Researching Through a Cloud

These days everyone talks about cloud solutions, how they will affect our lives, and how they will open up opportunities for a fully-digital world. Today, however, I want to talk about a different kind of cloud, a concept coined by Prof. Uri Alon, from the Weizmann Institute of Science's Department of Molecular Cell Biology. "The cloud" is a concept which relates to the stage in research in which experimental realities/results don't mesh with current knowledge leading to the feeling of being "stuck", which eventually develops into negative feelings such as frustration, incompetence and even depression. However, if a scientist wanders around in the cloud long enough and keeps an open mind, s/he might discover something new. In his 17-minute xTED talk (shown below), Prof. Alon presents his ideas about the cloud and emotions in science in a fun manner that reminded me of my own time in the cloud.

As a protein crystallographer I grow protein crystals to obtain structural details of proteins. To obtain such details the crystallographers need to obtain a protein crystal that can generate sufficient data for structure determination. Unfortunately, most proteins don't crystallize, and furthermore it is impossible to know a priori which protein can crystallize and which will not. Thus, protein crystallography is a classic high risk research endeavor during which crystallographers can get stuck quite easily at many steps along the way.

And indeed the fear of all protein crystallographers befell me: my protein was not crystallizing.  It took me around 1.5 years of banging my head against this problem, trying all kinds of rescue strategies, yet nothing worked – no crystals were growing in my plates. I was in the cloud,  I was wandering in all directions yet nothing led to a breakthrough. I was desperate, I was starting to loose faith that I would ever see the structure of this protein, and worse, I was not sure how I'd complete my PhD studies. All along, my supervisor, Dr. Raz Zarivach, offered practical suggestions for additional avenues, considered my own suggestions, and was there for me in those difficult times. And then, it happened. Raz suggested a direction which is rare and even more adventurous – trying to determine the protein's structure via Nucelar Magnetic Resonance (NMR). I was quite surprised by his suggestion since at that time I believed that my protein was way too big for NMR structure determination, and besides, Raz is a protein crystallographer and not an NMR spectroscopist. However, his idea gave me the hope I needed and together we started to look for an NMR spectroscopist willing to join our adventure. Eventually, we collaborated with Dr. Jordan Chill, and together we are pushing the boundaries of solution NMR limits. Through this approach we were able to look at the behavior of the protein in solution at high concentration. By doing so we realized that the protein undergoes a process of oligomerization which is correlated with its concentration. The higher the concentration, the greater the oligomerization. Since protein crystallography necessitates both very high concentration and homogeneity, this protein could not be crystallized since if one condition is satisfied,  the other is not. Thus, only by changing our research approach could we determine that we were heading towards a dead end all along.

So, returning to Prof. Alon's discussion of the cloud, mentoring and emotions, when you're in the cloud, expand your endeavors and experiment, try new things that will enable you to expand your reach and don't lose hope - because you never know when the next crucial discovery will take place!

Please share with us the moments in which your research was stuck - how you felt and how you overcame?