Development of fully automated macromolecular crystallography

Over the past two decades, automation has been introduced in macromolecular crystallography at a rapid pace, revolutionising both crystallisation procedures and the use of beamlines.

Over the past two decades, automation has been introduced in macromolecular crystallography at a rapid pace, revolutionising both crystallisation procedures and the use of beamlines. Nonetheless, crystal harvesting continues to be a relatively slow process, with potential implications for crystal quality, speed, reliability, and throughput. To address these shortcomings, in 2008, Jose Marquez and Florent Cipriani, scientists at EMBL Grenoble, developed the CrystalDirect technology and the web-based Crystallographic Information Management System (CRIMS) software. Together, these technologies enable a fully automated protein-to-structure pipeline that can be piloted remotely from any computer anywhere in the world.

EMBL has played a critical role in translating the initial idea behind CrystalDirect technology into direct applications in structure-based drug design. “[EMBL is] a fantastic place to do research and development, [it was] almost like an incubator because we started with the technological development and then applied it to different project cases,” said Irina Cornaciu, co-founder and Chief Executive Officer of ALPX. “Over the course of a few years, the attention and requests for services from third parties has increased to a level where spinning off the commercial CrystalDirect services into a separate company became the logical next step” to ensure that demand could be satisfied at a rapid pace, Cornaciu explained.

scientific image
CrystalDirect robot control software: signal from a video camera monitoring the laser working area. Credit: Zander, U, et al.

Scaling up CrystalDirect and CRIMS for industry

ALPX was founded in 2019 at EMBL Grenoble. It provides industry users with access to its high-throughput crystallisation and fragment screening facility, the HTX Lab, based on the CrystalDirect technology. CRIMS can be operated remotely to fully automate crystallography pipelines. It is capable of screening small-molecule libraries of more than 1,000 fragments, over multiple projects. CrystalDirect technology and CRIMS is in high demand among academic and industry users, with particular interest from the pharmaceutical industry, which uses the screening facility to support structure-based drug development programmes.

Throughout the development process, EMBLEM has been working and supporting the scientists behind the technology. "EMBLEM not only took care of securing intellectual property rights, such as patents, trademarks, and copyrights associated with the technology, but also helped to establish CrystalDirect services for industrial partners," said Jürgen Bauer, Deputy Managing Director of EMBLEM.

What the future holds

ALPX's services are increasingly critical to industry's -- and academia's -- efforts to improve and accelerate the drug development pipeline through faster screening of much larger numbers of candidate molecules and targets. This in turn could help to combat the spiralling cost of drug development and the resultant increase in the price of medicines. From this perspective, EMBL is supporting a strategic European industry and contributing indirectly to European Union policy commitments in the health sector around the affordability and equality of access to medicines and to Europe's Beating Cancer Plan. In addition, while ALPX is working mainly with the healthcare sector initially, its technology might also have important agricultural applications -- such as developing new pesticides and fertilisers, which could bring environmental benefits in the long term.

EMBL’s experimental services deliver substantial value to Europe by delivering scientific services and thereby enabling researchers to conduct novel and demanding experiments that could not be easily achieved at a purely national level, an independent review found.

The global consultancy Technopolis Group, specialising in research and innovation policy, conducted a survey and analysis of external (non-EMBL) users of EMBL’s experimental services. The survey aimed to identify whether users perceived scientific, technological, societal and economic benefits as a result of utilising the experimental services at EMBL Barcelona, Grenoble, Hamburg, Heidelberg, and Rome.