Q&A: Making continuous crystal structure analysis more accessible in the field

Scientists at EMBL Grenoble and the European Synchrotron Radiation Facility (ESRF) have developed a new method using in situ continuous crystallography (iSX) to study the structure of macromolecules. They recently described this new technique in a paper published in the journal IUCrJ. This method is currently being operated on the ID23-2 beamline jointly operated by EMBL and ESRF.

Nicholas Foose, lead author of this publication, is a member of the first generation of ARISE Fellows, a program aimed at supporting the development of new technologies and methods in the life sciences and training scientists in research infrastructure management. was a member of

After completing his PhD, Foose majored in biochemistry and molecular biology at the University of Marseille, France, gaining experience through postdoctoral positions at the SOLEIL and ESRF synchrotrons. In 2021, he joined the McCarthy team at EMBL Grenoble as part of the three-year ARISE program, focusing on developing methods and instrumentation for macromolecular crystallography. In this interview, he talks about this new method and the ARISE Fellowship Program.

What are the main features of this new method using in situ continuous crystallography?

The main feature of this method is that it works directly from the crystallization plate. A crystallization plate has an average of 96 wells (very small holes), and each well contains three small drops of crystallized protein. Harvesting these crystals to find just a few good ones is the usual method, but it is tedious and time consuming. Instead of picking only the “best-looking” crystals, in-situ experiments screen crystals directly in the crystallization plate and obtain data from them. However, this type of experiment was not considered a method for routine use.

To do this easily and efficiently, we developed a new method that relies on a microdiffractometer coupled with a plate holder that accommodates SBS-96 plates. These instruments offer excellent technical performance in terms of data collection behavior and accuracy, which is key to the quality of the final data.

Once you have the right tools, you need the right interface to use them in the best way. To ensure a reliable, accurate, and well-controlled method, we have developed a user interface tailored to the needs of our users. This is an important aspect of our work.

What are the advantages of this new method in structural biology?

The main advantage is that it creates a shortcut to the normal structure determination workflow. Our new method makes in situ experiments easy and efficient. This ultimately reduces the cost and time required for structural decisions, especially for difficult projects.

This is also a great approach for drug discovery projects. It becomes easier to screen compounds directly in the plate and experiments can be performed at room temperature. This is very important to study the target in its natural and flexible state. This improves the quality and reliability of the final output.

Taking this a step further, we are also opening up new opportunities for more automated experimental workflows. The development of a “plate-to-3D model” pipeline that requires no human intervention may soon become a reality. I believe this should be the end goal.

My goal in applying for the ARISE Fellowship was to encourage more scientists, and even experts, to use The goal was to make crystal structure analysis more accessible. We believe this method is another step in this direction.

What did you enjoy most about the ARISE program?

The ARISE Fellowship Program provides excellent training from day one. When applying for a fellowship, it is important to define in detail all aspects of your project, from the scientific and technical aspects to how you will address specific bottlenecks, the people you will collaborate with, and how you will communicate the project.

What is unique about this program is that it requires a secondment with time to work in a partner organization, another EMBL team, or a service delivery facility. During my three-year ARISE Fellowship, I worked closely with ESRF and with ARINAX, which commercializes EMBL Grenoble’s device prototypes worldwide, and with EMBL Grenoble’s spin-off company, which provides crystallography services to the pharmaceutical and biotech industries. I had the experience of working with an ALPX.

ARISE is a great option for people who, like me, enjoy working in an interdisciplinary field. This program is suitable for people who have a strong scientific background but are also interested in technical or methodological aspects, or who come from a technical field and want to imagine and create new solutions to support high-level scientific projects. It is aimed at people who are thinking. This approach enables bridges between people, academic research and industrial enterprises. Creating permeability is the strength of the ARISE program.

I also benefited greatly from the amazing mentors and ARISE community that supported my career development. ARISE brings together a unique and diverse group of colleagues with a unique sense of collaboration and mutual support. The dedication to supporting each other and the quality of the interaction was incredible.