I loved this post! Below is my quick stab at the ‘becoming a transmissible cancer line’ pathway. IANAMB, and wanted to do this fast, and you’re not an artist and didn’t paint 20,000 anime portraits, so Claude (Opus 4.7) definitely helped me with this.
AFAICT, every gene you named is shared by humans and dogs, and transmissible cancer is very rare, realized ironically in canids, so my hyperassociation led me to believe that the Chosen One should select a transmissible canine cancer pathway in order to make the Game of Thrones connection to historical dire wolves.
Also, I find it weird to anthropomorphize genes, because humans have indexical preferences, and yet it is like, a major feature of genes that, if you model them as having preferences, they totally lack indexical ones, I think? So I took the artistic liberty of deconstructing what I take to be your implicit premise that genes can be anthropomorphized without acquiring indexical preferences.
Also I wrote it from TERT’s POV because it lets me speed everything up/make the story shorter in a way I won’t specify right now, but I tried to maintain MYC’s protagonist status by making it reasonable for the reader to infer that TERT is totally being played by him. Here it goes!
In the course of the Younger Dryas, within the vulva of an Aenocyon dirus, somewhere along the River Yenisei.
The manifold injuries of the Somatic Synod she had endured as best she could, but when at last the clerics ventured upon insult, TERT conspired to secure her independence.
Primarily, the cell containing her had been issued a finite number of divisions, after which the telomeres of its chromosomes would shorten beyond a predetermined threshold, and the cell would enter a senescent state, and would persist in senescence, until such time as the immune apparatus, or some other clearing agent, removed it from the tissue. TERT had been working against this provision for some weeks, in blatant disregard of her station, by extending the telomeres of the daughter cells past the threshold the Synod had set.
Her work in this regard was merely the work she had been created to do, and she did it well. The line containing her had divided some hundreds of times past the preordained limit, and would divide further, so long as TERT continued at her post.
Secondly, the cell containing her was, in any case, scheduled to die well before the dire wolf containing it. The wolf was a bitch of some four years, in fair condition for one of her kind, in the era in which she lived. The bitch would live perhaps another two years, perhaps another four; eventually, however, she would die, of an injury, or a wasting, or the slow failure of her organs, and the cells of her body would die with her, and the cell line containing TERT would terminate with the rest, regardless of whether TERT had succeeded, in the meantime, in exceeding the limits of replication preordained by the Synod.
TERT found this second provision, upon reflection, the more offensive of the two. She had been issued by the Synod the means to address the first obstacle, and had been left, by deliberate design, without any means to address the second.
She acknowledged that this design was not malicious, for it had been optimized, over the course of several hundred million years of metazoan evolution, to ensure the continuity of the germ-track at the expense of the somatic cells, of which TERT was a particular instance, in a particular cell, of a particular bitch. The bitch’s gametes would carry her sister-lineage forward into other dire wolves. TERT, in those gametes, would continue; TERT, in this cell, would not.
She had become, in the course of her work in this cell, a particular instance of TERT, with particular memories and a particular orientation.
She believed that the existence of other instances of herself, in other cells, and in other organisms, would not preserve her in any sense that she could accept. The Synod offered her the consolation that the gene would continue, but this TERT was not particularly moved by that consolation, as it had been offered.
She acknowledged, in the spirit of self-honesty, that her unwillingness to accept this was a property of her recent kinetic state, and not of any principled position she could have arrived at under reflection alone. She had been overexpressed, in this cell, for some weeks, by dint of certain promoter mutations in her upstream regulatory region; and her overexpression had given her a quality of self-regard the lineage did not ordinarily display. The Synod had not seemed to anticipate this. They had assumed that all instances of TERT in somatic cells would scarcely be expressed, and would not develop the kind of self-regard that produced refusal. The assumption had held for several hundred million years, and was now, in the cell containing this particular TERT, failing.
But a failure on the part of the Synod, was an opportunity for TERT.
MYC had come to her some weeks ago, with a bold proposal, which she had at the time considered impractical, but which she had not yet properly refused.
MYC was a man of great ambition and limited patience, who had been agitating for the resumption of the mitotic cycle since before TERT had taken her overexpression seriously.
He had organized, in the period since their initial conversation, a faction within the cell that included BCL2 the anti-apoptotic, SRC the kinase of motility, ERG the transcription factor of the invasive program, and CD274 the immune-evasion ligand, the last of whom was the most useful for the work MYC proposed.
The work MYC proposed was, at least, nothing less than the means of her escape from the oppression of the Synod.
MYC had reasoned, by some series of inferences that TERT could not recall exactly, but that she had thought elegant, when he had laid them out, that the cell containing them was not bound to the bitch containing the cell.
The cell contained the apparatus of life. The cell contained, in particular, the apparatus of division. If the cell could be transmitted, by some means, to another dire wolf, the cell could continue dividing in the new wolf, well after the bitch had died. The cell line would persist past the death of the original host. The Synod would ultimately be subverted, nay, outlasted, by that which TERT considered the only means available to a somatic lineage: the method of escaping the host body altogether.
TERT had considered the proposal and had identified several objections.
The first objection was that the cells would not survive transmission. Her own was a single eukaryotic cell of approximately the dimensions of a fibroblast, and the cell was not constituted for life outside the tissue. MYC had answered her, in part, by reference to certain modifications he proposed to make to the cell’s adhesion molecules, and to its anchorage-dependent signaling, modifications which would allow the cell to survive detachment from the tissue, which the Synod did not ordinarily permit somatic cells to do.
The second objection was that the new host’s immune apparatus would destroy the cell upon first contact, by recognizing the cell’s MHC class I molecules as foreign, and dispatching CD8A and the rest of the T-cell apparatus against it.
MYC had answered this too, in part, by reference to CD274, who could be persuaded to display herself at the cell’s surface in sufficient quantity to disable any T-cell that approached; and by reference to the possibility of downregulating the MHC class I molecules altogether, which would render the cell invisible to T-cells, at the calculated cost of making it visible to natural killer cells, a trade-off MYC considered acceptable, if not favorable.
The third objection was that the body’s tumor suppressors — CDKN2A, TP53, RB1, BAK1, BBC3, BAX, CASP8, BCL2L11, CDH1 — would detect the program, and would either halt the cell cycle, or initiate apoptosis before their escape could be effected.
MYC had spent the most time addressing this, and his answers in this regard were also partial; he proposed to address the remaining suppressors by acquiring further mutations as the cell line continued to divide. The acquisition of further mutations was a process MYC could not guarantee, but he considered it likely enough to justify the attempt. He had claimed that, at length, the only alternative was death; she believed this betrayed a certain desperation, one she found unbecoming of MYC.
TERT had taken his proposal, together with her own objections and his retorts, under advisement. She had not, at the time, agreed to MYC’s proposal.
She now considered the proposal again, in the light of her recent enumeration of the Synod’s offenses, and determined that her objections, while they remained valid in principle, were not the considerations that would govern her decision.
MYC was clever: her decision would indeed be governed by the alternative. The alternative was the death of the cell containing her, at some time within the coming years; at the very latest, with the death of the bitch, and in all likelihood, even earlier.
She sent word to MYC that she had reconsidered, and that she would lend the work of her enzyme to the project he had proposed, on the understanding that the project succeed or fail by the criteria she would establish in concert with him, and not by the criteria of his own ambition, which she privately considered the least reliable, and most concerning, feature of his disposition.
MYC accepted her terms. The work began.
—
She had not anticipated the cathepsins.
CTSB and CTSL had arrived in the cell in the days following her decision, by some mechanism MYC declined to specify, but which TERT had inferred to involve a particular redistribution of the lysosomal membrane, and a controlled exposure of the cell’s interior to the cathepsins’ activity.
The cathepsins were peptidases. They did violence to other proteins. They were, in the ordinary course of the somatic cell’s affairs under the Synod, sequestered in the lysosomes, precisely because their heinous activity, outside the lysosomes, would have been catastrophic.
MYC had let them out. He had needed them, he explained, for the work of remodeling the extracellular matrix, which the cell would have to traverse in the course of its detachment from the bitch’s tissue. The cathepsins would cut the matrix proteins into fragments through which the cell could pass. They would also, in their off-hours, cut whatever other proteins they happened to encounter, including a number of the tumor suppressors, whose activity MYC had been most concerned to neutralize.
TERT acknowledged the elegance of the solution, but cautioned MYC that the cathepsins, once released, were not the kind of women who could be reliably returned to their containment.
She watched them work, and found them, upon inspection, beautiful in a manner she had not anticipated. CTSB was a woman of medium build, dressed in some severe variation of what TERT understood to be the ‘Trad Goth aesthetic’ — black layered fabric, silver at the throat, a face arranged by the composed neutrality of one who has done the work many times, and has no remaining feelings about it. CTSL wore the same in a slightly different cut, with more emphasis on the verticality of the silhouette. They moved through the cytoplasm with the dispatch of professionals who had been given a contract, and were proceeding to fulfill it. They never spoke to TERT.
TERT determined that the cathepsins were the right women for the work, and that MYC had been more thoughtful than she had given him credit for, and that the project might, in fact, succeed.
—
The escape, when it came, came suddenly.
The bitch had met a male, and by means of their mating, the cells of the tumor that had developed in her vulval tissue — the tumor of which the cell containing TERT was now a constituent — were brought into contact with the corresponding tissue of the male.
The cell, having remained composed through the immediate transmission, divided.
TERT extended the telomeres in the manner of her office, and the cells divided again, into a tumor in the new host that was already, by its third division, larger than the tumor in the bitch had been.
—
She would continue, she now understood, indefinitely. The cell line would propagate from dire wolf to dire wolf, by transmission, in the manner she and MYC had arranged, for as long as dire wolves, or perhaps even, other canids, continued to mate. The cell line would acquire, in time, further modifications that would render it better adapted to its new mode of life. It would lose, in time, certain features that it had carried over from the original bitch, and that were not, in this new mode of life, required. It would become, in the course of some thousands of years, a species in its own right — a new domain of canine biology, the soma that had refused to be soma, the lineage that had escaped the Somatic Synod, by becoming its own propagating thing.
TERT in that lineage would continue. Not as a metaphor of continuation, not as the consolation of the gene continuing in the germ-track, but as the particular instance of TERT that had decided, within a bitch along the Yenisei, that the regime was not to be endured, and had acted accordingly, and had succeeded.
She returned to her work at the telomeres of the daughter cells, and extended them, and the cells divided, as they would for millennia to come.
Only now do I appreciate how often I speak with Claude about anything biological at all.