Seeing the Invisible

Introduction

Imagine trying to understand how a complex machine works by only looking at its blurry shadow. For decades, this has been the challenge for scientists trying to decipher the intricate molecular machinery of life.

While powerful methods like X-ray crystallography have revealed stunning details of biological molecules, they've remained largely blind to the smallest actors in the drama—the hydrogen atoms and protons that often play crucial roles in how proteins and enzymes function. This fundamental limitation has left critical gaps in our understanding of life's processes, from how enzymes catalyze reactions to how drugs interact with their targets ¹ .

Named after the renowned German physicist Paul Peter Ewald, whose early theoretical work laid the foundation for X-ray crystallography, this next-generation macromolecular diffractometer represents a quantum leap in our ability to visualize the atomic structure of biological molecules ¹ . Currently under development for the Second Target Station at the Spallation Neutron Source in Oak Ridge National Laboratory, EWALD promises to break through what scientists call the "crystal volume barrier"—a limitation that has long restricted the use of neutron crystallography to exceptionally large crystals that are difficult to produce ⁵ .

The Invisible Machinery of Life

To appreciate EWALD's revolutionary potential, we must first understand the challenge of determining how biological macromolecules—proteins, nucleic acids, and viruses—function at the atomic level. These molecular machines are far too small to be observed directly, even with the most powerful microscopes.

For over a century, crystallography has been the primary tool for visualizing these structures ³ . The basic principle involves growing crystals of the molecule of interest, then shining radiation through them to produce diffraction patterns that can be transformed into three-dimensional atomic models ⁴ .

1912

Max von Laue discovers X-ray diffraction by crystals, earning him the Nobel Prize just two years later ³ .

1915

The Bragg team develops the fundamental law of X-ray scattering, winning the Nobel Prize and making Lawrence Bragg the youngest laureate in history ³ .

Present

EWALD builds on this century of progress to overcome the fundamental limitation of hydrogen invisibility in biological molecules.

However, a significant limitation has persisted: X-rays interact with the electrons surrounding atoms, making them excellent for locating heavy atoms but largely insensitive to hydrogen atoms, which contain only a single electron ⁴ . This poses a serious problem for understanding many biological processes, since hydrogen atoms and their movement often play starring roles in chemical reactions—particularly those involving proton transfers that are fundamental to enzyme catalysis, energy conversion, and signal transduction in living systems.

Comparison of Radiation Types Used in Crystallography

The EWALD Breakthrough

Neutron crystallography has long offered a solution to the limitations of X-ray methods. Since neutrons interact with atomic nuclei rather than electron clouds, they can readily detect hydrogen and deuterium atoms ⁴ . Additionally, neutron radiation causes minimal radiation damage, allowing researchers to study molecules at near-physiological temperatures, unlike the cryogenic conditions typically required for X-ray studies .

Unfortunately, until now, neutron crystallography has faced its own formidable constraint: it typically requires crystal volumes thousands of times larger than those needed for X-ray studies ⁵ .

The EWALD instrument shatters this barrier through innovative design that dramatically increases the efficiency of neutron detection. Named after Paul Peter Ewald, who developed the "Ewald's sphere" geometric construction that remains fundamental to interpreting diffraction patterns, this new diffractometer represents the culmination of a century of theoretical and technical progress ¹ .

The secret to EWALD's revolutionary performance lies in its position at the Second Target Station of the Spallation Neutron Source. This advanced facility produces neutron beams with characteristics particularly well-suited to studying biological molecules. The instrument's design optimizes every aspect of the diffraction process, from beam production to detection, resulting in unprecedented sensitivity that will enable researchers to tackle "grand challenge systems" that were previously beyond reach ⁵ .

The Evolution of Structural Biology Techniques

A Glimpse into the Future: What EWALD Will Reveal

The applications of EWALD span virtually all areas of biology and medicine, with particular significance for understanding fundamental life processes and developing new therapeutics.

The Scientist's Toolkit: Essentials for Molecular Exploration

Behind every breakthrough in structural biology lies a sophisticated array of tools and technologies. Here are the key components that make instruments like EWALD capable of revealing nature's secrets: