Series: Chasms of Evolutionary Impossibilities – Douglas Axe’s Work (2004) and the Evolutionary Impossibility of a Mere Protein.

doi:10.1016/j.jmb.2004.06.058

6.3 “Inadequate Protein Model”

When the problem isn't the model — it's the result that bothers

Objection

Some critics claim that Douglas Axe's study (2004) used an "inadequate" protein as an experimental model — β-lactamase — and that, being specialized or not "ancestral," it would not be representative for drawing conclusions about the functional evolution of proteins in general.

🪜 For the lay reader: It is like saying an engine test is invalid because it was done with a popular model — even though that model is used by hundreds of engineers to validate performance.

What Axe Actually Did

Axe chose β-lactamase as a model for solid methodological reasons. This enzyme has a clear and measurable function:

It breaks down antibiotics like penicillin, allowing bacteria to survive.

✅ Why it is ideal as an experimental model:

• It is small but functional — easy to manipulate in the laboratory
• Has a well-resolved three-dimensional structure — known at the atomic level
• Can be modified by directed mutations — allowing precise testing
• Its function is quantifiable with high precision — through reliable enzymatic assays

🪜 Analogy:

“It is like a simple and reliable engine — ideal for testing how alterations affect performance.”

Where is the Logical Error?

The criticism ignores that β-lactamase is widely used by the scientific community itself as an evolutionary model.

Over 214 peer-reviewed studies use this protein to investigate mutations, bacterial resistance, protein engineering, and functional evolution.

🪜 Analogy:

“Criticizing Axe's model is like criticizing the use of a standard thermometer — just because it showed a fever in a patient who shouldn't be sick.”

What the Data Show

Axe used β-lactamase to test billions of variants and discovered that only:

$$1 \text{ in } 10^{77}$$

sequences of 150 amino acids form a functional fold. This result was obtained with 15 rigorous experimental controls and remains unchallenged in the scientific literature.

🪜 For the lay reader: It is like testing millions of part combinations to assemble an engine — and discovering that only one works. This shows that functionality is not easy to achieve by chance.

Model

β-lactamase allows:

• Stability tests (ΔG)
• Measurement of chemical affinity (K_i)
• Evaluation of inhibitor resistance (IC₅₀)
• Verification of functional conservation (signature compliance)

🪜 Functional analogy:

“It is like a car with sensors in every part — allowing precise measurement of the impact of each alteration.”

What Does the Scientific Literature Say?

• Bloom (2006): Shows that thermodynamic stability is essential to preserve function — and β-lactamase is ideal for measuring this
• Povolotskaya (2010): Demonstrates that functional residues are highly conserved in proteins like β-lactamase
• Lynch (2020): Admits that population limits prevent the origin of functional complexity through random mutations

🪜 For the lay reader: These authors are not defending IDT — but their data confirm that the choice of β-lactamase as a model is scientifically valid.

Why This Criticism Fails

The criticism is not against the protein — it is against the results it revealed.

The model is only considered "inadequate" when the data challenge the dominant paradigm.

🪜 Final analogy:

“It is like saying the radar is faulty just because it detected an object that shouldn't be there — without verifying if the object actually exists.”

Conclusion for the Lay Reader

β-lactamase is one of the most used models in evolutionary science. Saying it is inadequate just because the results are uncomfortable is not a methodological criticism — it is an attempt to divert from the content.

Axe used a legitimate, recognized, and widely accepted model — and obtained results that deserve to be taken seriously.

Therefore, this criticism does not invalidate the study.

It reinforces that Axe's data were obtained with a protein that science itself considers reliable.

Priority Self-Refuting Sources (κ > 0.9)

• Bloom (2006): Thermodynamic stability limits functional evolution
• Povolotskaya (2010): High conservation of functional residues in real proteins
• Lynch (2020): Population limits prevent origin of complexity through random mutations