Reserve

Reserve — the red blood cell as a control loop

Background.A red blood cell spends its whole life holding one variable steady: its redox state. Oxidants keep arriving — from the oxygen it carries, from infections, from drugs — and each one would damage the cell if left unchecked. The defense is a feedback loop. Reduced glutathione neutralizes the oxidant; the pentose phosphate pathway spends NADPH to recharge the glutathione; and the enzyme G6PD sets how hard that pathway can push. NADPH is the reserve the whole loop draws on. Most of the time this runs silently. Then a drug arrives that raises the oxidant load — an antimalarial, dapsone, rasburicase, even fava beans — and two people on the same dose can diverge: one clears it without noticing, the other hemolyzes. The same drug, a different outcome. The difference is G6PD activity.

Hypothesis.If you model the cell as a control loop with two independent knobs — the loop gain (G6PD activity) and the disturbance (the oxidant load) — the clinical split should fall out without being written in. A high-gain cell rejects the disturbance and returns to its setpoint. A low-gain cell looks identical at rest, but past a large enough disturbance it cannot make NADPH fast enough: the reserve runs down, glutathione collapses behind it, and the cell tips into hemolysis. Severity should be a property of the loop, not an entry in a lookup table. The deficiency stays silent until the day it is challenged.

Method.A deterministic system of rate equations for the coupled redox and glycolytic state — NADPH and NADP+, the glutathione couple, ATP, 2,3-BPG, and a cumulative damage marker — integrated with a fixed-step Runge–Kutta solver. The G6PD step uses the published competitive product- and effector-inhibition rate law of Shimo, Nishino & Tomita (2011), driven by their per-patient parameters. The surrounding enzymes and the absolute concentration scales are reduced and illustrative — flagged as such in the source — pending the paper's full supplement. Damage keys off the NADPH reserve, not the glutathione that drains visibly ahead of it. There is no randomness: identical inputs produce an identical trajectory, every run.

Integration.The simulator below runs that engine in your browser — the same code, no server, no recorded video. Pick a genotype to set the loop gain, set an oxidant challenge, and watch the four reserves drain and either recover or give out. It opens on a severe G6PD cell under a moderate oxidant, which tips into failure on its own; switch to a healthy cell and the same disturbance is absorbed.

Status.In progress. The engine and this room are built and the model is deterministic, but the surrounding network and the absolute scales are still illustrative, not yet grounded against the full published model. A reasoning tool for thinking about the loop — not a clinical instrument, and nothing here is a patient prediction.