How to use: This is a diagnostic board game / audio drama hybrid. Play it as a group activity with cPNI classmates, or record yourself narrating all parts as an audio drama to listen back to. The format: a patient presents with chronic fatigue and low-grade inflammation. Five "detectives" (the five metamodels) investigate. Each uncovers a different contributing layer. The twist: they're ALL right. Because that's cPNI.
Inspired by: Module 8 (Diagnosis), the cPNI five metamodels framework
Patient: Maria, 42, former athlete, now office worker
Chief complaint: "I'm exhausted all the time. My doctor says my blood work is normal."
Lab findings:
The conventional doctor's verdict: "Everything looks fine. Maybe try sleeping more."
The cPNI detective team's response: "We need to investigate."
(Voice: thoughtful, philosophical, always asking "but WHY from an evolutionary perspective?")
"Let's start at the beginning. Not the beginning of Maria's symptoms — the beginning of our species.
Maria was an athlete. Now she sits 10 hours a day. Her genome expects daily movement. Her mitochondria expect cycles of energy demand and recovery. Her immune system expects the oscillation of physical stress.
She eats three meals plus snacks. Her genome expects intermittent fasting — periods of scarcity. Her AMPK pathway is dormant. mTOR is chronically activated. No autophagy. No cellular housekeeping.
She lives under artificial light until midnight. Her circadian rhythm — tuned over millions of years to the solar cycle — is disrupted. Melatonin suppressed. Melatonin is an antioxidant and immune modulator. Without it, her immune system loses its nighttime recalibration.
My conclusion: Maria's body is running ancestral software in a modern environment. Every system expects signals it isn't receiving. This is evolutionary mismatch — the foundational metamodel of cPNI."
(Voice: precise, numbers-focused, speaks in pathways)
"Look at the numbers. CRP at 2.8 — that's low-grade inflammation. Not acute. Not normal. The grey zone where chronic disease begins.
Fasting glucose 5.8 — she's insulin resistant. Her cells are refusing glucose because chronic inflammatory cytokines — TNF-alpha, IL-6 in trans-signalling mode — have downregulated GLUT4 translocation in skeletal muscle.
Vitamin D at 38 — insufficient. Vitamin D is an immune modulator. It promotes Treg differentiation, supports barrier integrity, and modulates the Th1/Th2 balance. At 38 nmol/L, her immune regulation is compromised.
Ferritin at 18 — she's iron-depleted. Iron is essential for mitochondrial electron transport chain Complex I and III. Low iron = low ATP = fatigue. But here's the twist: her immune system may be HIDING the iron. During inflammation, hepcidin rises, sequestering iron in macrophages to starve pathogens. This is anaemia of chronic disease logic, even at subclinical levels.
Zonulin elevated — gut barrier compromised. LPS translocation is likely. That explains the CRP.
My conclusion: A metabolic cascade — barrier dysfunction → immune activation → insulin resistance → mitochondrial underperformance → fatigue. It's all connected biochemically."
(Voice: empathetic but analytical, connecting emotions to hormones)
"Everyone's looking at her blood. I'm looking at her life.
Maria's cortisol rhythm is flattened. That's not just an endocrine finding — it's a psychological biography. Flattened cortisol means chronic stress without recovery. The HPA axis has been activated so long it's lost its rhythm.
I asked Maria about her life. She's going through a difficult separation. She worries about her children. She sleeps poorly and wakes feeling unrefreshed. She's lost her social network since leaving sport.
Loneliness. This activates the conserved transcriptional response to adversity (CTRA). NF-kB upregulation. Increased pro-inflammatory gene expression. Decreased antiviral gene expression. Her immune system is literally responding to social isolation as a physical threat.
Her flattened cortisol means glucocorticoid resistance — her immune cells don't respond to cortisol's suppressive signal anymore. The brain is sending "calm down" signals that the immune system ignores.
Her serotonin? Most is made in the gut — and her gut is compromised. Low serotonin means low mood, poor sleep, increased pain sensitivity. The kynurenine pathway is likely shunting tryptophan toward quinolinic acid (neurotoxic) instead of serotonin — immune activation drives this shunt via IDO enzyme.
My conclusion: Her psychology is not separate from her inflammation. It IS her inflammation. The P in PNI is not an afterthought — it's the driver."
(Voice: intense, urgent, protective)
"The immune system is doing EXACTLY what it should be doing. The problem is that it was never told to stop.
Maria has low-grade systemic inflammation. CRP 2.8. I guarantee if we measured IL-6, TNF-alpha, and IL-1-beta, they'd be elevated. Not dramatically — subtly. Chronically.
Her elevated zonulin means her gut barrier is permeable. Bacterial LPS is crossing into systemic circulation. Her innate immune system — via TLR-4 on macrophages — is responding to this endotoxin. NF-kB is activated. Inflammatory cytokines are being produced.
But where is the RESOLUTION? Where are her lipoxins? Her resolvins? Her protectins?
Her omega-3 index is probably low — she's not eating fish regularly. Without EPA and DHA, she can't produce specialised pro-resolving mediators. The eicosanoid class switch from prostaglandins to lipoxins is impaired.
Her macrophages are stuck in M1-like polarisation. Efferocytosis is incomplete. Apoptotic cells are undergoing secondary necrosis, releasing DAMPs, triggering more inflammation.
This is a resolution failure. Not an excess of inflammation — a deficit of resolution. Resoleomics in action.
My conclusion: Fix the resolution pathway. Omega-3 supplementation. Barrier repair. And remove the ongoing triggers."
(Voice: practical, solution-oriented, integrative)
"I've heard everyone. Now here's the treatment plan that addresses ALL the metamodels simultaneously:
1. Movement (Evolutionary)
2. Nutrition (Biochemical)
3. Intermittent Fasting (Evolutionary + Biochemical)
4. Psychology (Psycho-Neuro-Endocrine)
5. Barrier Repair (Immunological)
My conclusion: No single intervention. All five metamodels point to different facets of the same diamond. Treat them all. That's cPNI."
NARRATOR:
So who inflamed the patient?
Was it the evolutionary mismatch? The metabolic cascade? The psychological trauma? The immune resolution failure?
ALL DETECTIVES (in unison):
It was all of us. It's always all of us. That's the point.
NARRATOR:
In cPNI, there is no single cause. There are systems. There are connections. There are metamodels that each illuminate a different dimension of the same patient. The five metamodels aren't competing hypotheses — they're complementary lenses.
Case closed. But the patient's journey is just beginning.
Players: 2-6
Setup:
Variants:
| Metamodel | Key Concepts | Module |
|---|---|---|
| Evolutionary | Mismatch, intermittent living, circadian disruption, melatonin | 2, 10, 11 |
| Biochemical | Insulin resistance, mitochondria, vitamin D, iron/hepcidin, zonulin | 7, 10 |
| Psycho-neuro-endocrine | HPA axis, CTRA, cortisol rhythm, kynurenine pathway, serotonin | 3, 11 |
| Immunological | LPS/TLR-4, resolution failure, SPMs, M1/M2, efferocytosis | 4, 5, 7 |
| Clinical/Therapeutic | Multi-system intervention, integrative protocol | 8 |
| Cross-cutting | Low-grade inflammation, NF-kB, omega-3, gut barrier | All |