An obvious idea we’ve all missed

In 3+ decades as a clinical neurologist I saw several hundred unfortunate people with primary brain tumors. Not one of them was made of proliferating neurons. Not a single one. Most were tumors derived from glial cells (gliomas, glioblastomas, astrocytomas, oligodendrogliomas) which make up half the cells in the brain. Some came from the coverings of the brain (meningiomas), or the ventricular lining (ependymomas).

A recent paper in Nature (vol. 543 pp.681 – 686 ’17) decided that it might be worthwhile to figure out why some organs rarely if ever develop cancer (brain, heart, skeletal muscle). Obvious isn’t it? But no one did it until now.

Most of these tissues are terminally differentiated (unlike, skin, lung, breast and gut) and don’t undergo cellular division. This means that they don’t have to copy their DNA over and over to replenish old and dying cells, and so they are much less likely to develop mutation.

They also use oxidative phosphorylation (a mitochondrial function) rather than glycolysis to generate energy. So they looked for genes that were upregulated in terminally differentiated muscle (not brain) cells relative to proliferating muscle cell precursors. Not a complicated idea to test once you think of it (but you and I didn’t). They found 5 such, and tested them for their ability to suppress tumor growth. One such (LACTB) decreased the growth rate of a variety of tumor cells in vitro and in vivo (e.g.– when transplanted into immunodeficient animals). Amazingly it seems to have no effect on normal cells.

Showing how little we understand the goings on inside our cells, why don’t you try to guess what LACTB given your (and our) knowledge of cellular biochemistry and physiology.

LACTB changes mitochondrial lipid metabolism, by reducing the rate of decarboxylation of mitochondrial phosphatidyl serine — say what?

Even when you know what LACTB is doing you’d be hard pressed to figure out how this effect slows cancer cell growth (and possibly prevents it from occuring at all).

So given our knowledge we’d have never found LACTB and having found it we still don’t know how it works.

What is a hormone? What is an endocrine organ?

We all knew what hormones were back in the day. They were chemicals released by an endocrine gland into the blood where they went everywhere and affected distant organs. The classic example were the sex hormones (estrogen, progesterone, testosterone) eleased by the gonads affecting the reproductive organs, and not least the brain.

Things have changed mightily, and just about every tissue in the body does this now. There are at least 20 adipokines released by fat — examples are adiponectin, adipsin, and of course leptin. Muscle may be also getting into the act with irisin (although that is controversial). Other muscle produced hormones (myokines)  include atrial natriuretic peptide released by the heart and skeletal muscle releases at least 8 more.

There is even more stuff released into local tissue fluids which don’t get into the blood so they aren’t hormones. You can regard all neurotransmission this way. Paracrines are compounds which act only on cells close to them (because they don’t get into the blood). Examples include the huge class of prostaglandins and polypeptide growth factors such as the 22 member fibroblast growth factor family.

What to make of [ Cell vol. 166 pp. 424 – 435 ’16 ] which describes PM20D1 (Peptidase M20 Domain containing 1) which is secreted by fat cells. It’s an enzyme which builds compounds from substances already in the blood. The chemistry is simplicity itself — it takes a long chain fatty acid and an amino acid and forms the fatty acid amide — or an N-acyl amino acid.

What does the product do? It causes uncoupling of oxidative phosphorylation by mitochondria, so it just produces heat (something useful to an animal in the cold). Administration of N-acyl amino acids to mice increases energy expenditure and improves glucose metabolism. It’s possible that they could be used therapeutically.

Another example of how little we knew about what is going on inside us.