How Serial Crystallography is Capturing Life in Motion
Imagine trying to photograph a hummingbird in perfect focus while it hovers mid-air. Just as you focus your camera, it darts away. Traditional crystallography faced a similar challenge with molecules—they're dynamic, moving entities, but scientists could only capture blurry, frozen snapshots.
Now, a revolutionary technique is changing the game. Serial crystallography allows researchers to capture molecular "movies" rather than static pictures, revealing how biological molecules function at the atomic level in real time.
This approach has transformed our understanding of everything from how we see light to how plants convert sunlight into energy. Unlike traditional methods that require large, perfect crystals frozen at ultra-cold temperatures, serial crystallography uses millions of microscopic crystals flowing rapidly across an X-ray beam, capturing each molecule's structure in near-natural conditions 9 . At facilities like PETRA III in Hamburg and MAX IV in Lund, scientists are pushing these techniques further, making atomic-level movies of chemical reactions that occur in millionths of billions of seconds 6 9 .
Serial crystallography can capture molecular processes that happen in femtoseconds - that's one quadrillionth of a second!
This technique works with microcrystals that are much easier to produce than the large, perfect crystals required by traditional methods.
Traditional crystallography has been the workhorse of structural biology for decades, responsible for determining the structures of countless proteins, DNA, and viruses. However, it comes with significant limitations. Researchers must painstakingly grow large, perfect crystals—often just millimeters in size but enormous in the molecular world—then flash-freeze them to near absolute zero (-173°C) to reduce radiation damage. This process essentially captures a single, static pose of what are inherently dynamic molecules 9 .
Serial crystallography turns this approach on its head. Instead of one large crystal, scientists use millions of microcrystals suspended in liquid. These are injected across the path of a powerful X-ray beam in a continuous stream. Each crystal diffracts only once as it passes through the beam, providing one tiny piece of the overall structural puzzle. While each individual snapshot might be incomplete, sophisticated computer algorithms combine these thousands of diffraction patterns into a complete, high-resolution structure 6 .
| Feature | Traditional Crystallography | Serial Crystallography |
|---|---|---|
| Crystal Size | Large single crystals (0.1-0.3 mm) | Microcrystals (micrometers) |
| Temperature | Cryogenic (frozen) | Room temperature or physiological conditions |
| Data Collection | Single crystal, rotated in beam | Thousands of crystals, each giving one snapshot |
| Time Resolution | Static structure | Milliseconds to femtoseconds |
| Radiation Damage Management | Freezing to reduce damage | "Diffraction before destruction" |
The field is advancing at an extraordinary pace, driven by both new X-ray sources and smarter data processing. At the Stanford Synchrotron Radiation Lightsource (SSRL), researchers are tackling increasingly complex projects including membrane proteins and multi-component molecular machines. These proteins are particularly important as they represent over 60% of drug targets, yet have been notoriously difficult to crystallize using traditional methods 9 .
The time-resolved capabilities of serial crystallography represent perhaps its most exciting application. Scientists can now trigger reactions in crystals—by mixing them with substrates or exposing them to light—and observe structural changes as they happen. Tobias Weinert from Paul Scherrer Institute describes this as moving beyond "deciphering the structures of life" to capturing "atomic motion on the femtosecond scale" (one quadrillionth of a second) 9 . This allows researchers to see not just what molecules look like, but how they work.
The data deluge from these experiments is staggering. Modern detectors like the Dectris EIGER2 X can capture up to 133 frames per second, generating terabytes of data in a single session 6 . To handle this flood, scientists at DESY developed real-time processing systems using the ASAP::O platform combined with CrystFEL software, which can process diffraction data in less than a second per frame, providing immediate feedback during experiments 6 .
At the P11 beamline of PETRA III in Hamburg, scientists have developed an ingenious solution for time-resolved studies called the TapeDrive setup 9 . This system allows researchers to perform "mix-and-diffuse" experiments where protein crystals are mixed with compounds and immediately analyzed to watch structural changes unfold.
The TapeDrive system enables precise control over reaction timing, allowing scientists to capture molecular processes at specific intervals after mixing.
| Parameter | Specification |
|---|---|
| Beam Energy | 5.5 - 28 keV |
| Beam Size | 4×9 μm² to 200×200 μm |
| Photon Flux | 1×10¹³ photons/second |
| Maximum Frame Rate | 133 frames/second |
| Mixing Time Range | 50 ms - 180 seconds |
| Processing Latency | <1 second/frame |
The TapeDrive system allows scientists to control reaction times from 50 milliseconds to 180 seconds by adjusting the tape speed and nozzle distance 9 . This flexibility makes it possible to capture different stages of biochemical processes, from initial binding events to larger structural rearrangements.
In one application, this technology has shown great promise for drug discovery. At AstraZeneca, researchers have developed optimized serial crystallography workflows to screen 384 fragment compounds rapidly 9 . Helena Käck notes that by avoiding labor-intensive crystal harvesting and enabling room-temperature data collection, serial crystallography reduces the risk of structural artifacts introduced by cryo-cooling 9 .
The real breakthrough lies in what scientists can observe with these methods. Rather than guessing how a drug molecule might interact with its target based on a single static structure, researchers can now watch the binding process unfold, observing intermediate states that were previously theoretical.
Aina Cohen from SSRL notes that these developments "remove barriers to enable more widespread use of serial crystallography methods for studies of metalloenzyme structure and protein dynamics" 9 .
| Processing Step | Average Time (Blank Frames) | Average Time (Hit Frames) |
|---|---|---|
| Peak Searching | 87 ms | 87 ms |
| Indexing | Not applicable | 245 ms |
| Integration | Not applicable | 123 ms |
| Total Processing | 242 ms | 455 ms |
| System Capacity | Single 96-core node can process data at 133 fps | |
Behind every successful serial crystallography experiment lies a collection of specialized reagents and materials. While the X-ray sources and detectors capture the spotlight, these chemical workhorses make the research possible.
| Reagent/Material | Function | Application Notes |
|---|---|---|
| Crystallization Screen Solutions | Promote crystal formation by creating supersaturated protein conditions | Commercial screens systematically vary pH, salts, and precipitants |
| Crystal Harvester Solutions | Extract and preserve microcrystals without damage | Particularly important for traditional sample mounting |
| Ligand Solutions | Compound to be studied binding to the protein target | Used in mix-and-diffuse time-resolved experiments |
| Cryoprotectants | Prevent ice formation during flash-cooling | Glycerol, ethylene glycol, or oils for cryo-crystallography |
| Viscous Matrix Media | Suspend and deliver crystals in extrusion methods | Lipidic cubic phase (LCP) or other polymers |
| Polyimide Tape | Sample delivery substrate | Used in TapeDrive systems for time-resolved studies |
| Detergent Solutions | Solubilize membrane proteins | Essential for studying membrane-bound proteins |
| Buffering Agents | Maintain physiological pH conditions | phosphate, HEPES, or Tris buffers |
The global life science reagents market, valued at $65.91 billion in 2025 and projected to reach $108.74 billion by 2034, reflects the critical importance of these substances 7 .
The growth of biological reagents specifically is outpacing other segments, driven by demands for higher purity and specialized applications in techniques like serial crystallography 7 .
The implications of serial crystallography extend far beyond academic curiosity. In drug discovery, the ability to rapidly screen compound libraries and observe drug-target interactions in real time promises to accelerate development while reducing costs. Andreas Dunge and colleagues at AstraZeneca and the University of Gothenburg are already demonstrating serial crystallography's potential for high-throughput fragment screening of drug candidates 9 .
Serial crystallography can screen hundreds of drug candidates in the time it previously took to analyze just a few, dramatically speeding up the drug development pipeline.
The technology is also reshaping how scientists approach fundamental biological questions. At the Linac Coherent Light Source (LCLS), researchers are preparing for even more advanced capabilities with superconducting linear accelerators that can produce over a million X-ray pulses per second 6 . Such extraordinary speeds will enable studies of even faster processes, capturing chemical events that were previously too rapid to observe.
Future X-ray facilities will capture molecular processes at unprecedented speeds, opening new frontiers in our understanding of ultrafast chemical reactions.
Perhaps the most revolutionary aspect lies in data management. The real-time processing system developed at DESY, which can handle the data stream directly without intermediate storage, addresses what researchers call the "data deluge" problem 6 . As facilities generate petabytes of structural data, such efficient processing becomes essential.
Terabytes of data generated in single sessions
Real-time analysis at 133 frames per second
Machine learning algorithms enhancing data interpretation
Serial crystallography represents more than just a technical improvement—it's a fundamental shift in how we visualize and understand the molecular machinery of life.
By transforming structural biology from a study of static blueprints to the observation of dynamic processes, this technique is filling critical gaps in our knowledge. As these methods become more accessible and integrated with other technologies like artificial intelligence, they promise to accelerate discoveries across biology, medicine, and materials science.
The "molecular movies" enabled by serial crystallography don't just show us what life's building blocks look like—they reveal how they move, interact, and bring living systems to life.