Greg Hura and the Structurally Integrated BiologY for the Life Sciences (SIBYLS) team received the 2025 Klaus Halbach Award for Innovative Instrumentation at the 2025 User Meeting. In addition to Hura, the members of the SIBYLS team include: Michal Hammel, Scott Classen, Kathryn Burnett, Susan Tsutakawa, Brandon Russell, Aimee Chi Soe, Joshua Del Mundo, Nazar Gora, and Antonio Caliò.
The Users’ Executive Committee (UEC) recognized the team “for their pioneering work in developing the time-resolved, high-throughput, small-angle x-ray scattering (SAXS) technique at Beamline 12.3.1,” which specializes in the collection of data from biological samples at the ALS.
“A major inspiration for joining Berkeley Lab was the incredible and unique resources [the lab] has to solve biological problems, including those associated with disease. Synchrotron-based x-ray scattering is an underutilized tool that is super useful in this pursuit,” said Hura, staff scientist at ALS Beamline 12.3.1 and science deputy of the Molecular Biophysics and Integrated Bioimaging (MBIB) Division at Berkeley Lab. “Taking advantage of ALS brightness in combination with automation has been a long-term process, and I am super excited that our team has been recognized for putting in the hard work to make it happen.”
Crafting a beamline small molecule assay
Hura and the SIBYLS team focused on how to take advantage of SAXS for high-throughput structural biology projects, including for small molecule screening assays. Because synchrotrons enable collection of scattering data in milliseconds, as opposed to tens of minutes, they sought to deliver samples at a complementary rate. In this effort, the SIBYLS team faced many challenges.
Their approach focused on drawing liquid samples into the eye of a needle and robotically positioning the needle within the synchrotron x-ray beam. No small feat. Along the way, the team had to coordinate reproducible repositioning of the three-dimensional (3D) sampling needle, load samples without damaging the needles, and integrate automated robotic loading into the beam hutch to manage sample movement, beam exposure, and detector imaging.
“The SIBYLS team exemplifies the drive to make exceptional instrumentation and software by creating strides in both capabilities of the beamline as well as greatly increasing throughput,” said Aidan Coffey, postdoctoral staff in the ALS Photon Science Operations group and a member of the UEC. “The SIBYLS team has put in an enormous amount of effort to tackle the issues that arise and created a remarkable beamline and technique in the process.”
Accelerating science through automation
The SIBYLS discovery pipeline provides new opportunities in structural biology and drug candidate screening. According to Hura, the beamline allows users to efficiently monitor biomolecular structure in response to chemistry. This crucial early access to conformational information focuses drug screens towards mechanistically important states, dramatically accelerating the identification of promising small molecules that modulate protein function.
In this effort, the SIBYLS team engineered several high-throughput SAXS pipelines to tackle complex biological questions with unprecedented efficiency and detail, solidifying their critical role in advancing the capabilities of the ALS user community. Their innovation has enabled groundbreaking research in drug discovery and protein design that was previously impossible.
For example, the team developed a pipeline to detect a movement in a protein that signals cell death (apoptosis). The movement can be triggered by the addition of a single electron. Researchers from MD Anderson Cancer Center used the pipeline to assay a library of small molecules that modify cell death signaling by the Apoptosis Induction factor (AIF) protein. This approach involved intricate coordination of sample delivery, x-ray exposure, and data acquisition and analysis, all optimized for studying dynamic biological processes. The assay identified four classes of small molecules, out of millions, that modulate AIF’s signaling. These small molecules can now be pursued by pharmacological companies for drug development.
The SIBYLS beamline has also been used in the Nobel Prize-winning work of David Baker in protein design and engineering, contributing to 29 of Baker’s pivotal publications.
Beam of the future
Hura sees tremendous potential for the beamline to address major biological problems in the future. With a coordinated SIBYLS beamline and ALS upgrade, users will be able to take advantage of brightness, automation, and artificial intelligence. They will be able to perform novel assays to identify small molecules with unique influence on biology.
“It has been a long road and this innovation would not have been possible without teamwork,” said Hura. “We would like to share credit with all of our colleagues across the ALS.”
The Klaus Halbach Award for Innovative Instrumentation at the ALS was named for Klaus Halbach, a senior staff scientist at Berkeley Lab. Halbach pioneered the development of undulators using permanent magnets and other innovations in accelerator physics. Despite his 1991 retirement from Berkeley Lab, he remained active in lab projects and student training until his death in 2000.