“Survival of the fittest” (Herbert Spencer).
This is one of the most famous phrases to explain Darwin’s evolutional view. Darwin proposed the concept of evolution in his famous book “on the origin of species” in 1859. He suggested that heredity, variation and selection are the essence of evolution, and all live organisms are derived from a single common ancestor. This is an astonishing claim to make at that time because the common belief in Christianity was that the God made all species. Lamarck’s adaptational evolution theory also suggested the evolution as changes within each species. However, his idea was still constrained by the common belief. Darwin built his idea during his famous world tour including the Galapagos as well as from knowledge of breeding of domesticated animals and plants. He saw the world of life is as constant struggles for survival. Each organism constantly competes against others for foods and reproductive partners. An individual having small variations giving some advantage for this competition has a higher chance to become a winner. The winners take foods and reproductive partners. Their heritable traits sustain and propagate in a population.
The presupposition of this view is that the niche is limited and competitive, and two or more different species compete the niche. Is this true? I agree that the niche competition happens within one species. Because the competitions for foods and reproductive partners are, primarily an issue within individual species but unlikely between two different species. What does this mean? This means that natural selection is the issue within individual species. Natural selection does not help speciation, an emergence of a new species. For speciation, what is essential is the establishment of a reproductive barrier between two species. Neither competition nor selection is required.
Then, how does a new species survive without competition? Simply put, a new species takes a new open niche. An important realization is that the niche that each species occupies is usually narrow and specific. For example, if the food for a new species is different from the ones for existent species, no competition at all. If a new species can eat something uneatable for the old ones or can tolerate habitats colder than the existent species, then the new species just consumes it or spreads into the new habitat. One unfortunate scenario is if the new species can consume raw foods, whereas the existing species can only consume ripe foods, the old one may extinct because of no access to food. Take-over would happen.
New species do not emerge as the consequence of selection of variations. The first step is separation of two genetic pools by reproductive isolation. This can be achieved in various means, such as infertility based on meiosis block due to incompatibility of homologous chromosomes, no offspring after mating, no chance of mating etc. When the reproductive isolation is established, there is a chance of a new species appearing. If this new species can take a new open niche where is unlivable for the previous species, the chance of survival increases. Natural selection happens within a species as genetic drift that share the same genetic pool but is unlikely to be sufficient for speciation. Two different species do not compete each other for reproductive partners or for food. A new species appears because they find an unoccupied niche to survive. Historically, the large diversifications of metazoan happened when open unoccupied niches became available such as from seabed to ocean (Cambrian explosion), from ocean to land, and mammalian diversification after dinosaurs’ extinction.
Darwin’s view of evolution has been widely accepted and extended to explain various biological processes as well as human socioeconomic activities. The concept of “survival of the fittest” is likened to support the idea of capitalism. However, we also already know that innovation is essential for economic growth. Innovation creates a new market, new customers, and a new eco-system. Sometimes, there is no comparative product before, like an iPad. A portable tablet had never existed before Apple created. iPad was neither the consequence of gradual evolution nor the sum of small improvements. All parts consisting of an iPad were available by then. Reassembling available parts under a new concept and perspective. No direct competitor. After iPad, the market for portable tablets emerged. Competition and selection started. Importantly, competition and selection did not create iPad whereas imagination and a lot of prototypes (try and errors) produced innovation.
I also have an example of extinction. Smartphones, blackberry, and pagers. They are the devises for contacting a remote person. The history of cellphones appears the competition, but this is an example of take-over without competition. None of them emerged as the competitive winner of the previous ones. From the beginning, they were in different categories. We all know that competitions between various products and services occur frequently as companies try to expand their own share within the market by making small improvements. However, innovations can create a new market and own ecosystem as well as may cause extinctions of old ones.
The history of modern medicine is the process of understanding the causative mechanisms of human diseases. We have successfully identified the causes of infectious diseases like bacteria and viruses as pathogens. We also understand that some diseases are not caused by foreign pathogens but by a combination of own genetic predisposition and environment, like cancer, diabetes etc. Cancer is the disease that humans have been suffered by from the ancient time. In particular, the Darwinian perspective impacts our current view of carcinogenesis.
The first important discovery in modern cancer research was that our own cells become malignant cancer cells. Nothing foreign but all derived from own cells. Then, along the advance of molecular biology, oncogenes and tumour suppressor genes were discovered. The abnormality in DNA sequence of cancer cells was thought to be the cause of cancer - the somatic mutation theory. Cancer is the disease caused by cumulative mutations in malignant cancer cells. These mutations are selected as advantageous traits by selection to support clonal growth, similar to Darwin’s natural selection in environment. The key properties of malignancy in cancer are considered as invasion and metastasis. Thus, invasion and metastasis are captured as advantageous traits for the expansion of cancer cells. Cells gaining the ability of invasion and metastasis are selected based on the advantage during clonal growth. Search of the causative mutations was justified and continues. In this scenario, malignant cells appear gaining a lot of superpowers during carcinogenesis such as unlimited uncontrolled proliferation, manipulating their environment, escaping from immune surveillance, disseminating other parts of body and so on. Malignant cells are a monster growing within a patient to destroy him/her.
What are the presuppositions in this context? First, it is that ‘primary tumours have spatial constraint’. Similar to Darwin’s presupposition, the niche is limited. Therefore, the ability to disseminate will be an advantage for clonal expansion. Second, it is that the properties related to malignancy should be carried by malignant cancer cells.
I think these two presuppositions are wrong (or at least not a 100% correct). Primary tumours do not need have spatial constraint for dissemination, and malignancy is not caused by malignant cells alone. The fundamental question to ask ourselves again is what malignancy is and how it occurs. Is being malignant an advantageous trait for clonal expansion? I believe that malignancy does not need to link with clonal expansion and survival advantages of malignant cells. I think malignancy is simple side products of clonal expansion. During clonal expansion, the growing cells create too high intrinsic cellular stresses due to overloads of DNA replication, transcription and cell growth. I think that malignancy occurs as the combination of SOS signals from malignant cells against overloading stresses, and the proper homeostatic responses of surrounding tissues to the SOS signals. Malignant cells are not a monster with superpowers. Instead, they are screaming for help because of their uncontrolled growth conditions.
Imagine a motorcycle gang. Due to too many modifications on motorcycles and too much speeding, they may cause an accident. If an accident occurs, other vehicles - police cars, firefighters and ambulances appear and block the highway completely. A gang member caused an accident had no intention to cause an accident or block the highway. The only intension was riding his motorcycle faster. For commuters using the highway, the emergency vehicles are the cause of the block. Why did the accident happen? Because of crossing the limits of technical capability of a rider and/or poor machine integrity. More gang members with unreliable motorcycles cause more accidents. Deadlock of highways by the emergency vehicles due to too many accidents could become the death of modern cities due to dysfunctional logistics, equivalent to cancer death of a human patient. Ironically, without the emergency vehicles, the highway would be functional, and logistics won’t be destroyed.
The number of gang members and their riding skills are varied in each gang. They try to ride their bike as fast as possible by modifying it and/or ignoring the traffic rules. They crush by themselves, but emergency vehicles come to clean it up. Sometimes, firefighters destroy the surrounding structures like guard rails to rescue the riders. The emergency vehicles, not the accident itself, create a traffic jam. Ambulance takes the riders to a new location. The riders recover at the new location, recruit new members. The problem spreads.
What are these accidents in the analogy equivalent to in our body? I think type1 IFN response and cellular senescence. Uncontrolled clonal growth based on mutations implicates various cellular stresses like DNA replication, high transcription and mitochondria stress. When these stresses reach the threshold of a cell, the cell activates cellular stress responses. Then, the cell releases various cytokines and chemokines as type1 IFN response or senescence associated secretory proteins (SASPs). This is very similar to inflammation. This recruits the surrounding cells like tissue residential macrophages (TRMs) and mesenchymal fibroblasts, – these are the first responders. In contrast to pathogen insults or sterile injuries, no extracellular stimulation like pathogen pattern recognition motifs (PPRMs) or damage associated molecular patterns (DAMPs), thus there is no surge of inflammation. Instead, this results in low grade chronic inflammation that is difficult to clear up because of intra cellular stress-induced inflammation in proliferating cells. The size of local low-grade inflammation gradually expands and consequently recruits circulating immune populations like neutrophil, macrophages and lymphocytes. The highways will be further locked up, destroyed and remodelled.
The point I want to covey is that cancer cells do not intend to invade and metastasize. The intrinsic cellular stress response in cancer cells initiates low-grade inflammation forcing the surrounding cells to get involved. In some cases, none of inflammation, invasion, and metastasis would be advantageous for clonal expansion at all. Another important realization is that inflammation and new locations probably contribute clonal selection, similar to the concept of natural selection in evolution. Although clonal selection unlikely contribute to invasion and metastasis.
The importance of tumour microenvironment and innate immune populations in cancer has been emphasized recently, without challenging the current dogma. If the current view is considered as the fact, malignant cancer cells must gain the superpowers to invade and metastasize, to manipulate the surrounding cells and to escape immune surveillance all by themselves – which is unlikely. I do not think that cancer cells need such superpowers to kill one human being. What they do is making calls for help, like an injured rider calls for an ambulance. In this case, inflammatory secretions are the call for help, and the ambulance is the surrounding cells.
Presupposition is inevitable in building a scientific hypothesis. However, sometimes it is not fully obvious at the time of building the hypothesis. Each scientific hypothesis drives our understanding of the subject forward, but none lasts forever. When new evidence challenges the original presupposition, this is the time for a paradigm shift. A paradigm shift is very difficult to accept for many because it compromises their vested interests. However, our history has clearly shown that paradigm shifts are the driver of innovation. I am not sure if my views are entirely correct, but at least I can clearly say that now is the time for revising those old hypotheses in evolution and cancer.
I thank Keerthana Harwalkar for English editing.
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