On various occasions, we separate problems as acute or chronic, whether between two nations, two persons, or health conditions. What separates acute and chronic appears to be time. However, what exactly does time contribute to separating acute and chronic? When we seek a solution, can we take the same approach? In other words, what is the fundamental difference between acute and chronic problems?
When we approach a problem, we believe that breaking down the problem to identify its cause is the way to solve the problem. The reductionist approach. In this background, there is our naïve trust in the cause-consequence relationship. For a consequence (i.e. a problem) to occur, a cause should exist. Without a cause, there is no consequence, thus no problem. We trust removing the cause is the best strategy to restore the original condition, whatever the original is.
As you can imagine, defining the original condition is more challenging than many think. The original condition is highly arbitral. The original condition is the condition before the problem emerged. That is the condition that permitted the problem to occur – the permissive condition for the problem. Then, there should be the original original-condition that permitted the permissive condition to occur and so on. How far should we go back?
The cause-consequence relationship is inevitably context-dependent. The identical cause may lead to a different consequence in a different context. The context is as important as the cause. However, when dealing with a problem, we focus on the cause, not the context that permitted the consequence.
The original condition is often the context with temporal stability. Temporal stability is like balancing a bicycle but not fixed stability like a brick wall. Temporal stability is achieved by constant compensations—balancing at an equilibria state.
Chronic problems are chronic because early minor issues did not cause phenotypic consequences but compensated. Superficially, nothing has changed. But internally compensated. The superficial phenotypic condition is maintained as a balanced point despite minor issues. Imagine riding a bicycle with a bag carrying a heavy bowling ball on one side of a handlebar. It's unstable, but you can manage it. However, kids who have just learned to ride a bicycle cannot balance it because they cannot compensate for the imbalance. Perhaps there would be no issue if you took a paved, open, wide road. How about a gravelled road with up and down? Maybe there is one little rock letting the tire slip, and you fall.
The little rock is the direct cause of your fall—there is no doubt about it in hindsight. However, does the removal of this little rock solve the problem? Partly, yes, because the cause was the one little rock. You will never fall again based on the same tiny rock!
What is the context of the whole situation? The rock? The gravelled road or up and down? Or the bag? Or the heavy bowling ball? Or it would be best if you did not take a bicycle in the first place. Instead, you should have taken a three or four-wheel cycle. What allows you to take a bicycle? Your ability to ride a bicycle in imbalanced situations. Your balancing skills permitted you to avoid falling under other conditions. What was the fundamental cause of your fall? Where was the start? Could it be prevented?
In this example, all statements are hindsight. The fall happened because you had thought you would be Okay and had never imagined it. The fall was out of your imagination. You did not recognize the amount of compensation (we can rephrase this as stress) you had already invested.
A chronic issue differs from an acute one because the internal condition before the problem is already the consequence of highly complex compensations. This condition is phenotypically normal. However, the internal condition of the highly compensated state is entirely different from the initial condition.
Since each compensation process is always immediate and reactive against insults, the history of insults matters—not simply the types of insults but also their order. Notably, each compensation process is not predictive and retroactive. Thus, first come, first served. Even if the first and second insults are independent, the compensative reaction to the second insult could be constrained by the first reaction. The potential sequence and variation of insults are infinite. However, compensatory reactions against them are often limited. Thus, the history of compensatory reactions converges into several patterns but not infinite variations.
Chronic problems occur only in the complex compensatory system. This system can react to external and internal changes with thresholds of responsiveness but not in an immediate linear way. All insults under the thresholds are compensated and thus do not surface as the observable phenotype. However, the system gradually drifts away from the initial balancing point at the expense of the compensatory ability. In this unique condition, a tiny insult that used to be under the threshold can easily cause acute catastrophic problems. Imagine earthquakes or avalanches.
The most important realization is that a chronic condition cannot be created acutely because the sequence of events, not only the length of time, is the matter that permits the growth of chronic problems. The complexity of chronic issues comes from intrinsic compensatory reactions. The individual problems are often minor and straightforward, thus compensated. In other words, nothing is acutely problematic, and everything is working as it should. Therefore, the problem eventually arises at the nested highest level, where no more compensation is available.
Cancer is a chronic disease. It goes unnoticed until very close to the end. Why? Because all steps of carcinogenesis are compensated. Therefore, it is fundamentally unnoticed. Minor molecular problems are compensated at the cellular level, minor cellular problems at the tissue level, and minor tissue problems at the systemic individual level. When the capacity of compensation, an aggregate of interdependent networks, is past the tipping point, the system will collapse catastrophically. The patient dies.
What is the cause of cancer? Some may answer malignant cells. Malignant cells are cells that carry malignant mutations. A normal cell transforms into a malignant cell through unfortunate mutations and gains proliferative characteristics. Then, its progeny does terrible things to us. This is the central view in current cancer research, the somatic mutation theory (SMT). Mutations drive a cell to be malignant. Based on their superpower created by mutations, malignant cells proliferate, invade, metastasize, manipulate their surroundings, and evade the immune system. We do not notice their progression because malignant cells are highly clever and manipulative. They are smart enough to kill the host at the end.
Can you believe that? I do not. This sounds quite different from the paragraph I wrote above.
The idea of mutation-driving cancer is developed from cancer research, particularly cancer modelling, but not from the observation of cancer patients. Pathologists are the people who observe cancer at the microscopic level and have been serving to diagnose cancer since more than a century ago, before the identification of DNA. Pathologists primarily diagnose cancer based on microscopic views of cells, nuclei, and tissue structures but not the mutations within cells. Searching disorganization compares to normal organization.
Pathologists’ view of cancer is represented as a wound that does not heal: disorganization and inflammation. The tissue organization field theory (TOFT) was proposed in this line of thought. The TOFT suggests that the disorganized tissue structure itself is cancer. Notably, both mutations and disorganization always occur in cancer patients.
We must admit that the naïve belief of cause-consequence highly constrains us. When something happens (i.e. recognizing anomaly or changes compared to normal), there should be a cause. A cause that initiates the consequence - from one point (i.e., start) to another (i.e., goal); in between, there is a connection of a line (i.e., process). This view does not consider the preexisting circuits of compensation – the context. Our body has many nested layers of contexts, such as molecular interactions within a cell, cellular interactions within a tissue and hormonal interactions within an organism. The organism is a compensatory system as a whole because it consists of interconnected nested layers of multiple circuital networks.
In the compensatory system, neither mutations nor disorganization is the simple cause, but both contribute to disease progression. Mutations and disorganization are part of the cause and simultaneously the consequence of the other, creating a positive feedback loop.
‘Mutation’ is the word regarding the sequence, and ‘Disorganization’ refers to geometry. These words belong to two different contexts. Do mutations cause disorganization, or does disorganization cause mutations? What connects these two words belonging to two different contexts?
Do mutations cause disorganization? This is the belief of the SMT and most current cancer researchers. Various combinations of multiple oncogenic mutations in mouse models can cause tumour formation and mimic cancer-like symptoms. Mutation combinations are sufficient to create acute cancer-like conditions in mice. A few models can be considered chronic, taking a year or more — but still much faster than human patients. In addition, generally, in those models, the number of cells in which the mutations are introduced is enormous. The situation never occurs in patients. Those models generate faster and highly reproducible cancer-like symptoms. It is excellent, isn’t it? What do you think? How do you interpret them? Is our modelling strategy good? Can we conclude that mutations cause cancer in patients? I would precisely rephrase our current status as mutations are sufficient to cause acute cancer-like symptoms in mice when they are introduced in many cells simultaneously. However, human cancer is not acute and starts from a single cell. What would be missed?
Imagine an old house. You can live there but must deal with various minor issues daily. Some issues are associated with previous others. A new independent issue also arises. Regarding living, you can still live there because those issues are not high enough to make you decide to move out. You don’t mind working on them. Then, eventually, something makes you decide no more. This does not need to be something huge like a hurricane hit. The final decision may come from a very tiny problem. If the same problem happened as the first one, you could have dealt with it.
A hurricane can destroy new and old houses, forcing people to leave. If you are interested in decision-making about moving out, the hurricane-hit model is the best one. Quick and highly reproducible. Is it modelling the people who live in an old house? Not at all. The property of chronic issues is not captured at all. Almost all current cancer modelling is equivalent to hurricane-hit modelling. It is sufficient but may not be relevant to most patients’ contexts. Sufficiency would not capture the reality. The necessity of sufficiency modelling would provide temporal solutions for actual cancer patients, such as a protective roof for a hurricane hit. However, the real problems of an old house are not solved, although the roof may permit postponing the final decision about leaving. Our body system is fundamentally compensatory. Cancer develops because of it. All rationale solutions derived from acute modelling could be compensated because cancer is a chronic disease.
All pathologists know disorganization in cancer. However, many researchers do not take TOFT seriously because no one knows what causes disorganization and how disorganization connects with mutations. Because mutations in mice are sufficient for acute cancer modelling (i.e. hurricane-hit style modelling), who bothers to explore TOFT?
Let’s take for granted that cancer is a chronic disease created as a consequence of compensation history. Can we model chronic conditions acutely? It's challenging. There must be delicate considerations regarding the balance of compensation at the cellular, tissue, and organismal levels. Acute cancer modelling is designed to skip some critical compensation steps, often without realizing what was missed. Therefore, it is faster and highly reproducible. However, acute modelling inevitably risks providing artificial problems and solutions that do not exist in the original chronic problem.
Now, I would like to think about the word ‘disorganization.’ How do we recognize ‘disorganization’? To recognize disorganization, there should be a standard organized pattern – geometry. A disorganized tissue structure means the distribution pattern of multiple cell types is different from the standard pattern. In this sense, it is impossible to disorganize a tissue by malignant cells alone. They can create the breakpoint in an organized structure but cannot disorganize it. For disorganization, the contribution of other cells in the tissue is essential. Communication among many cells within the tissue is required for disorganization. By the way, how is the original standard tissue structure established? Cellular communication during development. Without cellular communication, tissues cannot be organized or disorganized.
What can cause tissue disorganization in our body? Inflammation. Nothing else. A disruption like an injury cannot disorganize the tissue but make a breakpoint in the organized structure. Subsequent inflammation leads to the temporal destruction of the organization. Only after the inflammation is cleared does the reconstruction of the organization occur to restore the original tissue structure.
What is inflammation? It is an alert signal for surrounding cells – a communication tool. It is essential to recognize that information is always initiated by cells. When a cell recognizes a danger with its specific sensors, it reacts to initiate inflammation. Inflammation is an alert signal initiated by cells to transduce information about the danger to other cells. Inflammation is a danger-communication strategy within an animal. This does not automatically happen but is tightly controlled. There are mechanisms for sensing dangers and initiating inflammation within each somatic cell when they encounter danger. When inflammation is initiated, the surrounding cells are forced to respond. One of them is tissue-resident macrophages (TRMs). TRMs are a local sentinel surveying its environment. When TRMs receive the inflammation signal, TRMs decide whether to ask for more support from the circulation system or not. Recruiting supporters from circulation is not always necessary and appreciated because those supporters deal with danger through their highly destructive powers and more inflammation. They have the strong destructive power for quick disorganization of the tissue structure.
How about a subtle danger to one cell? The cell will compensate for it within the cell. How about only one cell with a weak inflammation without a clear indication of other dangers? An adjacent TRM would sense it and compensate for it within the tissue.
Each somatic cell has mechanisms for sensing and reacting to various dangers, including initiating inflammation. Sensible dangers are pathogens (e.g., bacteria and viruses) and leakages of intracellular contents. The primary deactivation strategy against dangers is eating them to eliminate them from the environment. Then, they are digested inside the cell. If this does not work, like viral infection, the cell tries to kill itself to be eaten by TRMs. Whichever the case, the danger will be cleared, and no more inflammation will be initiated.
Chronic inflammation occurs when the danger stimuli are not cleared. Thus, chronic infection causes chronic inflammation. Cancer always shows disorganization, chronic inflammation and mutations. Chronic inflammation potentially generates disorganization. Do mutations cause chronic inflammation or tissue disorganization? In the SMT, the answer is ‘yes’. The search for the causative mutations was justified, but none has been identified.
Can we change our way of thinking? Several recent studies suggest that mutation-causative events, but not the mutations themselves, have the potential to cause chronic inflammation. Many DNA repair genes have been identified as the cause of heritable cancer syndromes and are dysfunctional in many cancers. The current interpretation of this is that the dysfunctional DNA repair pathway permits bad mutations to occur. I would argue that the dysfunctional DNA repair pathway is the cause of sterile inflammation due to the false activation of cellular viral detection systems. Mutations are not the causative of inflammation. However, both mutations and inflammation are the parallel downstream events of the dysfunctional DNA repair pathway.
DNA in eukaryotic cells is contained in the nucleus or mitochondria, which are cellular organelles surrounded by membranes. Cytoplasmic DNA is a sign of viral or bacterial infection. When cytoplasmic DNA is sensed, inflammation is initiated. Not limited to cytoplasmic DNA, DNA-RNA complexes, double-strand RNAs, RNAs without proper modifications, and so on are also sensed because they do not exist in normal conditions.
When a cell is placed in stressed conditions like low oxygen and nutrients or exposures to mutagens or stressors, the cell needs to respond to the stress through compensative reactions. The most important one is preventing it from entering the cell cycle. The cell focuses on its survival and retracts from other non-essential activities. The most crucial gatekeeper is the TP53 tumour suppressor.
Tp53 dysfunction is observed in almost all cancers. The general consensus is that its dysfunction can permit mutations to occur. As mutation rates increase, oncogenic mutations that drive carcinogenesis occur—the same line of thought about DNA repair pathway deficiency. We are back to the problem of the connection between mutations, inflammation and disorganization.
Tp53 dysfunction also permits a cell to enter the cell cycle when it should not, like in a stress condition such as inflammation, low oxygen, low nutrients, etc. DNA replication and cell division are the two events the cell does not want to conduct in stress conditions. But without tp53, the cell cannot sense or react to the stress. As a consequence, the cell enters the cycle and makes errors. Errors during DNA replication and cell divisions, such as stalled replication fork, DNA repair activation, and transcription replication conflict during DNA replication and lagged chromosomes and micronuclei formation during cell division. All of them are the risk factors for mutations. However, those events themselves generate cytoplasmic DNA that is sensed by innate viral detecting systems. Dysregulation of epigenetic pathways can also release endogenous retrotransposons that can be sensed in the cytoplasm because of the DNA-RNA complex. High mitochondria stress releases mitochondria DNA in the cytoplasm. All of them are sensed and cause sterile low-grade inflammation. No exogenous factors like pathogens exist, but intrinsic subcellular mislocalization of DNA initiates sterile inflammation. Without proper TP53 functions, our own cells cannot be removed. Low-grade sterile inflammation is unstoppable but always compensated. If the cell keeps entering the cell cycle, the magnitude of low-grade inflammation slowly and gradually expands the area of communication and compensation, leading to disorganization in the adjacent tissues.
It is not individual mutations but mutation-causative events that can induce inflammation. I hope you can see the formation of a circuit. Stress (inflammation or others) – cell-cycle entry – cytoplasmic DNA - inflammation – stress. As a side product, mutations accumulate, and some facilitate cell-cycle entry. This only starts in a single cell and is inherited in its progeny. The inflammation reaction in the cell fluctuates when cytoplasmic DNA is cleared. The cell is not accelerated to enter the cell cycle but cannot stop entering it. The cell and its progeny have no chance of being eliminated without tp53. The surrounding environment, including TRMs, compensates for this sterile chronic low-grade inflammation. The magnitude of inflammation is not high enough to recruit the circulating population. But there is no way to end this sterile chronic low-grade inflammation from one’s own cells. I believe that this is Cancer.
The only irreversible error that needs to occur in this cascade of compensatory processes is permitting the cell cycle entry in the stress condition. The rest of the downstream events are all normal reactions of homeostasis. Compensation.
We need to overcome our naïve belief in cause and consequence. In a complex compensatory system, everything contributes because everything is connected. When a chronic problem surfaces, everything is a part of the problem. However, everything is not equally problematic by itself. Connections of minor problems alter the original network and create a new network pattern. The order and magnitude of minor issues and their interconnectivity create a unique context with tipping points where the system loses its compensatory ability and becomes reactive.
Mutations do not cause cancer. Cancer happens because of our compensatory system. Since mutations are rather the consequence, target therapies to mutations only work temporally. It is eventually compensated by the system and as the system, not by malignant cells alone. Surgery works because all compensatory systems are removed simultaneously. To overcome the current dilemma, we have to treat Cancer as a whole system, not simply aiming to kill malignant cells. It is essential to realize that cancer happens because of the complex compensatory network with our non-cancerous cells. Malignant cells are not the evil dictators that manipulate non-cancerous cells. Malignant and non-cancerous cells cooperate to maintain the normal at the nested level by compensating for minor problems in the lower layers. Our body is designed to compensate for minor problems. All cells involved in cancer are doing their best to maintain their best to maintain normal. Therefore, we develop cancer. Cancer cannot be controlled by targeting malignant cells alone. We should not aim to kill malignant cells with their unique vulnerability. Stress would facilitate compensation. We should aim to reduce the communication of the circuitry responses among malignant cells and their surrounding non-cancerous cells.
There is no simple single cause of chronic problems. All contribute to the cause in a different degree. None is independent, but all are interconnected. The formation of the stressful background and the activation of a positive-loop circuit of default cell-cycle entry - low-grade sterile inflammation - disorganization is ‘malignancy.’ There is no single big cause. Many minor problems set the condition of entering the cell cycle under stress conditions. Mutations and inflammation are inevitable consequences and simultaneously potential risk factors. Slow and stealth are the essence of cancer. Compensation makes minor changes unnoticed and accumulate. Therefore, at diagnosis, all have mutations, inflammation and disorganization.
I strongly believe it is essential to rethink how we model chronic diseases in the laboratory because the context fundamentally differs between acute and chronic diseases.
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