I noticed on youtube an excellent podcast called Target Cancer, hosted by Sanjay Juneja, about all the latest technologies and treatments for cancer, and decided to review two of its episodes which I find particularly important and informative, the one in which a guest was Jason Fung: The Surprising Link Between Intermittent Fasting, Diabetes, and Cancer. Dr. Fung Explains - Part 2 , and the one in which a guest was Michael Levin: Fixing cancer cells and Immortality.
To me, there is no doubt about which of the two questions mentioned in the title of this essay is more important, it is cancer, however, the connection between them increases the importance of the other too. To an untrained eye in this issues, to which the existence of this web site may also come as a surprise: https://www.thethirdwayofevolution.com/ , let me sketch that connection. In his exposé, Dr. Fung uses this table to compare traits of three categories of living agents:
The last row raises the question, if multicellular organisms are genomically stable, how do they evolve? This question implies that we actually think that without a change in a genome, there is no evolution in the first place, which is of course not at all a safe assumption. If you are not sure about that, you can ask Chat GPT to summarize it for you, for example:
Are inherited epigenetic changes considered an evolution?
Are inherited epigenetic changes considered an evolution? another conversation
But if we assume that we do think that, just for the sake of argument, then it explains why Lenski experiment makes sense as an E. coli long-term evolution experiment, but it would not make any sense as some multicellular species long-term evolution experiment, because evolution of unicellular and multicellular organisms are two distinct subjects, which require different explanations, due to a mechanism of genomic stabilization which is not present in unicellular species. Hence, even if "random mutation directed selection" explanation was sufficient for the former subject, it does not necessarily mean it should be sufficient for the latter.
That is one issue, another is a fact that "replicator vehicle" paradigma is a rather parochial and naive scientific view that is based on two dogmas of molecular biology, Central and Anfinsen's, that paradigma intends to explain what are proteins supposed to do, as a result of how they are built, and this is extrapolated to explain also what are cells supposed to do, as a result of what proteins do. So, what proteins do is compared to a program that, once built and started, is autonomous in its behaviour, apart from eventually reading again further instructions on how to act from the same DNA it was created, while signalling from other proteins and cells is viewed as a result of something that must have been somehow coded in the DNA in the first place, at least what signals they may choose to exchange at certain points in time, if not already what signals will they precisely exchange and when. Because, the source of information in that simplistic view must be one, that is reliably transmitted (inherited) during reproduction, apart from allowing the noise in that transmission channel (mutation) which accounts for novelty through directed selection in the process of evolution.
However, besides DNA, the other information storage (memory) intricately connected to DNA that exists in every living organism is a bioelectric network that handles cell signaling, of which neural network is just one instance (excellent insight from Levin when he is talking about various problem spaces that such networks navigate through), and that network is supposed to handle critical signals such as the one for apoptosis, or SIGKILL in unix (kill -9).
Getting back to cancer, this is critical to understanding its causes, of which Fung and Levin give two distinct and complementary views. Levin focuses on something that may be seen by a traditional view as an intermediate cause, but that is common to each and every cancer, and that is the obstruction of normal communication between cancer cells and healthy cells, which results in cancer cells not perceiving themselves any more as an integral part of the "common collective self" of the multicellular organism, and they begin to perceive suddenly that organism as an environment, comparable to that how single celled organisms view the host they infected. This is where Levin sees the chance for an alternative treatment and prevention of cancer, by sending them signals to return to normal cooperative mode of operation. Under normal circumstances, this would trigger immune cells to intervene and suppress that rebellion, which is a proper analogy for this condition, that happens continously during life of a multicellular organism. That is why cancer is more than any other condition the one that can be ascribed to suppression of immune system. While for example infectious diseases can be ascribed also to the lack of hygiene, which can be defined as prevention of infectious agents to enter the organism in the first place. Fung focuses on something that may be seen as a root cause of the problem, it all depends on the verdict if the previously mentioned view is really that parochial and simplistic as I mentioned.
Namely, he explains that the main cause of cancer is a knock out of genes that make multicellular cells multicellular, by chronic sublethal injuries, that cause retrograde evolution, that is backward from cooperation to competition modus operandi, which is normally suppressed by genes that were developed later during evolution of multicellular organisms, but now get exposed due to a mentioned cycle of chronic sublethal injuries that selects cells that can survive those injuries, which must effect their DNA in order to become effective, that is, to start the expression of previously suppressed unicellular genes which normally exist in every cell of multicellular organisms. As a result, such cells get de-differentiated, have no purpose in the context of multicellular organism, and they basically start to proliferate uncontrollably, and read all the parts of their DNA in that process, particularly the ones that instruct them to act "selfishly, but having smaller self in mind", such as no normal cell would do, which causes their huge genomic instability/variety. Plus, they start to migrate in the process of metastasis, they change their metabolism from oxidative phosphorylation to glycolysis, and things get bad really fast, so that one can conclude that there is really just one thing worse than sublethal chronic injuries, and that is a lethal acute injury. And that explains from a new and insightful point of view why all previously known prevention measures should be honoured, such as avoid carcinogenic impacts (I am pretty much paranoid about that, particularly with respect to sun exposure), keep the immune system strong, adjust the diet (for example through intermittent fasting), etc. There are some additional novel insights in it, such as that metastasis is actually an early event in cancer development, which has its consequences as well, regarding treatment of cancer.
As I already mentioned, both views are very much worthy of considering, but I would get back once again to the main question, and that is if cells should really get affected at DNA level in order to produce cancer, which is not clear to me at the moment. I am not even sure if the two views are not partially opposing each other, regarding that question. One thing that is apparent to me, is that cancer cells, although very good at proliferating and mutating, are not devoid of any paracrine or juxtacrine signalling to their neighbours, if they can recruit them to produce for them new blood vessels, in the process of angiogenesis. That is much like a rebellion of peasants that decided they do not want to be anymore a part of feudal state which is oppressing them, but they realize they cannot survive on their own, although they would, if they were left alone by feudal soldiers, just taking into account their self sufficient ability to produce food (and other critical life sustaining commodities) for themselves, and to reproduce themselves in a traditional manner. So they have to resort to contact some other people, not originally part of their rebellion, to obtain goods for which they still lack skills to produce on their own. Eventually, if allowed (if not crushed before), they would even organize some kind of peasant state (or communist state, that would eventually fail on its own, without getting crushed from the outside).
Finally, one should mention that besides cancer, experiments with xenobots, also reveal the potential of cells that were originally part of multicellular organisms, to live for at least some time in circumstances in which they are not any more controlled by that greater collective self. They were simply mechanically extracted, and not genetically manipulated in order to do so. That is a really exciting discovery, and true achievement in experimental biology. But, what it actually tells us regarding our question, what is a root cause of cancer? Does it show that cells can act in unicellular mode altough they originate from multicellular organism, and they were not genetically manipulated? Meaning, it is not necessary for cancer cells to become that way either? This is argument pro Levin, if we recognize that there exists some kind of Levin vs Fung opposition regarding that matter.
However, an argument against Levin is another pair of videos, about somewhat different topic: Where is Anatomy Encoded in Living Systems?
https://www.youtube.com/watch?v=1Ecm8UgiXBU created by Adam Tildesley about Hox Genes
https://www.youtube.com/watch?v=AC2_S-wcJes Michael Levin about where is anatomy encoded
This maybe shows that we know where is anatomy encoded in the genome, and that Levin for some reason downplays that fact, and emphasizes that DNA contains only instructions for protein synthesis, leaving to free interpretation if these instructions can define anatomy by themselves or not, and the fact that we now know that anatomy defining information during morphogenesis eventually gets transwritten into bioelectric network (thanks to him) does not change the original fact about Hox Genes?
Finally, there is an issue of benign tumor, how do they fit in the picture? Such tissue is obviously dysfunctional and purposeless, ie, not exactly the part of a healthy body plan, but not as big a problem as a malignant one. How gray zone is this really?
I have made a recapitulation of all these questions by double checking them with Gemini and Chat GPT:
Multicellular Evolution: Beyond Random Mutation
Comments
Post a Comment