When we start working in a lab as scientists, our focus is on learning to conduct experiments, mastering techniques, and eventually presenting our results in a thesis or paper. We focus less on the question, at least initially, as this is usually provided or guided by our PI or supervisor. Yet, the ability to ask a question, and even more so, the right question, is not a given. Intuitively, asking a question seems trivial. Yet asking a meaningful question requires a specific set of skills that, if underdeveloped, leads to frustration and wasted effort. In addition, the explosion of knowledge (and AI tools) can make one feel there are no more questions to ask. I will briefly discuss these interconnected topics in this piece.
When I began my PhD, the number of papers on our lab's topic, Opa1 and mitochondrial dynamics, could be counted on one hand. Despite lacking exceptional memory, I could recall each figure from all published papers (and I remember my supervisor, Luca Scorrano, at the time, asking us to do so). We could analyse them in detail to understand their limitations and connections to our research. I also recall Luca telling us that we were fortunate, as the field was still relatively niche, and that there was still much to discover, unlike other, already well-established fields, such as cancer. I actually didn't appreciate how true that was (and lucky we were!). This freedom was exciting. But there was a time when, carried away by an inquisitive nature, I went to him, showing that some disparate treatments changed the mitochondrial reticulum in my cells. I was excited by the data because the changes were stark. Yet, he looked at me (noticeably less excited than I'd hoped) and asked: "Christian, why did you do this experiment?" And actually, I couldn't answer that question. I vividly remember the mix of embarrassment and frustration. He told me, rather simply, that every experiment we do must follow a specific question and add value to our projects when answered. Until then, I hadn't realised the importance of asking the right question, and I have to thank Luca for this, as, though the advice seemed simple, it changed the course of my approach to science. That moment taught me that curiosity without direction is just noise. So, how do we identify what question to ask then? We need to split this quest into two parts: how to ask a question, and then how to ask a good one.
The art of asking questions
Asking a biological question cannot be easily taught because it is inherently subjective and personal, largely based on one's curiosity. So, I don't have any secret to share, unfortunately. But only some suggestions. The first step is to exercise our "curiosity muscle" and always be inquisitive. From this perspective, a great way to train this muscle is to read papers (often laterally, i.e. not necessarily in our field) and critically discuss them with colleagues. This is a vital exercise to foster curiosity and to fully understand how scientific questions are asked and addressed. I always tell people in the lab that there are different levels of understanding a paper. Beyond the simple data presentation and the writing style (both of which, of course, are very relevant and may be the subject of another article), there is a deeper layer that reveals how the scientific question was identified and experimentally tackled. It is very exciting to see how different scientists think and approach the field by studying the structure of their papers. In brief, critical reading, not AI summaries, remains our primary source of curiosity and scientific insight. We just need to dedicate quality time, and it will definitely be worthwhile.
Reading and curiosity will bring one closer to identifying knowledge gaps more clearly. But it is not enough. I also suggest looking at any given piece of evidence with the "beginner's mind". This term is used in mindfulness to indicate that even after years of practice, every time one meditates, one should approach it as if it were "the first time". This allows us to approach the session with an inquisitive perspective, noticing what we might otherwise take for granted. The same applies to scientific thinking: approaching familiar problems as if seeing them for the first time often reveals questions that have been hiding in plain sight. I always suggest taking a step back when analysing the results and approaching the project from a 30,000 feet view, in other words, to see it with different eyes, instead of being entrenched in one's expectations and pre-existing thinking. This perspective becomes even more crucial as fields become saturated with data. There is compelling research on this, demonstrating how intellectual humility and beginner's mind enable scientific breakthroughs.
The art of asking GOOD questions
Once one practices questioning skills, the next step is to apply the "relevance filter". Indeed, one can sometimes have many questions. But are they good questions? What is a good question for a scientist? A good question is one that addresses a relevant problem in science, whether fundamental or translational, and can be addressed with specific experiments. Otherwise, even a good question can remain unanswered. But now we are entering a rabbit hole. What is a relevant problem in science? Perhaps the answer isn't in the abstract definition, but in our willingness to challenge what everyone else considers settled. As one of my mentors used to do all the time we discussed hard problems in science, ask yourself the "so what" question. Why does your question matter?
The second point about the quality of a question is more related to its "feasibility". This term is often used in grant evaluation, but it applies equally to evaluating one's own research ideas. As beautifully described by Uri Alon in his seminal article, what defines a "good" scientific problem depends on the temporal perspective available. For instance, for a starting student, the question has to be clearly addressable within a 3-4-year lifespan. Anything more ambitious would be frustrating and likely to fail. So, in conclusion, the quality of the question ultimately depends on its relevance to the field and the temporal perspective from which one answers it.
As a side note, the relevance of the questions is at least in part subjective and should be exciting (for us). What I found over the years is that what I find very exciting may appear as a quirk of nature to others, but that should not discourage one from pursuing it! Eventually, the excitement of the question one asks is the true driver of the project. If one is not convinced about the question, the first experimental hurdle will be a block, and frustration will inevitably arise. If instead the quest for knowledge is burning, no experimental failure can stop one.
A practical framework
Understanding what makes a good question is one thing. Constructing one yourself is another. Over the years, I have found that approaching this systematically, while still allowing room for intuition and serendipity, helps crystallise vague curiosities into actionable scientific questions. Here is a practical framework I have found useful, both in my own work and when mentoring students.
Identifying the Knowledge Gap
Begin with a targeted review of the relevant literature. Not a superficial skim, but the kind of critical reading I mentioned earlier. As you read, actively ask yourself: What do we know? What do we not know? Where do different findings contradict or leave open questions? Pay particular attention to the limitations sections of papers, as authors often inadvertently point toward their own unanswered puzzles. Jot down observations that strike you as odd, inconsistent, or incomplete. These are the seeds of potential questions. A knowledge gap is not merely the absence of information, but rather a conceptual hole that, when filled, would advance the field. More importantly, trust your instinct. Sometimes, it recognises the questions without you knowing it.
Testing for Personal Resonance
Once you have identified a potential gap, ask yourself: Does this genuinely excite me? Can I articulate in a single sentence why this question matters? This is the motivation test, and it is critical. I have seen many talented scientists pursue questions that looked good on paper but failed to sustain their passion through the inevitable setbacks and dead ends. Your excitement is not frivolous; it is fuel. A question that aligns with your curiosity will carry you through experimental failures. A question pursued merely because it seems trendy or fundable will not. If you cannot explain why you care about the answer, your commitment will falter.
Validation through the "So What" Test
Now apply the filter I discussed earlier. Ask yourself: Why should the field care about this answer? How does answering it change our understanding or practice? Who benefits from knowing this? This is the "so what" question, and it separates meaningful inquiry from mere curiosity. A good question addresses a real biological problem, not just an interesting observation. It should point toward a paradigm shift or practical application, even if modest. This test also helps you refine your question into something more specific and powerful.
Assessing Temporal Feasibility
Be honest about your life stage and timeline. A PhD student typically has 3-4 years. A postdoctoral fellow might have 5-7 years. An independent researcher can think longer term. Your question should be answerable within *your* available timeframe, not in some idealised future. I have seen brilliant questions abandoned because they required resources or time that early-career researchers simply did not have. This is not a failure of ambition; it is wisdom. Match your question to your reality.
Break down questions into quanta of feasible small projects.
Finally, regardless of the specific timeline one has in mind, a good exercise is to break down the question into smaller, well-executed questions that build credibility and open doors. An overly ambitious question that yields only preliminary data frustrates everyone.
These steps are not rigid. They flow into one another, and you may cycle back and refine your question multiple times. But they provide structure to an otherwise nebulous creative process. They transform "I'm curious about something" into "Here is a specific, addressable, meaningful question that I am equipped to tackle."
Asking good questions nowadays seems to me more difficult than ever before. Everything seems to have already been discovered, leaving an overwhelming sense that there are no good questions left to ask. I often find students discouraged by this so-called "burden of knowledge." This will be the subject of a follow-up article.
"Curiosity brings us together - we are siblings in our questioning." - Carlo Rovelli