Some of you may remember that line. It’s from “The Things“, that unabashed piece of fan-fic I wrote a while back (and which seems to be getting way more love than I was ever expecting). A few of you may even remember the research that inspired it — I blogged about it a few years back, rambled on about somatic evolution and intracellular competition. I mused about evolution in a world where Darwinian processes never really went away even at the intraorganismal level, where even within the organism it was Every Cell for Itself. I called it Cancer, For the Greater Good, and I wondered if some far-off world that played by those rules might have given rise to the shapeshifter from Carpenter’s movie.
Maybe not so far-off, as it turns out. If there’s anything to this paper by Davies & Lineweaver, I might as well have been talking about Earth — because if these guys are right, we are all cancer.
I don’t mean this proximally. I mean it in the sense that all birds are dinosaurs — because according to Davies & Lineweaver, cancer (more precisely, “tumor-like neoplasms”) is the common ancestor of all animal life. Every malignant lump on your breast, every metastatic colony proliferating through your marrow, is just a rebooted revisitation of your grandmother a million times removed.
The basic idea’s petty straightforward. Natural selection reaches into every corner of the biosphere, you see; and a billion years ago that meant every cell for itself because unicellular life was the only game in town. A mere six hundred million years back, though, all that had changed. Metazoans were everywhere — cells grouped into colonies with specialized subsystems called tissues and organs —and somehow, within those colonies, the whole beat-the-competition thing had fallen out of favor. Cells worked together, now; hell, red blood cells even gave up their nuclei for the good of the organism, which really puts the kibosh on any future solo career. I think it had something to do with inclusive fitness.
In between, presumably, there was something halfway between Cuba and the US, some intermediate form between everyone for themselves and everyone for the state. Some kind of loose affiliation of cells which valued their individual freedom, but were not above at least some level of cooperation. Modern-day sponges might be a pretty good example: some cellular specialization, a bit of the ol’ helping hand between cells, but nothing so altruistic as an actual tissue. Call it “Metazoa 1.0”. Davies and Lineweaver do.
According to D&L, that old 1.0 operating system is still sleeping down there in our genetic code; it’s just been turned off by the more recent regulatory genes of Metazoa 2.0. It hasn’t been eradicated outright, because a lot of those ancient genes are still useful (“…the genes responsible for the cellular cooperation necessary for multicellularity are also the genes that malfunction in cancer cells.”) It’s just been — tamed, is as good a word as any. Tamed, and deactivated.
Except when something happens to one of those bits of regulatory code that keep it comatose. When some base pair flips this way instead of that, Metazoa 1.0 wakes up, its ancestral toolkit intact, ready to party like it’s One Billion Years B.P.
You might be surprised at how extensive that ancient toolkit is; I know I was. I always thought of cancer as the uncontrolled growth of undifferentiated cells, jes’ regular folks except for the fact that something had broken their Off switch. But cancer has tricks up its sleeve; cancer’s got moves. The fact that it can grow its own blood vessels to keep its deepest cells fed and watered is just the beginning. Quoting directly from the paper:
Hallmarks of cancer include the silencing of tumor suppressor genes, switching off apoptosis and anoikis (programmed death when cells detach from the extracellular matrix), switching off senescence by manufacturing enzymes to repair eroding telomeres (Hanahan and Weinberg 2000), evading the immune system by removing surface receptors, dramatically changing the viscoelastic properties of cells to facilitate motility, invasion and colonization (Butcher et al 2009), 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 by switching off the normal oxidation—phosphorylation metabolism of healthy cells and using the glycolytic cycle instead (the so-called Warburg effect; see Warburg (1956)), 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 (Hanahan and Weinberg 2000), 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 fullblown aneuploidy.
The usual explanation for all these tricks is that every new iteration of cancer reinvents the wheel; after all, it’s cancer, right? It has a high mutation rate, it replicates fast. Put those two things together and it can evolve new traits way faster than baseline cells. But wait a second, Davies & Lineweaver ask: aren’t 99% of all mutations supposed to be deleterious? (Actually, no. Last I heard, we’d decided the majority of mutations were actually neutral. ) They also point out that advanced cancer cells have grossly deformed nuclei, chaotic chromatin restructuring, any number of structural changes that would spell certain death in normal cells — and yet these fuckers just don’t die. That’s kind of what makes them such fuckers in the first place.
I’m no expert on this stuff. But we seem to have a choice here between “Internal Darwinism” (each new cancer reinvents the wheel, just happening to stumble upon a similar sequence of beneficial mutations) and “Rebooted Atavism” (all those traits are part of a dormant ancestral toolkit in every cell, and the only difference between “cancerous” and “normal” is that something broke the switch that put it to sleep). If anyone still cares about parsimony, I know which option my semilayperson’s brain is edging toward.
Of course, it’s easy to be led astray when you’re not an expert in the field. Maybe Davies & Lineweaver misrepresented the facts (at the very least, they presented them in the light most favorable to Metazoa 1.0). The paper itself doesn’t present any new findings, it merely presents a new way of looking at old ones. Expert reaction seems to be mixed, from hmmm, could be something here to Cool metaphor, but don’t push it.
The authors have, at least, put forth a number of testable predictions of the Atavism Model: that “The complexity of cancer in a species should reflect the number of cell types in that species”, for example, and that “the progression of cancer should reflect reverse phylogenetic history”. (They also make a couple of predictions that could prove highly significant in the treatment of cancer.) I await more expert opinion on whether those predictions, even if borne out, would actually support the model (seems to me that a greater number of cell types might just provide more room for mutations of any kind, for example).
But the great thing about being a science fiction writer is that I don’t really have to wait if I don’t want to. Here is an idea, peer-reviewed and legitimately published, thrown into discourse: We are all descended from Cancer. We are borne of the Holy Tumor. Isn’t that a thought. Doesn’t that get your mind going: to the imagination of ancient habitats, somewhere on this planet or within it. To isolated refugia, cut off from the rest of the world when stromatolites were still young, where 2.0 never happened and the cancerous Metazoan prototype was free to chart its own evolutionary course through a billion years.
Maybe those shapeshifters have been here all along.
Maybe all we have to do is roll away the stone.
Image credit: eMedicine 2009.