Defining Miscibility and Solubility

Often it is useful to know what happens if you add substance A to substance B. Parameters describing important properties may be available, often it is interesting to know how well they mix. I will try to further clarify the terms miscibility and solubility based on my understanding of these concepts.

Miscibility is a binary property pertaining to two substances, commonly in liquid phase. Two liquids A and B are miscible iff: they form a homogenous distribution regardless of the amount difference between A and B. They are immiscible if this requirement is not met. We commonly talk about two liquids because all other phase interactions are either always miscible (gas-gas or molecular solid-solid interactions) or always immiscible (liquid non-liquid or solid-gas).

Solubility describes the ability/amount of A(any phase) to dissolve in B(liquid or gas). Dissolve means to homogeneously distribute itself. So nothing can dissolve in a solid (anything that disperses into a solid is a colloid) and if B is a gas only other gasses can dissolve in it. So water or ice can not dissolve into air(a gas) without boiling, e.g. humidity caused by evaporation is not actually homogeneous–without convection it tends to be higher near surfaces.

Describing solubility between two miscible substances is redundant. It can be said that miscible liquids have infinite or 100% solubility in each other—they are soluble in all proportions. By definition all gas-gas mixes are also miscible. Solids do not dissolve into other solids; yet powders can be mixed in all ratios so in theory all solid-solids could be said to be miscible if ground to fine molecular powders. An important conclusion is that a description of the parameter ‘solubility’ of A is only worthwhile iff: the solvent B is a liquid, and if A is liquid it is immiscible with B.

If A is a gas the pressure plays an important role in solubility. If it is a solid we should remember that a dissolved solid does not always have to break down into anions and cations.

When we think of immiscible liquids we typically imagine something like oil and water sitting separate in a glass bottle, the denser water below. But immiscible liquids need not completely separate. They can form colloids, suspensions or even solutions. E.g. part of A may still enter B and/or vice versa, how this fraction is distributed depends on the properties of A and B.  Small amounts of water can actually dissolve in oil, and vice versa. Another common example of non-separated immiscible fluids is an emulsion.

On a final note, sometimes it is not easy to determine by eye if you have a colloid or a solution. In extreme cases it may be that a particle or the heterogeneity is too small to qualify as a colloid (sub-nano scale). So technically it is possible to have a heterogeneous solution, simply because chemistry has no other word for it.


The “Warburg effect” is not the same as aerobic glycolysis

The Warburg hypothesis was based on the observation called the Warburg effect. Specifically, this observation made by Otto Warburg was: cancer cells have increased glycolysis and a lowered oxidative phosphorylation under norm- or hyperoxic conditions, relative to normal cells.

Now Warburg did not actually observe a lowered oxidative phosphorylation in all his experiments. He also forgot to mention cancer can also exhibit that behavior under hypoxic conditions. So it is not clear why he so strongly advocated his now obscure hypothesis—that damage to mitochondria was the cause of cancer. Also note at that time (late 70’s) the measurements were based on environmental O2 and lactate changes, with less understanding of the ATP generating pathways and DNA mutations. In other words his observation may be flawed. Nowadays the hypothesis has fallen out of favor but the related phrase Warburg effect still persists.

The meaning of the Warburg effect has become distorted over the years, now mostly synonymous with high or increased glycolysis, not implying anything about the functioning of mitochondria. Let it be clear that aerobic glycolysis or hyperglycolysis are more accurate definitions for this. The term Warburg effect allows for misunderstandings on the exact metabolic phenotype, because some—albeit a minority—still (correctly) associate it with a lowered mitochondrial metabolism.

In some places the Warburg hypothesis has been kept alive, perhaps due the repetition of the related observation in literature. This is despite advances in genetics and other observations of normal appearing mitochondria in cancer cells. These ‘Warburgians’ try to provide a short answer to a complex problem, fueling the alternative medicine market and drawing attention away from proper cancer research. I actually tried reading a 2010 article by T. Seyfried on the subject, he also has a book on it. The article was full of fallacies, a very unscientific read reminiscent of the old styles practiced in the Royal Society.

One suggestion to tackle this sensationalism is to stop using the term “Warburg effect” altogether, though it is useful when used correctly to describe the phenotype of increased glycolysis and decreased mitochondrial activity.

As the field of cancer research has close ties with medical practitioners, I predict high normoxic glycolysis will still be called the Warburg effect for a long time, despite its historic inaccuracy and abuse by the likes of Warburgians and ketogenic diet advocates. Personally I think ‘ahypoxic hyperglycolysis’ is an accurate term. The term ‘aerobic glycolysis’ is less preferred as it implies glycolysis is normally only active in anaerobic conditions, or that oxygen is actually involved in the glycolysis reactions somehow, neither is true.

Cancer metabolism

Why is there so much interest in cancer metabolism, specifically glycolysis and mitochondrial function? We know practically all cancer cells have DNA mutations—even if sequencing has a pretty high false negative rate. We observe cancer cell metabolism is somehow different than in normal cells. Now research is trying to find links between those mutations and pathways involved in metabolism. This area has been gaining more popularity since early last decade.

It is observed that mutations in cancer cells multiply over time, the explanation being that disrupted pathways cause additional mutations in a feedback loop. Warburgians hypothesize mitochondrial damage is a major initial source of this pathway dysfunction. There is contentious evidence on that aspect, but a larger consensus is that regardless of cause, an aberrant metabolic phenotype is crucial for cancer cell survival and malignant transformation.

Attempts at inhibiting the metabolic change have given results that indicate cancer cell (specific) death or reduced malignant behavior, such as slowed proliferation and less metastasis. Conversely, experiments on normal cell lines to induce a cancer-like shift in metabolism have been shown to increase carcinogenic behavior. This metabolic research has so far been constrained to in vitro or rodent models.

So far, research has found that some very common pathway anomalies (which in turn are caused by a variety of possible mutations) are associated with the regulation of glycolysis or mitochondrial function. Often these pathways can also be associated with functions related to the common hallmarks of cancer, such as apoptosis resistance and angiogenesis. It then becomes a short mental step to link the metabolic phenotype of a cancer cell to the predominant cancer hallmarks.

It is advantageous to explain cancers as arising from disruptions of single pathways that control both metabolism and so-called hallmark features; if the metabolism defects arose independently of the defective hallmark pathways, we would have the additional problem of investigating possible causality between the two.

Unfortunately the mutations observed are sometimes not in overlapping pathways. Pathways are often so interconnected that even mutations in parts that seem functionally isolated (e.g. hexokinase, a glycolysis enzyme) can exert influence on a hallmark associated pathway linked downstream in the glycolysis pathway.

If the link between metabolism and cancer can be exploited to stop cancer, it seems practical to first investigate and fully understand cellular metabolism in normal and cancer cells. Then enzyme kinetics might be used to explain the effects of one pathway on another.

Cancer is a disease of pathways, perhaps we should focus more on the hallmark pathways instead of the indirect metabolic ones. But in terms of possible therapeutic targets and spin-offs, for many the metabolic research will be too tempting to ignore.