One of the hardest things to figure out as a PI, especially a young PI, is "when to hold em and when to fold em" with respect to appealing/revising a paper with tough reviews. A few thoughts
1. Don't ever figure this out alone, or even just within your lab. Ask peers, mentors and THE EDITOR if the revision is feasible
2. If there are experiments suggested by reviewers which you feel are not reasonable or out of scope, discuss with the editor before you begin revising (and not 6 months later!)
3) It is critical, especially as an early career PI, to publish and demonstrate independence and upward trajectory. Sometimes holding out for the "big paper" ends up being a huge bandwidth and resource allocation which is too much for a lab to handle.
4) I always think about what is best for the trainee and the science. Postdocs going on the job market, whether it is fair or not, benefit from papers in the top journals. But holding out for 2 years to get that paper can be detrimental to the job search (and to science!)
5) On that note, as a PI the hardest thing I see is the relative "unfairness" of one trainee's paper getting good reviews and another's getting hit hard, even if the science and effort are similar. This is where we earn our chops as PI/leader, it is not easy...
6) @biorxivpreprint is your friend. It gets the work out (grants, job searches, science moves forward), and editors are reading it looking for papers. Put it out there early, and definitely post it if the review process/finding a home for your work drags on
7) On NIH study section, publishing multiple substantive papers matters more than one big paper. Don't forget that. It may be different for tenure/promotion reviews, but papers lead to grants and then grants lead to papers....
8) These are my own personal opinions, and I welcome others to chime in with their perspective, even if exactly the opposite! Our trainees and junior colleagues need to understand that the hill they are climbing is real and there are many ways to scale up!
