How Alfred L. Yergey III Illuminated the Building Blocks of Life
September 17, 1941 – May 27, 2018
In the hidden universe of our own biology—where hormones course through bloodstreams, proteins fold into intricate shapes, and genes switch on and off—the key to understanding life's mysteries lies in seeing the invisible. For centuries, scientists struggled to measure the infinitesimal quantities of biological molecules that dictate health and disease. That all changed with the work of pioneers like Alfred L. Yergey III, a physical chemist who helped transform mass spectrometry from a specialized analytical technique into an indispensable tool for biomedical discovery 2 .
Yergey, who spent the majority of his career at the National Institutes of Health, dedicated his scientific life to developing methods that could precisely measure the previously immeasurable.
His work allowed researchers to track how the body produces cortisol under stress, how infants absorb calcium from their food, and how proteins communicate within cells 2 5 . Through his innovations, the invisible world of molecules came into sharp focus, revolutionizing fields from endocrinology to nutrition and paving the way for today's proteomics revolution.
To appreciate Yergey's contributions, one must first understand the fundamental tool of his trade. At its heart, mass spectrometry is a technique for weighing molecules with extraordinary precision. The process converts samples into ions (electrically charged atoms or molecules) and then measures how these ions move through electromagnetic fields. Since heavier ions are harder to deflect than lighter ones, the technique can separate and identify different substances based on their mass.
Can detect substances present in minuscule quantities (as low as picograms—trillionths of a gram)
Can distinguish between molecules with nearly identical structures
Can measure not just what is present, but exactly how much is present 8
The true power of modern mass spectrometry lies in its coupling with separation techniques like liquid chromatography (LC). As Yergey and his co-authors noted in their book Liquid Chromatography/Mass Spectrometry: Techniques and Applications, this combination allows scientists to separate complex mixtures and identify their components with unparalleled specificity 2 . This LC/MS combination became Yergey's primary instrument for probing biological systems.
In the late 1980s, doctors seeking to understand stress disorders and endocrine diseases needed to measure how much cortisol the human body produces daily. Previous methods relied on radioactive tracers and were cumbersome, time-consuming, and less accurate 2 . Yergey and his team set out to develop a better method using the novel technique of liquid chromatography/mass spectrometry (LC/MS).
Yergey's innovative approach used isotope dilution—a technique where a known quantity of a stable, non-radioactive isotope of cortisol is added to a blood sample as an internal standard 8 . Because the instrument can distinguish between normal cortisol and the isotopically-labeled version, researchers can calculate exactly how much cortisol was originally present with tremendous accuracy.
| Method | Principle | Limitations | Yergey's Improvement |
|---|---|---|---|
| Radioactive Tracers | Following radioactive carbon-14 | Radiation exposure; complex procedures | Used stable, non-radioactive isotopes |
| Colorimetric Assays | Chemical color changes | Interference from similar molecules | Specific mass measurement avoided false positives |
| Gas Chromatography/MS | Separation by volatility | Required chemical modification of cortisol | Direct measurement of intact cortisol |
The methodology was groundbreaking in its precision and practicality. As detailed in his 1990 paper in Steroids, Yergey used a thermospray interface—an early technology that allowed liquid samples to be introduced directly into the mass spectrometer 5 . This represented one of the first practical applications of LC/MS to biomedical problems.
Yergey's method provided the first practical way to measure cortisol production rates without radioactivity, establishing a new gold standard for endocrine testing 5 . The approach was so robust that it could be applied to patients ranging from premature infants to adults, accounting for different metabolic rates across life stages. This work demonstrated conclusively that LC/MS could solve real clinical problems—paving the way for thousands of subsequent biomedical applications of mass spectrometry.
Yergey's innovations were made possible by both mastering existing tools and developing new ones. His laboratory at NIH became a testing ground for emerging technologies that would later become standard in laboratories worldwide.
| Tool/Technique | Function | Yergey's Application |
|---|---|---|
| Thermospray LC/MS | Early interface between liquid chromatography and mass spectrometers | One of first to implement for biomedical analysis; measured cortisol and acetylcholine 2 |
| Isotope Dilution | Quantitative method using stable isotopes as internal standards | Developed whole-body calcium metabolism studies; revolutionized nutritional science 2 |
| Ion Mobility-Mass Spectrometry | Adds separation of ions by size and shape to traditional mass analysis | Final research focus; analyzed therapeutic cyclodextrins for Niemann-Pick disease 2 |
| Computational Algorithms | Software for interpreting complex mass spectrometry data | Created "Neutron Cluster" for isotope calculations; developed protein analysis tools 1 |
Yergey's work transcended traditional disciplinary boundaries. After establishing new methods for steroid analysis, he turned his attention to calcium metabolism—a crucial question in pediatric nutrition. His team developed methods to extract calcium from blood, urine, and feces while avoiding contamination from environmental calcium 2 . These studies led to a better understanding of calcium bioavailability from different food sources and actually influenced how infant formulas are manufactured—a direct impact on child health worldwide.
As mass spectrometry technology advanced, so did Yergey's research. When proteomics (the large-scale study of proteins) emerged as a new field, he developed methods for de novo sequencing of proteins and improved approaches for protein quantification 2 .
Beyond his published research, Yergey made profound contributions through mentorship and teaching. For nearly 25 years, he taught an "Introduction to Mass Spectrometry" course at NIH, training generations of scientists 2 . His former trainees remember him as a devoted mentor who balanced rigorous science with a rich personal life—an accomplished botanical illustrator, gourmet cook, cyclist, and amateur brewer 2 .
"Anyone who knew Al knew how devoted he was to his family. What people may not appreciate is that Al treated members of his lab as a scientific family. He was always busy, yet he gave freely of his time; he was a role model in how to effectively balance your time between work and personal life."
Yergey remained active in research until his death in 2018, embracing emerging technologies like ion mobility-mass spectrometry. His final paper explored the behavior of cyclodextrin negative ions—typical of his career-long pattern of staying at the forefront of analytical technology 2 .
Focus Area: Chemical Ionization
Key Innovation: Studied ion-molecule reactions with pioneers Burnaby Munson and Frank Field 2
Focus Area: LC/MS Interfaces
Key Innovation: Pioneered thermospray LC/MS for biomedical applications 2
Focus Area: Metabolic Studies
Key Innovation: Developed isotope dilution methods for cortisol and calcium metabolism 2 5
Focus Area: Proteomics
Key Innovation: Created computational tools for protein analysis and de novo sequencing 1
Focus Area: Ion Mobility
Key Innovation: Applied new separation technology to therapeutic compounds 2
Alfred L. Yergey III exemplified how methodological innovations can unlock biological mysteries. From his early work on cortisol to his later research on proteins and protein modifications, he consistently identified limitations in existing analytical approaches and developed better solutions. His career demonstrates that tools matter—that progress in science often follows progress in measurement.
Perhaps most importantly, Yergey's legacy lives on through the countless scientists he trained, the methods he perfected, and the biological insights he made possible. His work helped transform mass spectrometry from a specialized technique in physical chemistry to a cornerstone of modern biomedical research—proving that with the right tools, we can indeed measure the previously immeasurable and see the invisible world that governs our health and biology.