Thoughts on Cancer

Edit (26/01/2016)

“The problem of cancer is not to explain life, but to discover the differences between cancer cells and normal growing cells. Fortunately this can be done without knowing what life really is. Imagine two engines, the one being driven by complete and the other by incomplete combustion of coal. A man who knows nothing at all about engines, their structure, and their purpose, may discover the difference. He may, for example, smell it.” – Otto Warburg 1956

If one could only learn about human health studying a single disease, I would pick cancer hands down. Its study boils down to askying why and how some cells either live or die. The distilled question is simple, yet cancer is everything but. It forces us to confront its behavior which is easily anthropomorphized: why are these cancer cells malcontent with simply being alive? What is this insatiable need for invading other body parts? Stranger yet, cancer is synonymous with death even though it is part and parcel with biological life – even trees get cancer or at least they also manifest uncontrolled cell growth. Stringent definitions are hard and tedious to establish but they really matter, so for the sake of clarity lets use the Hallmarks of Cancer. It embodies the 6 behavioral traits characterizing the disease:

• Evading death
• Ignoring anti-growth signals
• Self-directing growth
• Literally being blood-thirsty
• Invading other tissues
• Unlimited replication

The currently accepted Somatic Mutation Theory of cancer (SMT) is based in genetics. Basically, it asserts that a single cell suffering 1 or more random mutations conferring it with a growth advantage deleterious to its host, can cause cancer. In other words “it is a disease in which an individual mutant clone of cells begins by prospering at the expense of its neighbors” (Molecular Biology of The Cell, 6th Edition, page 1091). Progress towards cures for this still enigmatic disease has been thoroughly underwhelming. In my view, this is mostly because mainstream cancer researchers place too much confidence in SMT. To be fair, cancer cells are 1 big tangle of mutations. But they are not just that. They are also deformed (abnormal morphology). Maybe most importantly, how they make their energy changes. More specifically, their respiration is damaged. Or maybe not – and this is where the bone of contention lies. Some SMT proponents will argue that respiration is not actually broken, that it is just not used as much nor necessarily for the same purpose. Others, that it does not matter either way. The Metabolic Theory of cancer (MT) argues that the functional state of respiration in a cell really matters because broken respiration can cause cancer. The mutations seen in cancers thus result from, rather than cause, damaged respiration. MT is thus based in metabolism rather than genetics. MT proponents say that all cancer cells are characterized by faulty energy production systems. Theys can no longer produce their share of energy (ATP) by respiring and that respiratory function is substantially decoupled from ATP production. By analogy, the cell is stomping on both the accelerator and clutch simultaneously. This is not good for cars or cells. MT argues that such respiratory dysfunction instantiates changes (many of which are genetic) leading to the 6 behavioral traits somehow exhibited by the disease.

Mainstream research has primarily dimissed MT because of 2 observations. 1) A normal cell can be reliably turned cancerous upon suffering certain mutations. This is undeniable. Consequently MT proponents argue that such mutations leads to cancer to the extent that they interfere with normal respiration. 2) Not all cancer cells have a broken respiration system. This is disputed. MT proponents say respiration only appears functional because the cell is in fact ‘pseudo-respiring’. Pseudo-respiration is the generation ATP using the mitochondria’s respiratory apparatus for fermentation, but without consuming oxygen. Mitochondrial fermenatation involves a process called substrate-level phosphorylation.

Given that the first observation supporting SMT over MT suffers from a pesky alternative causal explanation and the accuracy of the second one is disputed, a good clarifying question to pose at this is point is whether it is easier to identify a cancer cell based on its profile of mutations or on the integrity of its respiratory apparatus? I would venture the latter. Consider the thousands of mutated genes strongly associated with cancer (oncogenes) that, when woven together into clinical interventions duly fail to save lives by and large. At this juncture it would be sound to question the entire conceptual premise upon which these interventions were conceived. Instead we do what so many health gurus excel at: polishing turds. We dress up our failure as success and give it a sexy name, ’personalized cancer genomics’. Tilt your head to the left and it is the most exciting, cutting-edge approach that is truly tailored to the special snow-flakes that we all are. Tilt your head to the right and it is an implicit admission that our interventions do not work to any significant extent  on a population level because the SMT underpinning them is plain wrong. Similarly, the notion that cancer is not just 1 disease but many different ones may stem from the same reluctance of recognizing failure. See the fascinating success story of treating Chronic Myeloid Leukemia (CML) with Imatinib (Gleevec). It is all the more interesting given how plausible MT-derived alternative explanations are.

There are many finer theoretical and experimental points that can and should be debated. However, the final point I wish to make is somewhat different. Consider the phenomenon of Epithelial to Mesenchymal Transition (EMT) which proposes a mechanism for metastases within the SMT framework: clonal selection (natural selection) acts upon a series of genomic alterations (mutations) such that a cell acquires invasive (metastatic) behavior. Simple, right? Not quite. Especially not when considering what metastases actually involve. Thomas Seyfried explains this best (bold highlights & numbering are my additions):

“It is difficult to understand how a collection of gene mutations, many of which are random, could produce cells with the capacity to [1] detach from the primary tumor, [2] intravasate into the circulation and lymphatic systems, [3] evade immune attack, [4] extravasate at distant capillary beds, and [5] recapitulate epithelial characteristics following invasion and proliferation in distant organs. This would be quite a feat for a cell with a disorganized genome.” (Metabolic Theory of Cancer, Chapter 13.2.1)

Yes, cancer cells are very clever but their genomes are also very messy. They are successful but not happy. Ultimately the ‘mutations all the way down’ explanation for their malicious behavior is unsatisfying. A better although incomplete explanation is tentatively available: damaged respiration usually forces a cell to (1) repair itself or (2) commit suicide. Things go awry when it ignores options 1 and 2. It is in the adaptation to (3) staying alive without proper repairs that cancer emerges. Adapting to alternative methods of energy production due to damaged respiration forces a cell to survive through different means. These different surival strategies call for a lot of glucose, glutamine, always more vasculature and tissues capable of sustaining the engendered momentum. Does MT do a better job of explaining the seemingly calculated behavior of metastases? Somewhat. The ‘energy seeking tumor’ explanation is more plausible in my mind than the one of ‘random mutations conferring super-powers’.

Regardless, cancer is a bitch.