What Causes Cancer? What is Cancer?

There is some frustration in the literature.

Fifty years into the war on cancer, what have we learned and gained? We do not have a general cure, though we have a few cures and a lot of treatments. We have a lot of understanding, but no comprehensive theory or guide to practice. While some treatments are pin-point specific to certain proteins and even certain mutated forms of those proteins, most treatments remain empirical, even crude, and few provide more than a temporary respite. Cancer remains an enormous challenge, clinically and intellectually.

Recently, a prominent journal ran a provocative commentary about the origins of cancer, trashing the reigning model of "Somatic Mutation Theory", or SMT. Which is the proposition that cancer is caused by mutations that "drive" cell proliferation, and thus tumor growth. I was surprised at the cavalier insinuations being thrown around by these authors, their level of trash talk, and the lack of either compelling evidence or coherent alternative model. Some of their critiques have a fair basis, as discussed below, but to say, as the title does, that this is "The End of the Genetic Paradigm of Cancer" is simply wrong.

"It is said that the wise only believe in what they can see, and the fools only see what they can believe in. The latter attitude cements paradigms, and paradigms are amplified by any new-looking glass that puts one’s way of seeing the world on steroids. In cancer research, such a self-fulfilling prophecy has been fueled by next-generation DNA sequencing."

"However, in the quest for predictive biomarkers and molecular targets, the cancer research community has abandoned deep thinking for deep sequencing, interpreting data through the lens of clinical translation detached from fundamental biology."

Whew!

The main critique, once the gratuitous insults and obligatory references to Kuhn and Feynman are cleared away, is that cancer does not resemble other truly clonal disease / population processes, like viral or bacterial infections. In such processes, (which have become widely familiar after the COVID and HIV pandemics), a founder genotype can be identified, and its descendants clearly derive from that founder, while accumulating additional mutations that may respond to the Darwinian pressures, such as the immune system and other host defenses. While many cancers are clearly driven by some founding mutation, when treatments against that particular "driver" protein are given, resistance emerges, indicating that the cancer is a more diverse population with a very active mutation and adaptation process. 

Additionally, tumors are not just clones fo the driving cell, but have complex structure and genetic variety. Part of this is due to the mutator phenotypes that arise during carcinogenesis, that blow up the genome and cause large numbers of additional mutations- many deleterious, but some carrying advantages. More significantly, tumors arise from and continue to exist in the context of organs and tissues. They can not just grow wildly as though they were on a petri plate, but must generate, for example, vascular structures and a "microenvironment" including other cells that facilitate their life. Similarly, metastasis is highly context-dependent and selective- only very few of the cells released by a tumor land in a place they find conducive to new growth. This indicates, again, that the organ setting of cancer cells is critically important, and accounts in large part for this overall difference between cancers and more straightforward clonal processes. 

Schematic of cancer development, from a much more conventional and thorough review of the field.

Cancer cells need to work with the developmental paradigms of the organism. For instance, the notorious "EMT", or epithelial-mesenchymal transition is a hallmark of de-differentiation of many cancer cells. They frequently regress in developmental terms to recover some of the proliferative and self-repair potential of stem cells. What developmental program is available or allowed in a particular tissue will vary tremendously. Thus cancer is not caused by each and every oncogenic mutation, and each organ has particular and distinct mutations that tend to cause cancers within it. Indeed, some organs hardly foster any cancers at all, while other organs with more active (and perhaps evolutionarily recent) patterns of proliferation (such as breast tissue, or prostate tissue) show high rates of cancer. Given the organ setting, cancer "driver" mutations need not only unleash the cell's own proliferation, but re-engineer its relations with other cells to remove their inhibition of its over-growth, and pursuade them to provide the environment it needs- nutritionally, by direct contact, by growth factors, vascular formation, immune interactions, etc., in a sort of para-organ formation process. It is a complicated job, and one mutation is, empirically, rarely enough.

"Instead, cancer can be broadly understood as “development gone awry”. Within this perspective, the tissue organization field theory is based on two principles that unite phylogenesis and ontogenesis."

"The organicist perspective is based on the interdependency of the organism and its organs. It recognizes a circular causal regimen by closure of constraints that makes parts interdependent, wherein these constraints are not only molecules, but also biophysical force."

As an argument or alternative theory, this leaves quite a bit to be desired, and does not obviate the role of  initiating mutations in the process.

It remains, however, that oncogenic mutations cause cancer, and treatments that address those root causes have time and again shown themselves to be effective cancer treatments, if tragically incomplete. The rise of shockingly effective immunotherapies for cancer have shown, however, that the immune system takes a more holistic approach to attacking disease than such "precision" single-target therapies, and can make up for the vagaries of the tissue environment and the inflammatory, developmental, and mutational derangements that happen later in cancer development. 

In one egregious citation, the authors hail an observation that certain cancers need both a mutation and a chemical treatment to get started, and that the order of these events is not set in stone. Traditionally, the mutation is induced first, and then the chemical treatment, which causes inflammation, comes second. They state: 

"The qualitative dichotomy between a mutagenic initiator that creates ’cancer cells’ and the non-genetic, tissue-perturbing promoter that expands them may not be as clear-cut. Indeed, the reverse experiment (first treatment with the promoter followed by the initiator) equally produces tumors. This result refutes the classical model that requires that the mutagenic (alleged) initiator must act first."

The citation is to a paper entitled "The reverse experiment in two-stage skin carcinogenesis. It cannot be genuinely performed, but when approximated, it is not innocuous". This paper dates from 1993, long before sequencing was capable of evaluating the mutation profiles of cancer cells. Additionally, the authors of this paper themselves point out (in the quote below) a significant assymetry in the treatments. Their results are not "equal":

"The two substances showed a reciprocal enhancing effect, which was sometimes weak, sometimes additive, and sometimes even synergistic, and was statistically most significant when the results were assessed from the time of DMBA application. Although the reverse experiment was not in any way innocuous it always resulted in a lower tumor crop than the classical sequence of DMBA followed by a course of TPA treatment. 

However, the lower tumor crop in the reverse experiment cannot be used to prove a qualitative difference between initiators and promoters."

(DMBA is the mutagen, while TPA is the inflammatory accelerant.)

So chemical treatment can prepare the ground for subsequent mutant generation in forming cancers in this system, while being much less efficient than the traditional order of events. This is not a surprise, given that this chemical (TPA) treatment causes relatively long-term inflammation and cell proliferation on its own.

"An epistemic shift towards a biological theory of cancer may still be an uphill battle in the current climate of thought created by the ease of data collection and a culture of research that discourages ’disruptive science’. Here, we have made an argument for dropping the SMT and its epicycles. We presented new and old but sidelined theoretical alternatives to the SMT that embrace theory and organismal biology and can guide experiments and data interpretation. We expect that the diminishing returns from the ceaselessly growing databases of somatic mutations, the equivalent to Darwin’s gravel pit, may soon reach a pivot point."

One rarely reads such grandiloquent summaries (or mixed metaphors) in scientific papers! But here they are truly beating up on straw men. In the end, it is true that cancer is quite unlike clonal infectious diseases, and for this, as for many other reasons, has had scientists scratching their heads for decades, if not centuries. But rest assured that this chest-thumping condescension is quite unnecessary, since those in the field are quite aware of these difficulties. The various nebulous alternatives these authors offer, whether the "epigenetic landscape", the "tissue organization field theory", or the "biological theory of cancer" all have kernels of logic, but the SMT remains the foundation-stone of cancer study and treatment, while being, for all the reasons enumerated above and by these authors, only part of the edifice, not the whole truth.

• Some more thoughts about crypto.
• Resistance is up to congress, ultimately.
• China takes purges quite a bit more seriously than we do.
• But we are getting there.

Eccentricity, Obliquity, Precession, and Glaciation

The glacial cycles of the last few million years were highly determined by earth's orbital mechanics.

Naturalism as a philosophy came into its own when Newton explained the heavens as a machine, not a pantheon. It was stunning to realize that age-old mysteries were thoroughly explicable and that, if we kept at it with a bit of diligence and intellectual openness, we could attain ever-widening vistas of understanding, which now reach to the farthest reaches of the universe. 

In our current day, the mechanics of Earth's climate have become another example of this expansion of understanding, and, sadly, another example of resistance to naturalism, to scientific understanding, and ultimately to the stewardship of our environment. It has dawned on the scientific community (and anyone else willing to look) over the last few decades that our industrial production of CO2 is heating the climate, and that it needs to stop if the biosphere is to be saved from an ever-more degrading crisis. But countervailing excuses and interests abound, and we are now ruled by an adminstration in the US whose values run toward lies and greed, and which naturally can not abide moral responsibility.

The Cenozoic, our present age after the demise of the dinosaurs, has been characterized by falling levels of CO2 in the atmosphere. This has led to a progression from very warm climates 50 mya (million years ago) to ice ages beginning roughly 3 mya. The reasons for this are not completely clear. There has been a marked lack of vocanism, which is one of main ways CO2 gets back into the atmosphere. This contrasts strongly with ages of extreme volcanism like the Permian-Triassic boundary and extinction events, about 250 mya. It makes one think that the earth may be storing up a mega-volcanic event for the future. Yeet plate tectonics has kept plugging along, and has sent continents to the poles, where they previously hung out in more equatorial locations. That makes ice ages possible, giving glaciers something to glaciate, rather than letting ocean circulation keep the poles temperate. Additionally, the uplift of the Himalayas has dramatically increased rock exposure and weathering, which is the main driver of CO2 burial, by carbonate formation. And on top of all that has been the continued evolution of plant life, particularly the grasses, which have extra mechanisms to extract CO2 out of the atmosphere.

CO2 in the atmosphere has been falling through most of the Cenozoic.

All this has led to the very low levels of CO2 in the atmosphere, which have been stable at about 300 ppm over the last million years, very gradually declining prior to that time. Now we are pushing 420 ppm and beyond, which the biosphere has not seen for ten million years or more, and doing so at speeds that no amount of evolution can accommodate. The problem is clear enough, once the facts are laid out.

But what about those glaciations, which have been such a dramatic and influential feature of Earth's climate over the last few million years? They have followed a curious periodicity, advancing and retreating repeatedly over this time. Does that have anything to do with CO2? It turns out that it does not, and we have to turn our eyes to the heavens again for an explanation. It was Milankovitch, a century ago, who first solidified the theory that the changing orbital parameters of Earth, and particularly the intensity of the sun in the Northern hemisphere, where most of the land surface of Earth lies, that causes this repetitive climatic behavior.  

Cycles of orbital parameters and glaciation, over a million years.

It was in 1976 that a more refined analysis put a mathematical model and better data behind the Milankovitch cycles, showing that one major element of our orbit around the sun- the variation of eccentricity- had the greatest overall effect on the 100,000 year periodicity of recent glacial cycles. Eccentricity is how skewed our orbit is from round-ness, which varies slightly over time, due to interactions with other planets. Secondly, the position of the Earth's tilt at various points of this eliptical orbit, whether closer to the sun in northern summer, or father away, has critical effects on net solar input and on glaciation. The combined measure is called the precessional index, expressing the earth-sun distance in June. The eccentricity itself has a period of about 93,000 years, and the precessional index has a periodicity of 21,000 years. As glacial cycles over the last 800,000 years have had a strong 100,000 year periodicity, it is clearly the eccentricity alone that has the strongest single effect.

Lastly, there is also the tilt of the Earth, called obliquity, which varies slightly with a 40,000 year cycle. A recent paper made a major claim that they had finally solved the whole glaciation cycle in more detail than previously, by integrating all these cycles into a master algorithm for when glaciations start/end. They were curious about exactly what drives the deglaciation phase, within the large eccentricity-driven energetic cycle. The rule they came up with, again using better data and more complicated algorithms, is that it reaches its maximum rate when, after a minimum of eccentricity, the precession parameter (the purple line, below) has reached a peak, and the obliquity parameter (the green line, below) is rising. That is, when the Earth's degree of tilt and closeness to the sun in Norther summer are mutually reinforcing. There are also lags built into this, since it takes one or two thousand years for these orbital effects to build heat up in the climate system, a bit like spring happening annually well after the equinox.

"We find that the set of precession peaks (minima) responsible for terminations since 0.9 million years ago is a subset of those peaks that begin (i.e., the precession parameter starts decreasing) while obliquity is increasing. Specifically, termination occurs with the first of these candidate peaks to occur after each eccentricity minimum."

 

 

Summary diagram from Barker, et al. At the very top is a synopsis of the orbital variables. At bottom are the glacial cycles, marked with yellow dots (maximum slope of deglaciation), red dots (maximum extent of deglaciation) and blue dots (maximum slope of reglaciation, also called inception). Above this graph is an analysis of the time spans between the yellow and red dots, showing the strength of each deglaciation (gray double arrows). They claim that this strength is proportion to an orbita parameter illustrated above with the T-designation of each glacial cycle. This parameter is precession lagged by obliquity. Finally in the upper graph, the orbital cycles are shown directly, especially including eccentricity in gray, and the time points of the yellow nodes are matched here with purple nodes, lagged with the preceeding (by ~2,000 years) rising obliquity as an orange node. The green verticle bars were applied by me to ease the clear correlation of eccentricity maxima vs deglaciation maxima.

I have to say that the communication of this paper is not crystal clear, and the data a bit iffy. The T5 deglaciation, for instance, which is relatively huge, comes after a tiny minimum of eccentricity and at a tiny peak of precession, making the scale of the effect hard to understand from the scale of the inputs. T3 shows the opposite, with large inputs yielding a modest, if extended, deglacial cycle. And the obliquity values that are supposed to drive the deglaciation events are quite scattered over their respective cycle. But I take their point that ultimately, it is slight variations in the solar inputs that drive these cycles, and we just need to tease out / model the details to figure out how it works.

There is another question in the field, which is that, prior to 800,000 years ago, glacial cycles were much less dramatic, and had a faster cadence of about 40,000 years. This is clearly more lined up with the obliquity parameter as a driver. So while obliquity is part of the equation in the recent period, involved in triggering deglaciation, it was the primary driver a million years ago, when CO2 levels were perhaps slightly higher and the system didn't need the extra push from eccentricity to cycle milder glaciations. Lastly, why are the recent glacial cycles so pronounced, when the orbital forcing effects are so small and take thousands of years to build up? Glaciation is self-reinforcing, in that higher reflectivity from snow / ice drives down warming. Conversely, retreat of glaciers can release large amounts of built-up methane and other forms of carbon from permafrost, continental shelves, the deep ocean, etc. So there may be some additional cycle, such as a smaller CO2 or methane cycle, that halts glaciation at its farthest extent- that aspect remains a bit unclear.

Overall, the earlier paper of Hays et al. found that summer insolation varies by at most 10% over Earth's various orbital cycles. That is not much, yet it drives glaciation of ice sheets thousands of feet thick, and reversals back to deglaciation that uncovers bare rock all over the far north. It shows that Earth's climate is extremely sensitive to small effects. The last time CO2 was as high as it is now, (~16 mya), Greenland was free of ice. We are heading in that direction very rapidly now, in geological terms. Earth has experienced plenty of catastrophes in the past, even some caused biologically, such as the oxygenation of the atmosphere. But this, what we are doing to the biosphere now, is something quite new.

• That new world order we were working on...
• Degradation and corruption at FAA.. what could go wrong?
• Better air.
• Congress has the power, should it choose to use it.
• Ongoing destruction, degradation.
• Oh, Canada!

Realism in Foreign Policy

Idealism or realism? This is not just a left-right issue, but a deeper issue of values in foreign policy.

Think tanks on both the right and the left tout foreign policy realism, impatient with the demands that the post-war era have placed on the US as the unique, exceptional (and rich) leader of the free and democratic world. Whether from a cost perspective or a peace perspective, backing off from our world-wide commitments and ideals is attractive to many. The current administration has dramatically taken up their banner, reversing US policy, dropping Ukraine, allying with Russia, and ending idealism, generosity and empathy as a elements of foreign policy. What was firmly planted after World War 2 and flowered under John F. Kennedy has now been buried. So, are we great yet?

Where idealism in foreign policy takes up moral crusades, like human rights, women's rights, and global equity, even climate change, realism sticks to power and assumes anarchy, not order, as the natural state of international affairs. Realists sell themselves as hard-headed, unsentimental, and into the bargain, less likely to get us mixed up in wars. The most recent US wars, after all, from Vietnam to Iraq, were all crusades to foster democracy, in one form or other. Better to wash our hands of it all, care less about saving the people of the world, and more about bullying our neighbors to get what we want.

These are not really exclusive approaches, but rather shades of emphasis. The raw power of military and economic kinds is central to both, even if soft power is more of a focus for the idealists. But if you think about it more deeply, even these distinctions fade away, and both approaches end up being idealistic, just differing in the ideals they vaunt. The current administration clearly has its ideals- of Putin, Victor Orban, and authoritarianism ascendant world-wide. Its lack of empathy is not realism, it is a crabbed idealism- that of the rich and powerful lording it over the masses, both domestically and internationally.  

International power is composed of many things. But mostly, it is made up of relationships multiplied by technological capabilities. Two people can always overpower one person, and the same is true internationally. Bigger countries can field bigger armies. Bigger countries can field more researchers and manufacturers to arm those people with better weapons. Alliances between countries can make even more menacing combinations. 

It is, at base, social relationships that create power, and this is where realism really falls down. If one's ideal is transactional and bullying, worshipping power and taking a small-minded and greedy approach to international affairs, (that is to say, a zero-sum approach), then one will find that the few friends one has are fair-weather friends of convenience. Alliances between such partners frequently fall apart and re-arrange, creating the extremely dangerous environment conducive to major wars. Relationships are fungible and disposable. Europe had a long balance-of-power phase in the 1800's after the Napoleonic wars, until it collapsed in the 1900's in cataclysmic world wars, thanks in both cases to unstable alliance structures, not to mention authoritarian manias. The post-World War 2 era, the one we are witnessing the collapse of right now, was founded on something much more stable- true friendship and shared ideals of democracy. 

One can reply that helping the weak defend themselves against the strong is a sure recipe for entanglement in a lot of wars. Our involvement (up to now) in Ukraine is a case in point. We encouraged Ukraine to pursue a democratic path, thwarting Russia's clear and stated interests. And then we got dragged into this cataclysmic war. Why not side with the strong against the weak, instead? Wouldn't that make for a more stable world? Well, at some point we may be the weak one, not the strong one. What then? In the ever-shifting constellation of international alliances in a transactional, "realistic" world, there is no telling what tomorrow may bring, since values are not anchored in natural friendship or sympathy, but in naked interests, which are subject to rapid adjustment and negotiation. The disastrous Ribbentrop-Molotov pact comes to mind, as an example of such "realistic" foreign policy.

That is not a good world to live in, even if it has represented most of history. Realists may be right that their view is the mafia-like baseline of international relations, devoid of any human values and run on a power basis. Well, we can do better, both morally and objectively. That is what the last eighty years of international relations were all about. They were about setting up an international system where big countries at least tried to cloak their leadership in common interests, progress, and values. Where there was order, of some basic sort, which led to prosperity and security. And the Soviets bought into it as well, trying desperately to sell their adventures as standing for some kind of progressive, pro-worker ideology. Which lasted all the way to the end of the cold war, till its contradictions had grown too glaring. The US-led system has had its contradictions and hypocrisies as well, but the latest leap into the authoritarian camp is hardly fore-ordained or natural to our traditions.

Now, it looks like Winter is Coming. If the US forcibly devolves the international system into a value-less scramble for power, no one can rely on, or be satisfied with, stable friendships, so the system will be in greater flux, as powers test each other. When friendships are devalued, what is left but competition, such as trade wars, causing general destruction, and eventually desperate measures to regain relative power. 

• The policy is plain.
• Social insecurity.
• Nothing strategic about it.
• Wells on the pandemic. For me, the remarkable memory is how little we collectively knew about the simplest things- masks, aerosols, surfaces. That was inexcusable.

The Train Tracks of Synapsis

Structures that align and tether the chromosomes in meiosis are now understood in some molecular detail.

It has been one of the wonders of biology- the synaptonemal complex that aligns homologous chromosomes during meiosis. While chromosomes regularly line up in the middle of the cell during mitosis, so that they can be evenly divided between the daughter cells, in this process they only have to join at their centromeres, which get dragged to the midline of the cell, and then pulled back apart at cell division. In meiosis, on the other hand, not only do the sister chromosomes that have just replicated stick together at their centromeres, but the homologous chromosomes, which have never bothered about each other since sperm fused with egg, suddenly seek each other out and pair up in an elaborate dance of DNA breakage, alignment, cross-over, and repair. Then in the first division, these cross-over-joined homologs line up at the midline and get pulled apart as their crossovers are repaired. The second division follows, much more like mitosis, where the duplicated sister chromosomes line up at the midline based on their centromere attachments, and then separate into haploid gametes.

Comparison of mitosis vs meiosis, which goes through an extra division and alternate chrosomosome pairing and separation processes in the firsts division.

The two divisions are fundamentally different, with the first involving novel chromosome pairings and attachments. The opening act of all this, which I won't go into further, is a sprinkling of ~400 DNA strand breaks induced specifically all over the genome, which sets up a repair process at each site, where the chromosomes (using Rad51) seek out good copies of the damaged DNA- that is, another, matching, DNA molecule. There are specific processes that appear to prevent use of the recently replicated "sister", which would be the most closely identical copy that could be used. Instead, there is a bias to use the "homologous" copy from the other parent. But these homologous chromosomes have just been replicated as well. How to line all this up so that the chromosomes all line up neatly and separate neatly during the first meiotic division? The answer is the synaptonemal complex.

Schematic of the synaptonemal complex joining two homologous chromosomes. The lateral elements are on each side, and the central element lines up the center. Crossing the gap is the transverse elements, now known to be composed of the SYCP1 protein. At bottom is a diagram from its atomic structure of how SYCP1 coils together, and how its ends join to zip up the synaptonemal gap. 

This is a train track of connecting proteins between the homologous chromosomes. It is evident that the DNA breaks come first, followed by the search for matching homologs, followed by the radiating and progressive assembly of the synaptonemal complex out from the break repair sites. The components of its major structures have been mostly characterized- the lateral element where the DNA loops line up; the transverse element that spans the gap between the homologous chromosomes, and the central element, proteins at the midline that help the transverse elements assemble. A paper from 2023 characterized the transverse element protein, SYCP1, which is a long coil of a protein that dimerizes to make a strong coil, and then dimerizes again head-to-head to create the symmetric bridge over the whole width of the synaptonemal complex. Which is about 100 nanometers in width. 

These authors then focus on a series of experiments using key mutations at the dimer-dimer head-to-head interaction area, to demonstrate how this head-to-head zippering works in detail. Mutating just two amino acids in this contact region eliminates the head-to-head interaction, making synapsis impossible. In these cases, the homologous chromosomes (from mice) remain in proximity, especially at crossover sites, but are no longer zippered up and closely aligned.

Spreads of mouse meiotic chromosomes, labeled as shown with antibodies against two synaptonemal proteins. From the top, wild-type SYCP1, then single individual mutations in the end-joining region, and at bottom SYCP1 with two point mutations that eliminate its function entirely. The chromosomes at the bottom are aligned only by virtue of their crossover points, but not by a zippered up synaptonemal complex. Needless to say, mice like this are not fertile.

Thus what was once a hazy mystery in the highest power microscopes has been defined in molecular terms, highlighting once again the power of curiosity, and the essentially moral aim of truth-seeking- to reveal what is true, rather than dictate it. But who cares about all that? Truth, knowledge, science... these values are now not only in question, but under active attack. Who is making America great, and who is diminishing it? Those in our institutions of power who have a voice will hopefully see the consequences and act on them, before our history and values are entirely corrupted.

• Sociopaths at work.
• Evidently the model is that we become a version of China/Russia, and make a tripolar world. Not a little Orwellian. And who knows, perhaps we will offer Russia a deal to partition Canada. That is, after we get done partitioning Ukraine.
• A black day.
• Oh, wait, the next day was even worse.
• Shades of Stalin, with a sad sartorial hat-tip to Steve Jobs.
• Unlawful and vindictive destruction at the NIH, and of biological research in general.
• And all for love.