Nothing makes sense in biology except in the light of evolution.
----Theodosius DobzhanskyCancer is when a small group of cells in the body goes feral and stops playing the multicelluar game with its neighbors. This can be viewed as a kind of antisocial break from a cooperative society, or a new species arising in an ecological environment. This post examines many aspects of cancer from an evolution point of view.
I am very interested in cancer as a good example of "unwanted evolution" that humans are wrestling with. Other unwanted evolutions include evolution of drug resistance, herbicide resistance, etc, but cancer stands out as being remarkably complex and different.
To kickstart the idea, I quote Daniel Dennett, The Normal Well-Tempered Mind (2013):
Every human cell in your body is a direct descendent of eukaryotic cells that lived and fended for themselves for about a billion years as free-swimming, free-living little agents... They had to develop a lot of self-protective talent to do that. When they joined forces into multi-cellular creatures, they became domesticated. They became part of larger, more monolithic organizations... We don't have to worry about our muscle cells rebelling against us, or anything like that. When they do, we call it cancer.
This is my wild idea, maybe only in humans, and maybe only in the obviously more volatile parts of the brain, the cortical areas, some little switch has been thrown in the genetics that makes our neurons a little bit feral, a little bit like what happens when you let sheep or pigs go feral, and they recover their wild talents very fast.He proceeded to explain how our neurons, by being a little bit wild and risky, give us intelligence, creativity, and mental diseases. It's interesting (despite being extremely speculative) and worth a read, but not relevant to this post.
What is cancer?
Cancer is a disease of multicelluar creatures where a small group of cells grow uncontrollably and spread to other parts of the body, causing the host body to become sick. The most widely used criteria for cancer is "the six hallmarks", proposed first in The Hallmarks of Cancer (2000). |
| Six hallmarks of cancer, figure from to The Hallmarks of Cancer: The Next Generation (2011) |
- Sustaining proliferative signaling: Typically, cells of the body require hormones and other molecules that act as signals for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals.
- Evading growth suppressors: Normal cells won't divide when they are DNA-damaged, but cancer cells divide even when the cell has severe abnormalities. Normal cells also stop dividing when they touch others, known as contact inhibition. Cancer cells do not have contact inhibition, and so will continue to grow and divide, regardless of their surroundings. They'll keep dividing until all the good cell neighbors are squashed to death.
- Resisting cell death: Normal cells have the ability to suicide (apoptosis). This is required for organisms to grow and develop properly, for maintaining tissues of the body, and is also initiated when a cell is damaged or infected. Cancer cells lose this ability.
- Enabling replicative immortality: Cells of the body don't normally have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide, or die. Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60–70 doublings, before their teleomeres become too shortened to support life. Cancer cells can keep dividing forever.
- Inducing angiogenesis: Cancer cells are able to cause new blood vessels to grow around them to feed their growth.
- Activating invasion and metastasis: Cancer cells can evolve the ability to invade blood vessels, survive in the harsh environment of the circulatory system, exit this system and then start dividing in the new tissue.
How cancer evolves in the body: a speciation event
The idea is simple: a tumor is essentially a colony of a species that arose from body cells gone wild. Thus, the start of cancer is essentially a speciation event, which is usually studied in ecology, not oncology.This idea is made famous by Mutation selection and the natural history of cancer (1975), by John Cairns. It's later paraphrased in Cancer and the Immortal Strand Hypothesis (2006), by John Cairns, which might be easier to read.
When we turn from the competition between the individuals of a species to the competition between the individual cells within a single animal, we see that natural selection has now become a liability. The dangerous mutations are now those that confer on a cell an increased survival advantage. We may therefore expect to find, especially in animals which undergo continual cell multiplication during their adult life... mechanisms for minimising the rate of production of variant cells and for preventing free competition between cells.As evidence that cancer cells are a product of evolution, he noted that epithelial (all kinds of skins) cancer accounts for 92% of all cancers, and sarcomas (cancer of connective tissue like bones and muscles and fat) and leukemias (cancer of bone marrows) only 8%. This means that cancer cells tend to arise in tissues where cells divide a lot, such as the epithelial tissues.
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| A chart showing that in the human body, lifetime risk of cancer in a tissue is proportional to total stem cell division number in that tissue. Figure from Variation in cancer risk among tissues can be explained by the number of stem cell divisions (2015), C Tomasetti, B Vogelstein. |
Peto's Paradox shows that bodies can suppress cancer effectively
As evidence that creatures have evolved effective methods to suppress cancer, he noted Peto's Paradox, which in Peto's own words from Epidemiology, multistage models, and short-term mutagenicity tests (1976):a man has 1000 times as many cells as a mouse. and we usually live at least 30 times as long as mice… However, it seems that, in the wild, the probabilities of carcinoma induction in mice and in men are not vastly different. Are our stem cells really 1 billion or 1 trillion times more “cancer proof”? This is biologically pretty implausible...The conclusion are two:
- Animal bodies have very effective ways to suppress evolution of cancer cells.
- The method isn't free, so animal bodies get away with the minimal amount of it possible. That's why old creatures get cancer: not enough energy is spent on long-term cancer suppression, and instead it's spent on reproduction in its youth.
Evolving a cancer cell species/colony step-by-step
Most experimental cancers are formed only after repeated or prolonged exposure to a carcinogen. Similarly, most human cancers appear in old age, as if they usually arise as the end result of a lifetime of carcinogenesis. For this reason it is generally believed that several steps are required to convert a normal cell into an uncontrolled, invasive variant.Cells don't just turn cancer suddenly. Multiple genes need to be switched on and off in order to turn a normal cell into a cancer cell, and grow a cancer colony, a settlement of fellow cancer cells. This is true for the evolution of any complex trait, like the eye or the wing. And the question is, what's the use of half a wing? Or, what's the use of a half-way-there cancer cell?
Quite a bit. It could grow faster, divide faster, soak up nutrition faster, or better at moving around and squeezing its healthy neighbors away from blood supply. Faster division is particularly useful, as it accelerates the evolution and mutation of this cancer lineage.
Strategies to protect against evolution of cancer cells
Protecting against evolution is first of all about protecting against mutation. If no mutation arises, no evolution would happen. So the question is, how to stop DNA copy errors? This is the same problem faced by human archivists, librarians, and traditionalists. The solutions they found are similar.
1. Have a lineage of immortal guardians.
In France, there's a small institute of language guardians holding an iron grip on the true French language. These "immortals" are housed in a stately house deep in the heart of France, insulated from corrupting influence of the outside world. They move slowly and rarely change anything.
And in animal bodies, there are lineages of stem cells, guardians of the true DNA. For example, the epithelial tissues (like your skin) are built in layers, from the deepest layer 0 to the topmost layer n. Every cell in layers 1 to n are on a one-way trip to layer (n+1), that is, shedding off as dead skin. Only cells in layer 0 are not resigned to such a fate, and they are the "immortal stem cells".
The job of an immortal stem cell is to divide once in a while into two daughter cells. One daughter is disowned and moved to layer 1, where she divides again, and again, but all her offsprings destined to death in a few months. Another daughter remains in place, to continue the immortal lineage.
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| The squares stand for the immortal stem cells in layer 0. The circle cells are in layers 1 and above, destined for a quick death. |
In this way, almost all mutations that appear in the epithelial tissues are quickly flushed out (literally flushed out, for intestinal epithelial tissue!). The only mutations that would stick around are the rare mutations in the rare immortal stem cells.
2. Keep an immortal master copy (the immortal DNA strand hypothesis)
In the middle ages, scribes copied books by hand, introducing errors everywhere. To reduce errors, they would keep one copy sacred and use it as a master copy, and always copy from that master copy instead of the other copies.
During a division of an immortal stem cell, the DNA is copied and each copy goes into one daughter cell. However, instead of giving the original copy and the new copy randomly, the cell could give the original copy to the next immortal stem cell, and the new copy to the daughter that's destined to a quick death. This eliminates copy error in the immortal stem cell DNA.
This hypothesis is still controversial, 45 years after John Cairns proposed it. For a list of references, check the introduction to The (not so) immortal strand hypothesis (2015) by Cristian Tomasetti, Ivana Bozic.
3. Put walls between departments so that stem cells can't compete with each other
So, whatever the number of restraints that must be overcome to convert a normal cell into a cancer cell, the risk that this occurs will be much increased if there are intermediate states with high survival advantage and if these variants are in fact able to displace their neighbours. We may therefore expect to find fast-multiplying tissues arranged in such a way that neighbouring stem cells (or sets of stem cells) are restricted to limited territories so that they cannot easily compete with each other.
If the cells aren't allowed to compete, then evolution can't proceed.
Cairns used the example of the intestinal epithelial tissue. The intestinal epithelium is the part of the body with the fastest cell division rate (cool trivia!), and thus cancer-suppression must be the harshest there.
The intestinal epithelium is divided into little pockets (crypts) separated by big hills (villi). Each crypt contains stem cells
... any variant stem cell with high survival advantage should quickly exclude normal cells from its crypt... [but] the only way it can reach neighbouring crypts is by moving down the other sides of the villi, against the continual flow of normal cells arising in these crypts.
We see therefore that the arrangement of the intestinal epithelium into crypts and villi will tend to limit the expansion of any population of fitter variants that might otherwise form an ever-increasing target for further mutational steps. Other epithelia are no doubt partitioned in other ways.
How cancer happens
With all these in mind, how does cancer appear anyway? How would carcinogens work?
The rate of accumulation of mutations will be proportional to the rate of division of the stem cells or perhaps, more specifically, to the rate at which they have to multiply to replace lost stem cells (that is, the rate at which new immortal strands have to be created). Anything that accelerates either of these processes could be carcinogenic.A carcinogen can directly increase mutation rate (mutagen), such as by damaging DNA, or can simply damage cells and forcing the stem cells to divide faster, or can simply damage stem cells directly and forcing new stem cells to be established, making stem cell mutations more likely.
There are also places in the body where immortal stem cell lineages are naturally being established at a high rate, such as the cervix and the mammary glands, where indeed there's a high rate of cancer.
This all makes me think about how new species, new ideas, tend to proliferate and take hold during/after a time of great damage, be it the Great Oxygenation, the K-T alien missile attack, or the Warring States Period (Legalism in Chinese Philosophy, Stanford Encyclopedia, section 1.2).
Cancer spreads as an invasive species
Metastasis is similar to an invasive species getting shipped to a faraway vulnerable island environment.
Cancer sleeps, waiting for better times
From Protracted dormancy of pre-leukemic stem cells (2015):
Cancer stem cells can escape therapeutic killing by adopting a quiescent or dormant state... leukemia-propagating cells, most probably pre-leukemic stem cells, can remain covert and silent but potentially reactivatable for more than two decades.
This sounds a lot like how creatures like fungus, tardigrades, and many other hardy creatures can enter into a long "sleep" when the environment gets tough, waiting for better days.
Cancer colony as a little ecology
A cancer colony is not just a big blob of identical cancer cells. It's more like a little ecology all in itself. From Cancer as an evolutionary and ecological process (2006):
Neoplasms are composed of an ecosystem of evolving clones, competing and cooperating with each other and other cells in their microenvironment, and this has important implications for both neoplastic progression and therapy.
Many of the genetic and epigenetic alterations observed in neoplasms are evolutionarily neutral.and most remarkably,
There is evidence of competition, predation, parasitism and mutualism between co-evolving clones in and around a neoplasm.
It really is an ecosystem!
Competition. For neoplastic cells in a heterogeneous population, competition exists in the form of resource consumption (oxygen for example). However, neoplastic clones can also have direct negative effects on each other... Neoplastic clones injected into opposite flanks of mice and rats can inhibit each other's growth... one clone can stimulate an immune response that clears other clones...
War on cancer? More like war of cancers.
Predation. Neoplasms evolve various mechanisms to escape predation from the immune system, including downregulation of the major histocompatibility complex... One dissimilarity here is that a predator will go extinct if its prey goes extinct. This is clearly not the case for T cells if they clear the neoplasm.
This one is pretty obvious.
Parasitism. There is little evidence of clones within a neoplasm parasitizing each other. However, there is ample opportunity for clones to be free-riders on the metabolic investments of their neighbours, such as stimulating associated fibroblasts to release growth factors, stimulating neo-angiogenesis or the breakdown of the extracellular matrix and the release of growth factors contained within, and so on. Such parasitism... can be referred to as a 'cheater strategy' because the parasitic clones gain a fitness benefit from their neighbours at no cost to themselves.
Cancer cells could cheat not just the body they are in, but each other too!
Mutualism and commensalism. A mutant clone can increase the fitness of other clones in commensal interactions, and even confer a metastatic phenotype on an otherwise non-metastatic clone. Clones in a neoplasm could cooperate through diffusible factors, and thereby circumvent the requirement that a single clone has to accumulate all the hallmarks of cancer. To date, the only known case of mutualism in a human neoplasm is the relationship between neoplastic epithelium and activated fibroblasts, both of which get a fitness advantage from the association and seem to be co-evolving.
In advanced disease, metastases can form a metapopulation with genetically diverse colonies of cells, leading to the kinds of population structure that could favour cooperation within the cell colonies... models have shown that reproductive division of labour can evolve within neoplasms with certain cells acting as a kind of ‘germ-line’ of the tumour and perhaps corresponding to what cancer biologists have observed as ‘cancer stem cells' that are capable of recreating a tumour, and other cells acting as a ‘somatic line’ by limiting their own proliferation and enhancing the fitness of the ‘stem-like’ cells. Together these findings suggest the possibility that cancer progression can be characterized by the evolution of new ‘protomulticellular’ entities inside the host that recapitulate the foundations of multicellular cooperation.
This is so remarkable. It's like anarchists breaking out of a government, only to form their own government later.
However, since cancer cells behave like asexual single-celled organisms, there are limits to what they could do:
Neoplasms do not contain many species or food webs. There is little diversity of resources in a neoplasm, so there are probably limited opportunities for specialization to different niches, except to the extent that there are different microenvironments in an organ.
Cancer in different creatures
A good survey of cancer in all creatures is Cancer across the tree of life: cooperation and cheating in multicellularity (2015).
Mammals get cancer at roughly the same rate, when they get older
Cancer rates among mammals seem to vary by less than a factor of 2. In a population of wild Mus musculus raised in the laboratory, 46% had gross tumours at death; about 20% of dogs die because of cancer; and 22% of annual human deaths in the United States are directly caused by cancer.
Vertebrates that don't get cancer
There used to be a myth that sharks don't get cancer, but they do. For example, in Shark Cartilage, Cancer and the Growing Threat of Pseudoscience (2004), 42 specimens of shark cancer are reported.
The naked mole rat is a cancer-free mammal, even in old age. From Resistance to experimental tumorigenesis in cells of a long‐lived mammal, the naked mole‐rat (Heterocephalus glaber) (2010):
The naked mole‐rat is an exceptionally long‐lived rodent of considerable interest to biomedical gerontology. In a colony of 1500 animals in captivity, the oldest individuals are more than 30 years of age and animals routinely maintain good health well into their third decade. Animals aged over 24 years show evidence of frailty, and apparently die of age‐related causes. Nevertheless, death because of cancer has never been observed, and necropsies have not revealed incidental tumors.
Invertebrates in general
According to Invertebrate Oncology: Diseases, Diagnostics, and Treatment (2016)
Literature reports of neoplasia are frequent in mollusks and insects, infrequent in Cnidaria and crustaceans, and are yet to be documented in Porifera and Echinodermata. Most neoplasms described in the invertebrate literature have been benign.
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| This is a calicoblastic epithelioma in elkhorn coral (Acropora palmata). The closest thing to cancer in sponges is such abnormal growth. It only causes some mild symptoms like decreased number of offsprings (polyps). |
Importantly, the study of invertebrate neoplasms has revealed that many genes and pathways involved in neoplastic transformation and metastasis are evolutionarily conserved and invertebrate models of neoplasia, particularly in Drosophila spp and Caenorhabditis elegans, are contributing significantly to the understanding of tumorigenesis.
Bivalves
Interestingly, bivalves seem to be particularly affected by cancer. There are several documented kinds of transmissible (infectious) cancer in various species of marine bivalves, and some have caused widespread deaths. Furthermore, some bivalve transmissible cancer originated in one species, but infects another species.
Outbreaks of fatal leukemia-like cancers of marine bivalves throughout the world have led to massive population loss... we show that the genotypes of neoplastic cells do not match those of the host animal. Instead, neoplastic cells from dispersed locations in New York, Maine, and Prince Edward Island (PEI), Canada, all have nearly identical genotypes that differ from those of the host. These results indicate that the cancer is spreading between animals in the marine environment as a clonal transmissible cell derived from a single original clam.
In mussels and cockles, the cancer lineages are derived from their respective host species, but unexpectedly, cancer cells in P. aureus are all derived from Venerupis corrugata, a different species living in the same geographic area. No cases of disseminated neoplasia have thus far been found in V. corrugata from the same region.
These findings show that transmission of cancer cells in the marine environment is common in multiple species, that it has originated many times, and that while most transmissible cancers were found spreading within the species of origin, cross-species transmission of cancer cells can occur.
Crustaceans
Crustaceans (like shrimp, lobsters, crayfish and crabs) seem to be almost free from cancer (there's a pun here). According to How to minimize formation and growth of tumours: Potential benefits of decapod crustaceans for cancer research (2008), Günter Vogt:
Analysis of the literature and information from cancer and diseases data bases revealed a total of 15 incidences, some of them being questionable.Crustaceans can get quite old, but still no cancer:
I have searched for neoplasias in old specimens of the marbled crayfish, which has a life span similar to mouse and zebrafish, but my efforts were without success. The virtual absence of age‐related cancer in the Decapoda may be related to their negligible functional senescence, which is in contrast to mammals and insects
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| Benign tumor (epidermal papilloma) in a Pacific white shrimp (Litopenaeus vannamei). |
The authors proposed that the marbled crayfish be used as a model species for studying crustacean biology. It is a truly remarkable crustacean species, by the way. Almost a cancer in itself. It appeared in 1995 and exploded in population, probably from a single mutated individual.
The mutation made it possible for the creature to clone itself, and now it has spread across much of Europe and gained a clawhold on other continents. In Madagascar, where it arrived about 2007, it now numbers in the millions and threatens native crayfish.
The immortal hydra
According to Naturally occurring tumours in the basal metazoan Hydra (2014), cancer in animals without two-sided symmetry (pre-bilaterians) is undocumented... until now! Hydra is an ancient lineage of animal, has radial symmetry, and it can get cancer, which suggests that cancer is an ancient problem for animals:
Here we provide first evidence for naturally occurring tumours in two species of Hydra... these tumours are transplantable and might originate by differentiation arrest of female gametes. Growth of tumour cells is independent from the cellular environment. Tumour-bearing polyps have significantly reduced fitness... this study shows that spontaneous tumours have deep evolutionary roots...The authors weren't surprised by this, as they have previously studied the genetic history of cancer and found that a cancer suppression gene evolved at roughly the same time as multicelluar animals (more on this below).
Plants
They don't get cancer, because they are too stiff for the cancer cells to move around. At most they get local cancer colonies that cannot spread.
Sometimes plant cancer is considered beautiful and actively selected for by humans, as in the case of "crested cacti":
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| Beautiful cancer in cactus. |
Fungus
Yes, mushrooms do get some mild forms of cancer.
Cancer-like phenomena in basidiomycete fungi. A cross section of the mature fruit body of a commercial mushroom, Agaricus bisporus. The abnormal growth demonstrates a cancer-like phenomenon with inappropriate cell differentiation. This is also known as rosecomb disease.
Bacteria
This is just a joke. Single-celled creatures can't get cancer!
Cancer as a side effect of infection
This is not what I'm interested in, since it's rather unsurprising. Basically, some viruses and pathogens can cause cancer as a side effect. This is unsurprising since they are causing damage to the tissue, and thus have a carcinogenic effect. Such cancer-causing viruses are called oncovirus.The World Health Organization's International Agency for Research on Cancer estimated that in 2002, infection caused 17.8% of human cancers, with 11.9% caused by one of seven viruses.
Cancer breaking free from the body
In a body, a species of cancer cells might enjoy a brief period of prosperity, but its success will be its downfall. Like a bacteria that kills too quickly, each species of cancer goes extinct after it has ravaged its own environment (the host) to death. (Humans should be careful not to ravage earth like cancer does.)
Unless it can break free! If cancer can spread across bodies, then it can survive indefinitely. It would become much more like a "proper" species of pathogens that ecologists usually study. This is called a clonally transmissible cancer.
Pregnancy as benign cancer
Now, this section isn't supposed to be taken seriously. But think about it. Pregnancy is kind of like a benign tumor, isn't it? Normal pregnancy and cancer are the only two cases where antigenic tissue is tolerated by a normal immune system.
Of course, once in a while, pregnancy can be downright lethal... as we talked about before in the post Nematode matricide, evolution of ageing, and offspring-mother conflicts.
Also, as a side note, 1 in 1000 American human pregnancies happen in mothers with cancers. The treatment during such cases is complicated, since both the fetus (a benign cancer) and the cancer (a malignant fetus) are sensitive to many cancer therapies.
Human-human cancer transmission
Usually, cancer doesn't spread between people even by deliberate transplant. This has actually been done, many times! From Induced immunity to cancer cell homografts in man (1958):
It has been previously reported that human volunteer recipients show a marked difference in their natural resistance to subcutaneously homotransplanted cancer cells according to whether they are normal healthy adults or patients with advanced debilitating neoplastic disease...
Basically, the healthy people rejected the transplanted cancer with a big inflammatory response and the cancer cells died off in a few weeks, just as they would reject any transplanted normal tissue. The patients though rejected them only very slowly, and without an inflammation.
According to Genetic Analysis of a Sarcoma Accidentally Transplanted from a Patient to a Surgeon (1996), cancers usually can't be transplanted from one individual to another, but sometimes they can:
We describe the accidental transplantation of a malignant sarcoma from a patient to a surgeon. Using molecular methods, we showed that the sarcomas in the unrelated patient and surgeon were genetically identical.
In a more unfortunate case, a single organ donor's cancer cells killed three out of four organ recipients, as reported in Transmission of breast cancer by a single multiorgan donor to 4 transplant recipients (2018):
The diagnosis of breast cancer was occult at the time of donation. All of the recipients developed breast cancer within 16 months to 6 years after transplantation. Three out of 4 recipients died as a result of widely metastasized disease. One of the recipients survived after transplant nephrectomy followed by cessation of immunosuppression and chemotherapy.
2 kinds of Tasmanian Devil Facial Tumour Disease (DFTD)
Tasmanian devils, while relatively docile with humans, are known for biting each other on the face as they fight over mates and food. This is the route by which both cancers, which cause similar facial tumors before metastasizing, spread from devil to devil. But even though the cancers manifest similarly, they originated in two different individuals, probably years apart.
There are only eight known naturally occurring transmissible cancers: one in dogs, two in Tasmanian devils, and five in various species of marine bivalves, so to see two such cancers appear in such a short time in a single species was quite surprising.
Canine transmissible venereal tumor (CTVT or Sticker's sarcoma)
The one problem that pathogens must deal with is that they can't be too lethal, else they kill off their host before they can spread. So some pathogens have evolved to be less lethal. One prominent example is the dog sex cancer (CTVT). The cancer is typically transmitted during mating when the malignant tumor cells from one dog are directly transferred to another dog via fucking, licking, biting, or sniffing tumor-affected areas (the genitals, nose, or mouth).From Origins and evolution of a transmissible cancer (2009). By analysis of the genes, the authors found that the first CTVT started more than 6000 years ago from either dogs or wolves, and perhaps originated when dogs were first domesticated. But that first tumor has long disappeared, and all modern samples of CTVT have a common ancestor of extant tumors lived within the last few hundred years, long after the first tumor.
This tumor has a genome of its own, quite distinct from its dog hosts:
There is solid evidence that this tumor is passed on as an allograft, including the fact that CTVT cells have a strikingly different karyotype from the host's cells, yet are similar to each other even when the hosts are from different continents.Unsurprisingly, this cancer cell, by adopting the lifestyle of an asexual pathogen, also adopted the gene style of it:
The genetic and genomic patterns we observe are typical of those expected of asexual pathogens, and the extended time since first origin may explain the many remarkable adaptations that have enabled this mammalian cell lineage to live as a unicellular pathogen.So here's a biological, almost philosophical, puzzle: is this a new species? Or are they horcruxes of an i̦̳m̷̟̝̮m̙o͉͟ṛt̝̼͚̮͢a̸̜͎̯̬̖͔ͅl̺̹ ҉̜̣̰͇̥̭a̺͈̖͈̰n̥͖̭̫̪̰c̸̪͚i̟̹̬͕̘̞͚e̦͔̟̟̫̞n̳̳t͙͉͚̜͓͝ ͙͙͍͎̩w̬͉̤̲̪̝o͎̖͙͙̝̦l̩͍͙̙̻f̗̙̫̗̫͙ͅ ̶͉̗̤ṇ̶̜̗e̼̘̪̟c̸͔ŗ̠͚͚̗̖o̘̪͍̹̜͔͞m̱̘͚̰̱̯àn͔͓̤ͅc̝̩͔͍̪͙e͘r?
Well, just take a look at the family tree, and make a decision yourself!
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| Figure taken from Clonal Origin and Evolution of a Transmissible Cancer (2006) |
Unlike most cancers we've examined so far, the dog sex cancer is actually quite tame:
Although capable of metastasizing, CTVT often does not require treatment, as spontaneous regression is the general rule.and metastasis usually only happens in dogs with broken immune system. This is similar to how an HIV-positive human was infected by metastasizing cancer from a parasite, detailed below.
HeLa immortal cells
There is one species of human cancer that has settled comfortably into its niche: the HeLa immortal cells, with its niche being the petri dishes. HeLa, a New Microbial Species (1991), by Leigh Van Valen, seems to be the first proposal for considering HeLa as a new species.
Regarding HeLa cells as a separate species opens several cans of worms. Most obviously, perhaps, how should this species be classified? It's way of life has no resemblance to that of, say, mammals, but is instead convergent on that of amoebas. It obviously can't be classified with amoebas, however, because of its entirely different origin. We leave this question open...
I think the best way to describe the HeLa cells is that it's a symbiotic species that cooperates with human biologists. The human biologists give it free food and housing and the HeLa cells let the biologists study them.
The mainstream seems to consider HeLa as not a genuine species, because it's "unnatural" as in "requires petri dishes made by humans to exist". But honestly, that's a philosophical problem, and my answer is that humans are a part of nature, and HeLa is just a single-celled organism that happens to be particularly specialized to a niche that could only exist in the wonderful and strange time of Anthropocene. Similarly, there's no way that modern dairy cows, with their huge mammary glands, could exist in any niche but the niche of dairy farms in the Anthropocene.
By weight, the HeLa is an extraordinarily successful species:
Scientists have grown an estimated 50 million metric tons of HeLa cells.
Just like the dog sex cancer, the HeLa has settled into a comfortable niche and achieved long-term survival. However, while dog sex cancer could still have a long future, HeLa might not. Dogs might last several thousand years into the future, but human biologists might not need HeLa for another century, with the speed of human science. Time will soon tell whether HeLa is going extinct soon.
On the other hoof, perhaps the HeLa is not a species, but rather a full taxa of species. This is a creature that replicates every 24 hours or so, and has been doing so for 60 years. It has accumulated lots of mutations in lots of labs around the world, and even metastasized in places they are not supposed to, as reported:
HeLa cells ruined expensive scientific studies because many research teams that thought they were studying different tissue types from many individuals were all unknowingly working with HeLa... Many cell cultures, some of them ostensibly pure ''reference strains'' from national repositories, have been unmasked as HeLa cells growing under other labels.
The HeLa cells, now living in petri dishes all over the world, start to speciate again, like Darwin's finches scattered across islands. This has prompted another crisis in biology research, as a fresh-off-the-press research, Multi-omic measurements of heterogeneity in HeLa cells across laboratories (February 2019, just last month!!) showed:
HeLa Cells from different labs vary in genetics and phenotype. This could account for some reproducibility problems in cell line research, according to the authors of a comprehensive analysis of HeLa variants. In the study, researchers gathered 14 HeLa samples from 13 labs across six countries, and cultured them under the same laboratory conditions... [and found they behaved differently]
In a separate experiment, the team investigated whether gene expression changed in individual HeLa variants over time by culturing a cell line for three months. The researchers documented a roughly 6% difference in gene expression between an early and a later generation of cells.
“It was certainly very dramatic how much these cells differed, and how quickly they changed even in the same lab,” remarks coauthor Ruedi Aebersold. He estimates that if a graduate student had done an experiment with a HeLa cell line at the beginning of his or her project and were asked to repeat it after six months, “they might have gotten different results.”
Cross-species infection of cancer
There has been a rare case where a human with dysfunctional immune system is infected by cancerous stem cells from a parasite. As reported in Malignant Transformation of Hymenolepis nana in a Human Host (2015), or in this news rephrasing:Cancer cells originating from a common tapeworm have been found inside a patient with HIV. The cells formed into cancer-like tumors that looked nearly identical to human tumors in the patient's body.
For people with healthy immune systems, the tapeworm usually stays in the gut and doesn't cause any symptoms or health issues. But in patients with HIV, the compromised immune system isn’t telling the parasites to stay in the gut. "These parasites take cues from the immune system, but in the absence of those cues, things go awry," said Olson.
That means the larvae likely traveled through the patient using the lymphatic system. And traveling with the larvae were tapeworm stem cells, which probably lodged themselves in other parts of the body. This patient was just unlucky enough to have at least one tapeworm whose cells started growing out of control.
Cancer in "usual" evolution
We return from the strange world of cancer evolution to the "normal" world of "usual" evolution. Here we find that cancer is still making itself felt, as multicelluar life must evolve ability to suppress cancer.Origin of multicelluar life = origin of cancer defence
There are two kinds of genes that suppress cancer:- The gatekeepers, who keep the gates of replication closed for most cells, except the select few who are allowed to reproduce.
- The caretakers, who keep the mutation rate low by using DNA checkpoints, initiating DNA repair, or programmed cell death for those cells that are too broken to be repaired.
In Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa (2010), the authors reconstructed the evolutionary history of the caretakers and the gatekeepers. They noticed that a burst of caretaker genes appeared when single-celluar life evolved, and a burst of gatekeeper genes appeared when multicelluar animals (Metazoa) evolved.
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| The green peak coincides with the emergence of celluar life. The red peak with the emergence of multicelluar animals. |
Cancer selection theory
In Cancer selection (2003), the authors discussed possible violations of Peto's paradox, and how they could be explained by evolution:
The idea that changes in morphology and life-history can expose animals to an increased risk of cancer has been argued most forcefully by James Graham in his 1992 book Cancer Selection. As a businessman familiar with manufacturing, he notes that changes in the design of a product often result in a transient decline in its quality. Analogously, the evolution of a novel morphology might interfere with the quality control of development — a breakdown that manifests itself as an increased incidence of cancer.
If cancer arises as a side effect of evolutionary change, it should be particularly common after very rapid bouts of evolution, before protective devices have had a chance to evolve.Thus, abnormally high rates of cancer should happen in body parts that has recently underwent rapid positive (bigger, longer, heavier...) evolution.
Domestic chickens are notoriously prone to cancers of the reproductive tract: in one study, one-third of females developed ovarian and/or oviductal cancer by 4 years of age. A likely, if unproven, reason for these high rates is that chickens have long been selected for high rates of egg production. In addition, dog breeds such as Great Danes, Newfoundlands and St Bernards, which have been selected for very rapid growth and large body size, have a 180-fold greater risk of osteosarcoma than smaller breeds. Breeds that are selected for small size do not show an increased incidence of cancers.So that's for chickens and dogs, how about humans?
Children are at greatest risk from osteosarcomas during the pubertal growth spurt. Juvenile osteosarcoma might, then, be a by-product of recent evolutionary changes in human growth. The pubertal growth spurt, in particular, seems to be an evolutionary novelty. It is absent in great apes and, some have argued, also in our predecessor Homo erectus.
The most common paediatric cancers are of the immune system (such as leukaemia or lymphoma). As a general principle, the immune system is expected to be among the fastest evolving systems in any species, because it will be constantly selected in new directions by co-evolving pathogens and parasites.The immune system is always undergoing rapid evolution due to an evolutionary arms race, as anyone knows from the yearly influenza.
The second most common class of paediatric cancers are of the CNS. We attribute this high frequency to the fact that our brains have increased threefold in size compared to those of chimpanzees.
The War on Cancer is a War on Evolution
In 1971, the American president Nixon started the War on Cancer. 48 years later, cancer is holding up well, despite repeated assualts from humans. In view of how cancer is an evolutionary disease, perhaps the reason why cancer is so difficult to fight is because it's a creative enemy. Evolution is a boundless source of creativity and surprises. Drug resistance and antibiotic resistance are just two instances of how humans are not doing well in a fight against evolution.Indeed, this perspective of seeing cancer as an evolutionary disease has informed some therapy proposals that treats cancer as a chronic pest to manage and tame, instead of a mortal enemy to fight at all costs. For example, instead of aggressively radiate a tumor to death, which usually leaves behind a few radiation-resistant cancer cells to come back with a vengeance, it might be better to cull the population with light radiation and keeping it in its place, without trying and failing to eradicate it. The radiation resistant tumor cells are not as efficient in reproduction as nonresistant tumors, so without aggressive radiation, the cancer colony would not become resistant as a whole.
Similarly, instead of using the most aggressive chemotherapy, a more restrained therapy schedule designed to shepherd the cancer colony could keep its population smoothly undulating in its place, without exploding and metastasizing.
Why is cancer interesting for non-biologists
Cancer is a good source of examples for evolution and its inhumanity. Evolution is often thought of as promoting of health, intelligence, and other cool stuffs. This is a reminder of the wildness and the inhumanity of evolution. As an example of somebody failing to get the point about the wildness of nature, here's some creationist dismissing cancer as an example of evolution:Not many of us who have seen friends suffer or die from cancer would sanctify tumors as “biological innovations” leading to anything good... mutation and selection can produce cancer, which destroys the human body. How does that support evolutionary theory?What a human, all-too-human thought, to say that cancer can't lead to "anything good", or to say that evolution is "anything good". They love humanity, and then wrongly demand that the evolutionary process by which humans are made is also loveable.
Cancer is a model of cooperation-vs-defection, the basic dilemma in societies, whether it's a society of cells or humans or bees. The emergence of multicelluarity is the first attempt to solve the problem of cooperation, and human society represents the latest attempt at solving cooperation. The ways that an animal body defends against cancer can be used by a society to defend against individuals who are going to harm it, and individuals who want to exploit a society from within can learn from cancer. A paper that explains this idea in depth is Cancer across the tree of life: cooperation and cheating in multicellularity (2015).
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| The five foundations of multicelluar cooperation, and the five ways that cancer subverts them. Figure from Cancer across the tree of life: cooperation and cheating in multicellularity (2015). |
Ecologically, humans are very similar to cancer. It's a species that's taking up a great chunk of the energy in an environment for their own growth and diversification. They evolve and congregate in big urban colonies, and metastasize tirelessly across the epithelium of earth. They reroute the energy flow of the ecology, via farms and livestocks, into their bodies. Roads carrying in wheat and barley springs up in an intricate network around their colonies like a web of angiogenesis.
Humans must take warning from the deadly fate of most cancer specieses. They have run out of space to metastasize on earth. In order to survive, humans must transform into a transmissible cancer, escape the prison of earth, to metastasize across the universe. Or become less cancerous and take care of its host better, that also works. Such sentiments are expressed in books like Only one earth. The care and maintenance of a small planet. (1972).
Keep in mind that I do not mean any moral judgment in comparing humans with cancers, in keeping with my extreme nihilism in regards to morality as a useful scientific concept. I simply describe it as a scientist sees it, that humans are like cancer in some ways, just as fetuses are like cancer in some other ways.
Cancer breaking out of a single body to become a species with independent existence is a shocking example of a species originating where species are not supposed to originate. It puts the whole idea of a "species" uncertain. Could perhaps misshapen proteins break out, and establish a new species? It would be more sophisticated than kuru, without needing human cannibalism for its own existence. Could dog sex cancer mutate again and gain control of dog brains, and build a dog zombie army?
Keeping in mind of the uncertainty of species helps us get to the brute reality of biology, where there are no species, no individuals, no cells, no genes, only atoms and the void. Abstractions, like laws, are useful, but must be broken when they are no longer a good description of reality.
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