Biological complexity: feedback loops are vital (Introduction)

by David Turell , Thursday, September 19, 2019, 20:07 (1892 days ago) @ David Turell

Without precise controls of chemical levels, life cannot survive. There are chemical cycles which produce necessary outputs and there are feedback controls which are also loops and control outputs when too low or too high. They are fully automatic and have to be:

https://www.quantamagazine.org/math-reveals-the-secrets-of-cells-feedback-circuitry-201...

"Whether in industrial control systems or in nature, negative feedback is an omnipresent strategy to help systems cope with disturbances. “People have noticed these feedback systems in physiology for as long as people have been studying physiology,” said Noah Olsman, a control theorist at Harvard University. Homeostasis, the self-regulation of biological systems, keeps many physiological parameters like body temperature, blood pressure and levels of blood glucose within exacting limits, whether we’ve run a marathon, gone scuba diving, or binge-watched Netflix all day. And for good reason: “If life couldn’t respond to changes and learn, it wouldn’t last very long,” Olsman said.

"Vital as that negative feedback is, however, biologists have been hard pressed to explain how cells and more complex organisms implement feedback systems with the necessary responsiveness and precision... Most recently, in an important advance this past summer, a team led by Khammash demonstrated a synthetic feedback system that could be installed in cells to help them adapt perfectly to disturbances, just like the robot. The work is backed by a mathematical proof that no simpler answer exists — a good indication that natural feedback systems probably work the same way.

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"When blood calcium plunges, the parathyroid gland produces more parathyroid hormone, which stimulates calcium ions to leave the skeleton and corrects the error proportionally. In turn, elevated parathyroid hormone levels ramp up the rate of 1,25-DHCC production in the gut, which promotes absorption of calcium in the small intestine. Because the rate of 1,25-DHCC [a special form of vitamin D called 1,25-dihydroxycholecalciferol] production is tied to the concentration of parathyroid hormone, this feedback mechanism takes on a mathematically integral nature.

"Khammash wasn’t the only one realizing nature uses integral feedback to achieve robust perfect adaptation. Earlier, in 2000, Doyle showed mathematically that the effectiveness of bacteria’s directed movements to find food was due to integral feedback. Later, El-Samad, Khammash and Doyle collaborated and showed that heat shock responses in bacteria — their production of protective “chaperone” molecules when overheated — are robust for the same reason. (my bold)

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'the two controller molecules must have a very specific relationship: They have to bind to each other and neutralize each other’s biological activity. One must be the antithesis of the other.

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(attempts in the lab to reproduce natural control)

"In the fall of 2017, while his colleagues continued struggling in the lab, Gupta attended a conference in Ohio. There, he met other researchers also trying to build integrators in cells using the theory of the antithetical controller. All of them were struggling. Gupta thought there might be another design that would be easier to execute, making life easier for the experimentalists.

“It’s a legitimate question to ask whether, maybe, there is a simpler way,” Lillacci said. “And then it turns out that there isn’t.”

"Gupta found that the mathematical constraints for robust perfect adaptation were so huge, they restricted the circuit designs that would be stable in a noisy setting. All of them required an antithetical pair of controller molecules.

'Khammash and Gupta were elated at the mathematical proof that their approach, while arduous, was not just sound but inescapable. And for Aoki and Lillacci, who were already seeing signs that their cells could adapt to disturbances, the news kept them going.

“'To find out that there’s really only one underlying topology that should be able to achieve this is really, really quite amazing to me,” Aoki said."

Comment: Without these control loops, homeostasis in life is impossible, as is life itself. This research supports my contention that most bacterial and cellular responses are automatic or tightly controlled. So much for free-thinking and free-acting bacteria or cells.