{"id":58537,"date":"2023-05-15T12:00:00","date_gmt":"2023-05-15T10:00:00","guid":{"rendered":"https:\/\/www.embl.org\/news\/?post_type=embletc&p=58537"},"modified":"2025-05-08T11:39:22","modified_gmt":"2025-05-08T09:39:22","slug":"behind-the-scenes-of-innovation","status":"publish","type":"embletc","link":"https:\/\/www.embl.org\/news\/embletc\/issue-100\/behind-the-scenes-of-innovation\/","title":{"rendered":"Behind the scenes of innovation"},"content":{"rendered":"\n

Have you ever wondered how groundbreaking new scientific technologies come into being?<\/p>\n\n\n\n

Or how scientists and engineers work together to push the frontiers of innovation? <\/p>\n\n\n\n

We caught up with several members of EMBL Grenoble\u2019s technology-related teams, who opened their doors to give us a sneak peek into this process of innovation. Their skills and collaborative strengths are demonstrated aptly by one of their latest projects: the complete automation of an integral step<\/a> in X-ray crystallography, a technique used by scientists worldwide to determine the 3D structures of proteins and other macromolecules.<\/p>\n\n\n\n

Synergies driving innovation<\/strong><\/h2>\n\n\n\n

EMBL Grenoble has been at the forefront of technological developments<\/a> in the field of structural biology for three decades. This expertise has been built over time thanks to collaborative work between structural biologists and engineers. <\/p>\n\n\n\n

Franck Felisaz, a mechanical engineer in the team of Gergely Papp, joined EMBL in the mid-nineties to work on instrumentation projects. \u201cThe early days of instrumentation at EMBL Grenoble involved what were pretty much craft projects, based on progressive iterations,\u201d explained Felisaz. \u201cThe teams were not structured like they are today, but there was a family-type work environment, where engineers would talk with the scientists over a cup of coffee about the challenges they faced.\u201d <\/p>\n\n\n\n

According to Felisaz, such informal interactions often led to creative solutions to issues scientists face in their work. He referred to this interactive and problem-solving spirit as a \u201cvirtuous circle creating a trustful relationship between engineers and scientists\u201d \u2013 something that still persists at EMBL Grenoble.<\/p>\n\n\n\n

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Franck Felisaz, a mechanical engineer in the Papp team, and Marcos Lopez Marrero, former mechatronics engineer in the Papp team, at the MASSIF-1 beamline. Credit: Stuart Ingham\/EMBL<\/figcaption><\/figure>\n\n\n\n

With the opening of the European Synchrotron Radiation Facility (ESRF) next to EMBL Grenoble in 1994, the use of X-ray-based techniques for determining the structure of macromolecules became popular with structural biologists. EMBL Grenoble started to jointly operate crystallography beamlines dedicated to structural biology with the ESRF, through the Joint Structural Biology Group (JSBG).<\/p>\n\n\n\n

Macromolecular crystallography allows scientists to examine the structure of crystallised macromolecules by bombarding them with X-rays. However, the process involved many challenges. <\/p>\n\n\n\n

“Scientists realised in the late nineties that manual operations were a real bottleneck,\u201d said Felisaz, who was already thinking of automating processes back then. \u201cI had been discussing with them for some time about how we would reduce the time wasted and inaccuracies that result from manual manipulations.\u201d<\/p>\n\n\n\n

This need for technological improvements came at the same time as Florent Cipriani taking over the leadership of engineering activities at EMBL Grenoble, and the decision to create separate instrumentation and synchrotron teams. \u201cBenefitting from experiences from the industrial world, the newly structured instrumentation team at EMBL Grenoble started to offer solid and appropriate solutions for structure determination based on macromolecular crystallography,\u201d said Felisaz.<\/p>\n\n\n\n

The team started to develop prototype instruments allowing reliable and reproducible automation of processes. These innovations included, among other things, sample holder standards (to hold crystals and facilitate robotic handling), sample changers (to handle crystals), and goniometers (to present the crystals to the X-ray beam), and were real game-changers for scientists who rapidly adopted them. Many were also commercialised for use all around the world.  <\/p>\n\n\n\n

Felisaz explains that the innovation cycle doesn\u2019t stop here: once a technology has been adopted by scientists, they will eventually find new ways of using it for their research and, together with engineers, arrive at opportunities to take it to the next level. <\/p>\n\n\n\n

Combining technologies<\/strong><\/h2>\n\n\n\n

One of the recent additions to the portfolio of EMBL inventions is the CrystalDirectTM <\/sup>technology, originally developed by the Marquez and Cipriani teams in EMBL Grenoble. This technology streamlines the preparation of crystals for diffraction experiments and makes it possible to integrate crystallisation and synchrotron data collection into a continuous experimental workflow than can be controlled and operated over the internet. <\/p>\n\n\n\n

The CrystalDirectTM <\/sup>technology is currently implemented at the crystallisation facilities at EMBL Grenoble and EMBL Hamburg, and has been utilised by hundreds of users from academia and industry around the world. <\/strong>The integration of a CrystalDirect™robot at the  MASSIF-1 beam line, which offers new and exciting experimental opportunities, is a good example of the synergies between scientists and engineers at EMBL. <\/p>\n\n\n\n

This massive project involved the three technology-related teams at EMBL Grenoble: the Marquez Team<\/a>, running the High-throughput crystallography platform (HTX), the McCarthy Team<\/a>, operating the EMBL-ESRF beamlines, and the Papp Team<\/a>, leading the instruments development.<\/p>\n\n\n\n

It also included the Structural Biology group at the ESRF, in line with the long-standing and fruitful collaboration between EMBL Grenoble and ESRF over the last few decades through the JSBG. The project benefitted from the latest upgrade to the synchrotron in 2020 (EBS \u2013 the \u2018Extremely Brilliant Source\u2019) \u2013 which made ESRF the most powerful source of X-ray worldwide, allowing unprecedented possibilities in terms of research and technological developments.<\/p>\n\n\n\n

This project is therefore the culmination of several innovations developed in parallel at EMBL Grenoble, as it combines CrystalDirect™ \u2013 an automated crystal harvester developed in 2008 by the Marquez and Cipriani teams \u2013 and MASSIF-1 \u2013 a unique automated beamline dedicated to macromolecular crystallography, jointly developed and operated by EMBL and the ESRF.  <\/p>\n\n\n\n

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\n What is a beamline? <\/h3>\n

Macromolecular crystallography requires a high intensity X-ray beam which is produced by a specific ring-shaped infrastructure, called a synchrotron, composed of \u2018beamlines\u2019 that use X-rays generated\u00a0 by accelerating electrons to near-light speeds in the ring.<\/p>\n <\/div>\n<\/article>\n\n\n\n\n

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\n What is crystallisation? <\/h3>\n

To carry out diffraction experiments at a synchrotron, large numbers of crystals have to be produced and prepared for data collection. This typically happens at dedicated robotic facilities like the HTX lab in EMBL Grenoble.<\/p>\n <\/div>\n<\/article>\n\n\n\n\n

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\n What is CrystalDirect™? <\/h3>\n

The CrystalDirect™<\/a> technology consists of an extremely precise robot that streamlines the step of crystal sample harvesting and preparation for X-ray diffraction at the beamline. It automatically harvests the biomolecular crystal from the crystallisation plate where it has been grown, and preserves the crystal sample by cryo-cooling it.<\/p>\n <\/div>\n<\/article>\n\n\n\n\n

\u201cCrystalDirect and MASSIF-1 were a perfect match at the perfect time,\u201d said Matthew Bowler, EMBL beamline scientist in the McCarthy team, in charge of operating MASSIF-1. Bowler joined EMBL in 2012, after spending several years at the ESRF where he started developing ideas for a fully automated beamline \u2013 MASSIF-1 \u2013 which became operational in 2012 and received a major upgrade<\/a> in 2020.<\/p>\n\n\n\n

\u201cWhen MASSIF-1 was coming online, CrystalDirect™ was being developed. The latter started to generate a large number of crystals, and we actually had the capacity and automation to run them with MASSIF-1 without anybody having to do it manually. So the obvious next step was to marry these two technologies to have CrystalDirect™ on the beamline,\u201d added Bowler.<\/p>\n\n\n\n

\"Two
Matthew Bowler, EMBL beamline scientist in the McCarthy team, and Didier Nurizzo, ESRF scientist, both in charge of operating the MASSIF-1 beamline at the ESRF. Credit: Stuart Ingham\/EMBL<\/figcaption><\/figure>\n\n\n\n

Overcoming challenges<\/strong><\/h2>\n\n\n\n

This idea was first tested in 2018 as a proof of concept on another beamline, ID30B, putting together three technologies developed at EMBL Grenoble: the \u2018Flex\u2019 \u2013  a robotic arm in charge of moving crystal samples from one place to another, the goniometer \u2013  an instrument presenting the crystal to the beam, and CrystalDirect™ \u2013 a machine that harvests the crystal samples. They identified key issues that were likely to stall the project and would need to be resolved before integrating the CrystalDirect™ machine in the beamline.<\/p>\n\n\n\n

\"CrystalDirect
The CrystalDirect harvester (top right) integrated into the experimental hutch of the MASSIF-1 beamline, together with two pieces of equipment: the robotic arm \u2018Flex\u2019 (middle) to collect the crystal samples from the CrystalDirect harvester and transfer them to the goniometer for X-ray diffraction experiments, and a humidity control device (left) used for room temperature experiments. T. Credits: Stuart Ingham\/EMBL, Isabel Romero Calvo\/EMBL<\/figcaption><\/figure>\n\n\n\n

After a successful proof of concept, the construction and integration phase started in 2021 on MASSIF-1, led by the Papp team \u2013 with Frank Felisaz in charge of building the machine, mechatronic engineer Marcos Lopez Marrero in charge of the electronics, and software engineer Jeremy Sinoir in charge of preparing the machine software for its integration in a beamline environment. The engineers kept the user firmly in mind during the process.<\/p>\n\n\n\n

\u201cThe experimental room of MASSIF-1 is very small, so it has been very challenging to fit everything into this space within the imposed constraints. We wanted to make sure that the ergonomy of the installation would be optimal for scientists so that they could easily handle their samples, even if it would be more complicated for the maintenance,\u201d said Felisaz.<\/p>\n\n\n\n

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