average. These new findings help explain why natural selection does not eliminate the scourge of cancer. If tumors are really a way to return to ancestral form, we can expect to drive cancerAncient ways and mechanisms have the strongest protection and preservation capabilities, because they can achieve the most basic of lifeFunction. It is impossible for organisms to get rid of these pathways and mechanisms without disasters coming to the relevant cells. The mutation gene [8] we studied is an example.

Another reason for the failure of evolution to eliminate cancer is related to embryogenesis. Thirty years ago, we discovered that some oncogenes play an important role in embryonic development. If these genes are eliminated, it can lead to catastrophic consequences. Generally speakingThese developmental genes remain silent in adult organisms, but if something awakens them, it can cause cancer, which is like an embryonic developmental error in adult tissues. Regarding this, the author George Johnson To sum it up well, he called the tumor "the evil twin brother of the embryo." Obviously, the early developmental stage of the embryo is the process of establishing the basic shape and configuration of the organism, representing the earliest stage of multicellular organisms.The very different environment that is faced in early embryonic development. When the oncogene switch is turned on, the genes and epigenetic regulators of the information flow will be systematically disturbed. This disturbance involves both changes in the way the regulating genes are connected and also involvesChanges in gene expression patterns. Our research team is trying to find these changesWe hope that, in addition to confirming the physical characteristics of cancer I mentioned in the previous section, it is also possible to identify unique information characteristics of cancer. This information characteristic is like an indicator software that can be used in the clinical analysis of cell and tissue morphology.Before changes are noticed, cancer is predicted to provide early warning.

The ancestral theory of cancer is important not only for the diagnosis of cancer, but also for treatment. We believe that seeking a universal cure for cancer is just a waste of time and money. Realizing that cancer is deeply rooted in the body of multicellular lifeAfter that, we can challenge cancer through material conditions that are not conducive to its ancient ancestral lifestyle, and better manage and control rather than eliminate cancer. When facing this deadly disease, only full understandingThe position of cancer in the entire evolutionary history will have a significant impact on human life expectancy.


[1] Recently, the fourth treatment option-immunotherapy-has received a lot of attention. It destroys cancer cells by pressurizing the body's immune system. Early research results show that it has a bright future, but we must know thisIt's too early to say whether technology will have a revolutionary effect.

[2] Multicellular organisms have appeared independently several times, but true multicellular organisms are limited to eukaryotes. However, bacteria can accumulate in large numbers and sometimes show cancer-like phenomena.

[3] When will this be? It is when the "little hat" called a telomere at the end of the chromosome is worn out.

[4] As before, "stress" here refers to a threatening microenvironment, such as carcinogens, radiation, or hypoxia. "People with high psychological stress may develop cancer"The widely disseminated view is not significantly related to the physical stresses I'm discussing here.

[5] The difference between a trigger and a root cause is like running a basic and commonly used computer software package, such as Microsoft's word processing software Word. The "Open" command triggers the word processing software, but makes itThe root cause of this phenomenon is word processing software, which appeared in the early computer industry.

[6] In this study, it refers to genes that have been proven to have a causal relationship with the development of cancer.

[7] In technical terms, they are called "interspecific homologous genes" of those genes in bacteria.

[8] Mutagenic genes: Genes that can increase the mutation rate of genes .—— Editor's Note

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