Building Backwards: Why Top-Down Models Could Revolutionize Pain Research

Watch Episode 170

Thinking Differently

Pain research has long followed a familiar route: from molecule, to cell, to animal, to human. But as Dr. Alex Serafini explains, this conventional bottom-up approach often fails to deliver therapies that truly help patients, especially in the pain field.

In his work, Serafini emphasizes a phenotype-driven, patient-relevant perspective, where animal models closely mirror human experience before mechanistic reductionism begins. This approach reflects his focus on developing models that behave like patients before molecular exploration takes over.

"I'm particularly interested in model development... seeing if we can bring preclinical models much closer to the actual human experience than what we're using now."

Learning from COVID-19

One striking example came from his COVID-19 work during his PhD. Rather than starting with a molecular hypothesis, Serafini’s team noticed that hamsters infected with SARS-CoV-2 exhibited persistent pain-like behaviors. This observation triggered deep RNA-seq profiling and new hypotheses.

This patient-centric and behavior-first approach uncovered robust gene expression signatures linked to pain, without being constrained by pre-existing assumptions about which molecular players to interrogate.

Why This Approach Matters

In pain research, bottom-up approaches often fail to translate. Drugs that look great in vitro fall apart in humans. By starting with phenotype-first studies, Serafini’s approach offers a translational lens more tightly aligned with clinical realities.

He also integrates concepts like sex differences, epigenetic inheritance, and neuroimmune crosstalk — factors often absent in reductionist models. This allows him to see how inflammation, cognition, and pain circuits overlap, and how GPCRs might serve as more responsive therapeutic nodes.

A Call for Patient-First Science

Serafini’s strategy isn’t just about method — it’s about mindset. It asks researchers to consider the entire ecosystem: from patient to molecule, not just the other way around. And it challenges the GPCR community to use its tools not just to explain, but to intervene.

Takeaway

We don’t need better in vitro data — we need better models of reality. Dr. Alex Serafini makes the case for building pain research from the clinic down, not the bench up.

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Keyword Cloud: GPCR podcast, pain modeling, GPCR online course, translational research, neuroimmune signaling.