Dec 31, 2017

The dark side of the new popularity of cryo-electron microscopy

The field of cryoEM has much to celebrate — with its election of the “Nature method of the year” in 2015, and now crowned with this year’s Nobel Prize for Dubouchet, Frank and Henderson, three pioneers of our field — single particle analysis has stepped out into the limelight after being in the shadow of crystallography for several decades.

Finally, SPA is recognized and accepted as a powerful tool for addressing structural biology questions in its own right. Electron tomography is also quickly gaining popularity, with an increasing number of biologists valuing this method for its unprecedented ability to study intact cells in three dimensions and at macromolecular resolution.

This exposure of cryoEM in the prime scientific spotlight is an exciting development for sure. Finally, despite the high cost of the instrumentation and expert staff, many institutes now invest in this method. Even in smaller universities and institutes, the substantial costs for high-resolution cryoEM instrumentation are not preventing the establishment of local expert laboratories. Here, a basic level, local cryoEM instrument is often sufficient to optimize samples, that then can then be imaged in one of the high-end open access EM facilities elsewhere.

While open faculty positions in cryoEM were relatively rare in the recent past, today there are a wide variety of positions for all experience levels available. Scientists in the field of cryoEM are now popular speakers in numerous scientific conferences in many different fields, and not just the specialized technical meetings.

So what is the downside? Unfortunately, I do believe that this newfound popularity poses a danger for cryoEM specialists. We increasingly face unrealistic expectations when publishing in scientific journals, as well as obtaining funding for new grant applications.

Let me elaborate with two personal examples that I encountered in the past year. The first example was in the role as a reviewer of a scientific paper. The research study in question was put forward by a research group that specializes in genetics and fluorescent light microscopy experiments. In my opinion, the study was well done and beautifully answered an interesting research question. However, one of the other reviewers harshly commented that the study lacks proof with electron cryotomography, and requested that the authors needed to perform such experiments in order for the study to be considered for publication. In the eyes of this reviewer, the suggested experiments would be easy and quick to do and should not take more than two weeks. While I am certainly one of the greatest advocates of this method, this request was more than unrealistic. Being familiar with both the biological system and research organism in question, I estimate that performing the required data acquisition would require a full PhD study in a specialized cryoEM laboratory. Even my passionate objections against these electron cryotomography experiments (a first for me!) did not sway the other reviewer and the paper got ultimately rejected.

The second example is the reviews I received myself from one of my own grant applications. Unfortunately, the application in question was not only denied, but on top of that received such a bad score that it even prevents me from applying again. While the objective level of importance regarding the scientific topic of the application may not reflect my own enthusiasm, the criticism was surprisingly only focused on the methodology itself. The comments that doomed my proposal were ‘this is routine in the field already’ and ‘this has already been done before.’ I strongly believe this to be untrue, and to my knowledge, the core aim of the proposed research to resolve molecular machines at sub-nanometer resolution in intact cells has not been achieved yet.

These two personal experiences are likely not isolated events. I fear this will become the new norm, and unrealistic expectations, such as 2A resolution for all SPA structures, or sub-nanometer resolution for ECT subtomogram averages, will keep rising. The wider scientific community is now aware of our prime research studies on ideal samples, but they often mistake these groundbreaking benchmarks as the new standard. Most often, the researchers that ultimately decide on the fate of papers and research grants are not specialists in our field. Their view on what is possible with the diverse cryoEM methods is often formed by how cryoEM is publicized at conferences, news articles and social media reports. This opinion is easily skewed by over-enthusiastic reporting and by glossing over any shortcomings.

While we should certainly celebrate every occasion when a member of our research field overcomes old barriers, we need to make sure that we keep in mind that, like any other research method, cryoEM is primarily a tool to solve scientific questions. Ultimately, the quality of the research is based on the amount and impact of the insight we can gain by our experiments, and that is not directly correlated to a resolution value.

What can we do? I think we need to stand together as a field, and support our colleagues by accepting to review their papers and grant applications in order to ensure a fair evaluation. In my opinion, we need to collaborate, support and acknowledge each other as best as we can so we can successfully move forward together into a bright future in cryoEM.


Happy New Year 2018!