Life may not be like a well, but ‘control’ of events in the cell is like a box spring mattress

Yet another totally unsuspected mechanism of control of cellular events has emerged.  4 papers on the subject appeared in the 14 October Cell (vol. 147 pp. 344 – 357, 358 – 369, 370 – 381, 382, 395).  The whole notion of control in the presence of feedback is far from clear cut.  Sorry to tantalize, but the topic is so huge (and important) that it’s going to be the subject of a future post.

Here’s the story of the first inklings of feedback in endocrinology.  I watched it happen.

Endocrinology was pretty simple in med school back in the 60s. All the target endocrine glands (ovary, adrenal, thyroid, etc.) were controlled by the pituitary; a gland about the size of a marble sitting an inch or so directly behind the bridge of your nose. The pituitary released a variety of hormones into the blood (one or more for each target gland) telling the target glands to secrete, and secrete they did. That’s why the pituitary was called the master gland back then.  The master gland ruled.

Things became a bit more complicated when it was found that a small (4 grams or so out of 1500) part of the brain called the hypothalamus sitting just above the pituitary was really in control, telling the pituitary what and when to secrete. Subsequently it was found that the hormones secreted by the target glands (thyroid, ovary, etc.) were getting into the hypothalamus and altering its effects on the pituitary. Estrogen is one example. Any notion of simple control vanished into an ambiguous miasma of setpoints, influences and equilibria. Goodbye linearity and simple notions of causation.

As soon as feedback (or simultaneous influence) enters the picture it becomes like the three body problem in physics, where 3 objects influence each other’s motion at the same time by the gravitational force. As John Gribbin (former science writer at Natureand now prolific author) said in his book ‘Deep Simplicity’, “It’s important to appreciate, though, that the lack of solutions to the three-body problem is not caused by our human deficiencies as mathematicians; it is built into the laws of mathematics.” The physics problem is actually much easier than endocrinology, because we know the exact strength and form of the gravitational force.

What does this have to do with the cell?  Every metabolic process in the (normal)  cell is under feedback control.  Biosynthetic pathways in bacteria are inhibited by the final product of the pathway.  The cell cycle is subject to at least 4 checkpoints (particularly mitosis).  When there aren’t enough amino acids around, the cell shuts decreases protein synthesis.  Cell wait until they are large enough to divide.  If you can think of a cellular mechanism without feedback control, write a grant proposal to discover it.  The feedback is there.  One might regard cancer as a loss of feedback control on cell proliferation.

So, like a box spring, when you push anywhere, every spring in the mattress is changed, and pushes back to restore things.

Just another reason drug discovery is hard.

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