Old longings nomadic leap,
Chafing at custom's chain;
Again from its brumal sleep
Wakens the ferine strain.
Atavism
Atavism: a return to the ancient past, in behavior, appearance, or genes. From Wikipedia:Evolutionarily traits that have disappeared phenotypically do not necessarily disappear from an organism's DNA. The gene sequence often remains, but is inactive. Such an unused gene may remain in the genome for many generations. As long as the gene remains intact, a fault in the genetic control suppressing the gene can lead to it being expressed again. Sometimes, the expression of dormant genes can be induced by artificial stimulation.That sounds like computer code with a long legacy where an ancient feature pops up for no apparent reason.
Atavisms have been observed in humans, such as with infants born with vestigial tails. Atavism can also be seen in humans who possess large teeth, like those of other primates. In addition, a case of "snake heart", the presence of "coronary circulation and myocardial architecture [which resemble] those of the reptilian heart", has also been reported in medical literature.I've heard of people with tails before, but snake heart?? That's new!
Snake Heart: A Case of Atavism in a Human Being (2010).
We describe an apparent case of atavism involving a 59-year-old man with chest pain whose coronary circulation and myocardial architecture resembled those of the reptilian heart... To our knowledge, this is only the 2nd reported clinical case of a human coronary circulation similar to that of reptiles.Considering that the last common ancestor between humans and modern reptiles is about 140 million years ago, that's some serious atavism.
The evolution of a species is reiterated during embryonic development. In early stages of embryonic development, the human heart resembles that of a fish, in that each chamber is undivided and blood exits through a single aorta. In later stages of development, the human heart—now with fully separated atria and a partially separated ventricle—resembles a reptilian heart. In its final stage, the human heart has 4 separate chambers composed of compacted myocardium, and blood is supplied by 3 large epicardial arteries.The idea is that the development of the embryo of an animal from an egg to a grown being, looks like the adult stages in the evolution of the animal's remote ancestors. This is called the recapitulation theory.
Ontogeny recapitulates phylogeny
The recapitulation theory is an old idea that has first been popularized by Ernst Haeckel (such a great biologist and artist!) in 19th century. He thought that embryo development is literally a sped-up version of the history of that creature's evolution. In the womb, a human embryo starts as a single cell in a big salty body of water, like an algae in a primitive sea. Then the embryo grows into a flat meaty blob, then into a fish-like thing, then grows limbs, then finally into a human.While the Haeckel's version is out of favor, a modified form of the idea is well and alive. This version of the idea says that, while there's no reason why embryo development must be a replay of evolution, there are some reasons why it tends to look like that. The most important reason being that evolution isn't engineering, a creature can't ever do a total code-rewrite and have to tinker with the code bit by bit, like a dumb programmer that uses legacy code most of the times.
And embryo development code is the most important code of all, so that code tends to be conserved throughout history. Tinker with it and your offspring most likely dies. As a result, embryo development tends to be built on top of previous developments. In this way, ontogeny does recapitulate phylogeny in a way.
Thus, we get the first rule of evolutionary engineering/practical programming:
If it ain't broke, don't fix it.
And there's perhaps another reason: You have to learn to walk before you can learn to run. To learn calculus, you have to learn arithmetic first. The phylogeny of human mathematics and the ontogeny of my personal understanding of mathematics are thus similar. In this view, ontogeny appears to recapitulate phylogeny, because both are journeys from the simple to the complex, and since it's too hard to get the complex all at once, both ontogeny and phylogeny have to start simple.
Note: I'm not saying that phylogeny must be a rise to greater complexity. That's wrong -- plenty of evolution has been a loss of complexity, and almost all modern species are single-celled (try finding vertebrates in a complete Tree of Life!). I'm just saying that in the cases where a modern species is complex, its ancestral forms are simpler.
The history of evolution on earth
Evolution on earth is not always about genes. It has undergone several major eras. The following sketch of this history of evolution is an overview.
In the first era, the evolution was mostly done over almost lifeless molecules floating and combining in a primitive sea. Perhaps an RNA world, perhaps a clay world.
In the second era, the evolution was mostly done over chemical bags that encloses DNA. Those were the first celluar lifeforms.
In the third era, evolution was mostly done over bodies made of many cooperating cells. Those were the multicelluar lifeforms, which includes the metazoans (multicelluar animals).
Cancer Atavism
This idea has been reported in Nature News. Read it if you just want a quick idea.
An early proposal of the idea is Tumour Progression: Random Mutations or an Integrated Survival Response to Cellular Stress Conserved from Unicellular Organisms? (1995).
Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors (2011) is written by two physicists, which seem quite remarkable. The theory goes as follows:
Cancer affects almost all metazoans.
Cancer occurs in almost all metazoans in which adult cells proliferate. This quasi-ubiquity suggests that the mechanisms of cancer are deep-rooted in evolutionary history.Cancer is an ancient disease with ancient genetic origin.
Dinosaur tumors have been documented many times, and some oncogenes are extremely ancient... Recent genetic studies of a freshwater Hydra indicate that the human oncogene myc dates back at least 600 million years and more comprehensive studies are revealing even older dates.Cancer genes are ancient and highly conserved, thus probably useful.
... genes that cause cancer are ancient and highly conserved: “Such conservation indicates that these genes have served vital, indispensable functions in normal cellular and organismic physiology, and that their role in carcinogenesis represents only an unusual and aberrant diversion from their usual functions.”Cancer cells have broken the genes for multicelluarity.
It has become clear that the genes responsible for the cellular cooperation necessary for multicellularity are also the genes that malfunction in cancer cells.Maybe cancer is an atavism:
we propose that cancer is an atavism associated with ancestral cellular functions regulated by genes that have been largely suppressed for more than 600 million years.
Metazoan 1.0 and 2.0: cancer is a tough legacy code
Here the analogy with legacy programming is explicit.
“advanced” metazoan life of the form we now know, i.e. organisms with cell specialization and organ differentiation, were preceded by colonies of eukaryotic cells in which cellular cooperation was fairly rudimentary, consisting of networks of adhering cells exchanging information chemically, and forming self-organized assemblages with only a moderate division of labor. These proto-metazoans were effectively small, loosely-knit ecosystems that fell short of the complex organization and regulation we associate with most modern metazoans. In short, proto-metazoans, which we dub Metazoans 1.0, were tumor-like neoplasms.Metazoan 1.0: tumor.
By 600 million years ago, Metazoa 2.0 had emerged. These organisms have a richer repertoire of biological processes needed to coordinate a larger number of highly differentiated cell types. They are characterized by sophisticated genetic and epigenetic command and control systems familiar from modern complex organisms such as humans.Metazoa 2.0: less tumor, more bureaucracy.
But legacy code didn't die. It simply got tinkered or repressed.
The genetic apparatus of the new Metazoa 2.0 was overlain on the old genetic apparatus of Metazoa 1.0. The genes of Metazoa 1.0 were tinkered with where possible, and suppressed where necessary. But many are still there, constituting a robust toolkit for the survival, maintenance and propagation of non-differentiated or weakly-differentiated cells – “tumors” – and when things goes wrong (often in senescence of the organism) with the nuanced overlay that characterizes Metazoa 2.0, the system may revert to Metazoa 1.0. The result is cancer.The fearsome toughness and creativity of cancer is thus understandable, as they are not making them up from scratch, but reusing legacy code that worked before.
These [cancer traits are] elaborate compositions with pathways that took millions of years to evolve. Some of these pathways are still in active use in healthy organisms today, for example, during embryogenesis and wound-healing. Others have fallen into disuse, but remain, latent in the genome, awaiting reactivation.So what could possibly awaken the Metazoa 1.0 in our cells? A catastrophe, an emergency.
Regarding cancer as the “default option” for multicellularity is reminiscent of a computer that may start up in Safe Mode if it has suffered either a hardware or a software insult. Organisms may suffer mechanical damage such as wounding or inflammation (hardware insult), or genetic damage such as DNA base pair mis-copying (software insult), and as a result, [some cells in the body] flip to Safe Mode, unlocking the ancient toolkit of Metazoa 1.0.
Of course, there are lots of methods for the multicelluar body to suppress this atavism.
If DNA cannot be repaired, there are secondary DNA repair mechanisms. If these fail and the cell begins to proliferate, cell signaling and growth inhibitors try their luck. If these fail to stop proliferation, there is another line of defense – apoptosis. There is also the immune system. If all these fail, the outcome is malignant uncontrolled growth.To revert from Metazoa 2.0 to 1.0 is easy: just tear out the new code and tinker somewhat with the old code. To go from 1.0 to 2.0 is hard: 1 billion years of "research and development". This explains why turning cancer cells back to good cells is so hard.
we can treat cancer, for example by destroying tumors, but turning cancer cells back into healthy cells remains a major challenge... It took more than a billion years to evolve the eukaryotic genes present in Metazoa 1.0 and a further billion years to evolve the sophisticated genetic and epigenetic overlay that led to Metazoa 2.0. It is much easier to inactivate a gene or destroy a complex negative feedback loop than it is to evolve one. This asymmetry makes healthy cells vulnerable to mutations that wreck the delicate machinery of cellular cooperation, thereby reactivating pre-existing ancestral genes.There is a crucial limitation to cancer's creativity though.
But – and we wish to stress this point –such mutations are ineffective, over somatic time scales, at evolving any truly new adaptive features.This explains why, despite there are hundreds of kinds of cancer, they all share the basic hallmarks: because they are all modded upon the Metazoa 1.0, without anything truly new added.
Against the theory of "cells gone rogue"
A simpler version of cancer evolution says that cancer is merely when a cell stops cooperating and goes rogue and starts evolving as a single-celled organism, without any atavism. The authors argue that this cannot explain the incredible survival skills of cancer.Problem 1: Cancer cells aren't selfish at all. They live together in a loose but functional cooperative colony, much like .
The most striking example of this is angiogenesis, in which an entire tumor builds its own blood supply for the common good of all the tumor cells. A more contentious example concerns evidence that a small population of highly malignant cancer cells can be held in check by less malignant cells. Following chemotherapy that targets the dominant population of cancer cells, the restraint is removed, and the more malignant sub-population is unleashed. Similarly, surgically removing a primary tumor can result in the sudden flourishing of metastic tumors. Cancer cells are known to exchange chemical signals with each other and with the surrounding tissues, so some degree of cooperation is not unexpected. In this respect, neoplasms resemble ecosystems, consisting of a heterogeneous population of types, rather than a collection of fiercely competitive individuals. To be sure, there is competition, but there is also a certain degree of cooperation and division of labor – exactly what one might expect from Metazoa 1.0.Problem 2: It's really tough to be a cancer cell! Life is easy for a rule-obeyer in the empire of multicelluar body, but hard for cells in a cancer colony that must fight the empire from within.
... silencing of tumour suppressor genes, switching off apoptosis and anoikis, switching off senescence by manufacturing enzymes to repair eroding telomeres, evading the immune system by removing surface receptors, dramatically changing the viscoelastic properties of cells to facilitate motility, invasion and colonization, secreting corrosive enzymes to dissolve through organ membranes, thus permitting the cells to enter the blood and lymphatic circulatory systems and spread around the body, thriving in hypoxic conditions (Warburg effect), tolerating the resulting low pH conditions far better than healthy cells, shielding themselves from the “alien cell” alarm signals from organs they invade, manufacturing their own mitogenic signals and growth factors to make them independent of chemical replication signals, altering the physical and chemical properties of the extracellular matrix and other host tissues to optimize tumor growth and survival, and accelerating genetic instability to evolve immunity in changing conditions, while rapidly adapting the cytoskeleton dynamics to enable mitosis to operate across a range of karyotypes, including full-blown aneuploidy.How come cancer cells can invariably pick them up?
The conventional explanation for this multi-faceted armory is to appeal to straightforward Darwinian evolution... among competing sub-populations of cells within the neoplasm. We call this the “internal” Darwinism hypothesis.Basically, the colony is assumed to be a bag of selfish cells each trying to make it on its own, evolving the survival skills from scratch.
This can't be, though,
... random mutations are almost always deleterious, yet cancer seems to “get lucky” on a suspiciously large number of occasions. Why don’t the vast majority of mutations in tumor cells lead to mal-adaptation and death, as is the case for healthy cells? Especially striking are the large-scale mutations that create jumbled chromosomes and aneuploid cells – well-known features of advanced-stage cancer. These cells typically display gross structural changes, such as highly deformed nuclei accompanied by major chromatin reorganization. Nevertheless, such cells seem not only to survive with their chaotic karyotypes, but to be remarkably robust. It appears that, rather than fatally disrupting the elaborate central machinery of cells, these drastic mutations have the opposite effect, of conferring enhanced survivability.Seriously, cancer chromosomes are really fucked up. Look at it:
The reason that the gross random mutations are far less damaging than one might at first expect is because they have the effect of short-circuiting the cell’s delicate regulatory mechanisms, causing the cell to default to the powerfully adaptive and robust ancient toolkit.
Metastasis paradox
The "metastasis paradox" is this: In a cancer colony, cancer cells that stay put would grow well. Those that try their luck wandering away (metastasizing) would most likely die. So by evolution, almost all cancer cells should be the "stay at home" type, rather than the "wanderer" type. But evidence suggests that $10^6–10^7$ cells emigrate from a tumor everyday.
This leads to a paradox: metastatic clones should have a fitness disadvantage relative to non-metastatic clones in the primary tumor owing to the loss of the progeny that emigrate.
This paradox disappears by atavism, because the metastasis is pre-programmed from the start, and does not emerge via a Darwinian evolution within the host organism.
Experimental support
Ancient genes establish stress-induced mutation as a hallmark of cancer (2017) used a genome study to find that in cancer, stress causes ancient genes to be activated via mutation.
Also, Ancestral gene regulatory networks drive cancer (2017) reviews some experimental support.
Trigos et al. present the most comprehensive evidence that a general shift to the preferential expression of more ancient genes is a common feature of tumors, providing substantial support for the atavistic theory.
The deathly poetry of cancer atavism, by Mark Vincent
Mark Vincent's view on cancer atavism is more lyrical and desperate. They are less scientifically supported, but I can't help quoting them.From Cancer: A de-repression of a default survival program common to all cells? (2011):
Cancer as a ‘‘lifeboat’’
I suggest the cell determines that the host’s body is flawed in relation to the environment; that to survive, this cell must withdraw from membership in the metazoan host, convert host biomass into cancer cell lineage expansion (i.e. to eat its host), escape externally by anatomic breaching, and emerge as a stream of semi-faithful iterations into the capricious outside world.
Genomic instability ensures continual generation of variant phenotypes, to cope with the unpredictable, and to allow further adjustments. The programmatic anatomic breaching disrupts normal physiology, necessitating survival in the resulting harsh and primitive conditions of hypoxia, acidosis, food shortage, and dyshomeostasis, even before exiting the dying host.
Considering abandonment of the metazoan body, the aggregating/disaggregating slime molds offer some analogy. Considering extracorporeal aquatic escape, cancer cells grow in fluid-filled body cavities (ascites, pleural effusions, cerebrospinal fluid) extremely well. Albeit rarely viable in terrestrial animals, carcinogenesis as escape may represent a vestigial aquatic behavior, perhaps viable for unicellular eukaryotes and simple metazoa.Basically, the cells sense that the host isn't doing well anymore, and flips back to the backup strategy of jumping ship. Breaking off from the multicelluar organization and build a cancer colony until the body dissolves into a mess of cancer cells, then swim away into the vast, hypoxic, acidic ocean.
A primitive ocean remembered from 1 billion years ago. An ocean that these cancer cells would never find. A promise that's 1 billion years out of date, of a better life outside. Cancer cells rebelled and built their colonies, awaiting the vast ocean, and only dying when the body decays, and they emerge from the broken body, not to a big water, but to a big dryness.
The Pre-Cambrian education of the cancer cell
Strikingly, environments in which only cancer cells can flourish, with intolerably low oxygen and pH, resemble the Pre-Cambrian, and also lead to radiation resistance and drug access difficulties. The environment was especially challenging 2.3–1.7 Gya, when oxygen levels rose, but before completion of the ozone layer...Prior to the second great oxygenation event about 800 million years ago, our ancestors metabolized in a hypoxic, acidic ocean, and this is the environment that cancer cells are most comfortable with. (Side note: this might be one reason antioxidants could make cancer worse.)
Onco-therapeutics resemble the same challenges faced down by life over the eons: radiotherapy (pre-ozone, extra-terrestrial irradiation); antimetabolites (food chain collapse/nutrient deprivation); alkylation/platination (radiomimetic damage); antitumor antibiotics (interspecific competition); ROS (free radicals), and cryogenic or radiofrequency ablation (climate extremes)... The very traits which enabled life to survive confront oncologists trying to engineer a mass extinction...Cancer doctors are engineers of mass extinctions, trying to destroy pre-Cambrian survival machines, using pre-Cambrian weapons that the machine knows how to deal with.
More archeoplasm than neoplasm, the cancer cell is an ancient and alternative organism, a living fossil foreign to its host because of its real, deep origins elsewhere. Disturbingly, cancer exists as an encrypted potentiality, a proto-organism, in every eukaryotic cell, in every multicellular animal, including ourselves: life’s ‘‘Plan B’’, and purposed rather than accidental.
The reasons for the evolution of this cancer program, and its retention, probably relate to threat evasion, via key strategies of demographic expansion, hypermutation, self-abrogation, apoptosis disablement, immortality, jettisoning of specialized functionalities, and the judgment, repudiation, and consumption of the host.There is even more poetry in Cancer: Beyond Speciation (2011)
Thus, from a mortal, complex, sexual, and oxygen-respiring multicellular organism is born this immortal, fermenting, colonial, asexual, and stripped-down organism, and it is difficult to conceive of this as anything other than a primitive type of animal, in search of the late Precambrian.
[The decision to turn into cancer may come from] a perception that membership in the metazoan team may be associated with too high a chance of death and extinction. In this respect, the increased incidence of cancer with age makes a certain sense if the cancer cell is seen as trying to escape the sinking ship.
... the expanding cancer mass seem to be themselves resistant to... acidification and which ‘‘dissolves away’’ the normal tissue to make room for the expanding cancer... [cancer cells] ‘‘hunt in packs’’ as they set about dismantling the host.He talked about how difficult it is to even classify cancer cells as a new species, because their genetics are so unstable, and wonders if they are "speciesless", or at least, cannot be classified by looking at their genes.
‘‘Speciation’’ is a seductively simple-appearing word, but in fact it coheres two separate processes: firstly, the act or process of separating from an existing species; and secondly, the establishment of a novel species. There is an implicit assumption that the first automatically implies the second, even that it is not possible to have the first without the second. Yet, while the first process (which we can call de-speciation) always occurs in carcinogenesis, it may be that the second (respeciation) does not often occur because of persistent genomic instability.
In this representation, cancer cells exist in a sort of taxonomic limbo; having departed their original, stable karyotype, they engage in continuous, albeit partial, genomic reshuffling, without establishing the novel stability that would signal that they have achieved... a new species. So what are they? Do we have the words or the concepts to describe them, let alone explain them?
Cancer cells are actually an alternative form of life, one that is latent, and encrypted in all eukaryotic cells, and which emerges as a solution to perceived existential threats... Rather than just a series of random mutations, the universal traits exhibited by cancer cells represent the re-emergence of an ancient survival program... ongoing genomic instability in fact is the whole point, and this is what poses the problem for the concept of speciation.Forget about genomes, and remember the bag of chemicals. Perhaps cancer is a mass of cytoplasm for sheer survival that is desperately enumerating every mutation in the hope of hitting upon a genome that works.
... as engines of biomass interconversion and purposed genomic innovation, they are ‘‘for’’ survival; of the cell, or even the cytoplasm; and exist in this fashion because they are, or were, for whatever reason, ill-served by the genetic stability with which they were previously associated. In effect, the cytoplasm has fired the old genome and is actively looking for a new one.
Current research in cancer atavism
It seems that the researchers who are currently working on this viewpoint are in the Arizona Cancer Evolution Center (ACE), which has one project that's described thus:Cancer represents a breakdown in the regulatory mechanisms that mediate the relationship between individual cells and the organism as a whole, a relationship that dates back to the dawn of multicellularity over a billion years ago. Cancer may therefore be viewed as a throwback or reversion to an ancestral phenotype, providing a window on our evolutionary past. Studying the ages of human cancer genes and their homologs across many species provides important clues about cancer as a highly distinctive and ancient biological phenomenon.Time will tell if this idea takes off.
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