The decision arrives: major revision. Some comments are straightforward. Others could mean weeks or months of experiments. Before reorganising the laboratory around the report, it is worth asking what each request would actually establish.
A reviewer may have identified a missing control, a weak inference or a conclusion that reaches beyond the data. They may also have suggested an interesting extension that would take the project in a different direction. These situations need different responses. The difficult part is working out which one you are facing.
My starting point is the relationship between the claim and the evidence. If an experiment is needed to support the central conclusion, the request deserves serious attention. If the conclusion can be supported more accurately by narrowing its scope, that deserves consideration too.
Start with the concern behind the request
“Please repeat this in another background” is a proposed action. The underlying concern could be specificity, reproducibility, generality or a confounding feature of the original material. A second background will not necessarily address all four.
Rewrite each substantial comment as a scientific question. Does the phenotype depend on the proposed gene? Could a developmental difference explain the result? Does the analysis account for the structure of the experiment? Is the mechanism demonstrated, or inferred?
Read the editor’s decision alongside the reports. Identify any priorities the editor has stated, especially where the reviewers disagree. Then ask the coauthors to agree on what the manuscript currently claims. A revision plan becomes much easier to assess once everyone is working from the same interpretation.
Work out what would change the conclusion
For each request, write down the claim at stake, the unresolved alternative and the evidence that would distinguish it. Then decide which response is scientifically defensible:
- Generate new evidence. A missing control or unresolved alternative may leave the main finding unsupported. Prioritise the experiment or analysis that directly addresses that weakness.
- Make existing evidence assessable. The relevant comparison may already exist but be difficult to find, incompletely reported or analysed inappropriately. Check whether clearer reporting or a justified reanalysis resolves the concern.
- Narrow the claim. The results may support a useful finding while leaving directness, mechanism or generality unresolved. Revise the conclusion wherever it appears.
- Discuss a substantial extension with the editor. A new system, cohort or research programme may materially change the study. Explain the scientific issue and the response you propose before committing to a long programme of work.
These choices require judgement. Calling a request “outside the scope” does little on its own. Explain what the requested work would establish, why it changes the scope, and what the present evidence can still support. The editor may judge that the additional work remains necessary for the journal.
A worked example: does “regulates” mean “directly regulates”?
Imagine a manuscript reporting that loss of a transcription factor changes the expression of a candidate gene. The authors describe that gene as a direct target. A reviewer asks for evidence of promoter binding.
The concern is reasonable: altered transcript abundance does not establish direct promoter regulation. Additional expression measurements may strengthen the association without resolving directness. Binding evidence would address occupancy, but occupancy alone would still leave the functional consequence to be tested.
If direct regulation is central to the paper’s main mechanism, the revision needs an approach suited to testing that inference. Depending on the system, this may mean combining binding evidence with a functional test of the relevant regulatory sequence. The design should distinguish direct regulation from plausible indirect effects.
If the contribution rests on a genetic or physiological relationship, a narrower conclusion may be appropriate. An illustrative response could read:
We agree that the expression data do not establish direct promoter regulation. We have removed the direct-target claim from the abstract, results and model, and now describe the finding as X-dependent expression. The revised discussion states that the route linking X to Y remains unresolved.
That response is useful only if it accurately describes the evidence and the actual changes. If removing the direct-target claim undermines the main advance, changing the wording will not repair the study.
Choose an experiment that can resolve the concern
A revision experiment should have a clear purpose and interpretable outcomes. Before starting, ask what a positive result would establish, what a negative result would mean, and which alternative explanation would remain.
For example, failure to detect a response is difficult to interpret if assay sensitivity, treatment effectiveness or biological replication is inadequate. Consider the experimental unit, relevant controls, timing and plausible effect size before collecting more data. More samples or another technique can consume substantial effort while leaving the original inference unchanged.
Practical constraints matter when planning the revision. Discuss access to material, technical feasibility and timing openly with the coauthors. Where a substantial delay is unavoidable, ask the editor about an extension or the acceptability of a proposed alternative. A deadline does not supply missing evidence, but early discussion can clarify the decision you need to make.
Make the response easy to evaluate
Once the scientific decisions are made, write the response around what changed. Address every substantive point, give the answer early and identify where the revision can be found. Distinguish new results from evidence already present in the original submission.
William Stafford Noble’s guidance on responding to reviewers recommends complete, respectful and self-contained replies. These principles help the reader assess the reasoning without reconstructing the revision from scattered references.
Where you disagree, state the scientific reason and explain any alternative change you have made. Avoid claiming that a concern has been resolved if an important limitation remains. Check that the response letter, abstract, figures and discussion now tell the same scientific story.
For broader advice on the response document, see Common Pitfalls When Responding to Peer Review.
Before sending the revision back
Read the revised manuscript once without the response letter. Can a new reader see the evidence, understand its limits and reach the conclusion you are asking them to accept?
A successful revision plan makes the scientific decisions explicit: which concerns required new evidence, which were resolved through analysis or clarification, and which required a more precise conclusion. That is the work to complete before polishing the final reply.
Working through a difficult reviewer report?
Helical Scientific helps researchers assess reviewer concerns, prioritise experiments, strengthen the manuscript and prepare clear responses. Explore our manuscript revision and reviewer response support.
