Inside the Box
Geneticist Matthew Meselson with the Beckman Model E in 1958. (Courtesy of the Archives, California Institute of Technology)
What would you call a several-hundred-pound, hulking, grey metal box adorned with ungainly, old-fashioned knobs and dials that is large enough to entirely fill an ordinary office? Most readers are likely to shrug—unless they happen to be biochemists, who would immediately proclaim the answer: the Beckman Model E.
More precisely, this beast is the Beckman Model E analytical ultracentrifuge, a fine example of which is displayed in the Museum at CHF. The instrument was developed in 1947 and is organized around a vacuum chamber where a rotor can be spun at very high speed, and which holds a sample that can be viewed and photographed. The most common use of ordinary centrifugation is for separation and purification of macromolecules. Analytical ultracentrifugation, by contrast, is a powerful way to characterize the sizes, shapes, and interactions of proteins and nucleic acids. Thus, one can determine essential properties like the molecular weight of a molecule and whether it binds together with other molecules.
Before ultracentrifuges were available commercially an enterprising scientist had to build his or her own instrument from scratch. The first to do so was the Swedish chemist Theodore Svedberg in the 1920s, and his everlasting reward is that the fundamental unit of sedimentation (symbol S) is named after him. (Sedimentation is the rate at which particles move in a fluid.) Using his technique Svedberg was the first to show conclusively that proteins are discrete molecules of high molecular weight. This fact seems so obvious now that we might forget how mysterious and little understood these fundamental entities of life were just a hundred years ago.
The most famous experiment that relied on the Model E is undoubtedly the Meselson-Stahl experiment. The two Harvard researchers, Matthew Meselson and Frank Stahl, showed that in the synthesis of a new copy of DNA during replication—mitosis—each of the double helices created contains one strand from the original DNA and one newly synthesized. The experiment was complex technically but simple in concept, and has been accordingly dubbed “the most beautiful experiment in biology” by author Horace Judson in his classic history of molecular biology, The Eighth Day of Creation (1971).
My personal interaction with the Model E occurred in 1976 when I was working on the structure of the bacterial ribosome. This gigantic macromolecular assembly of 55 different proteins and 3 RNA species was nearly intractable to then-existing physical chemical techniques. Breaking down the problem into smaller parts, I used the Model E to prove that one particular protein (named L24) indeed bound to a specific sequence in the ribosomal RNA. Although this was a useful (and thrilling) finding at the time, the work is now completely superseded by the determination of the complete X-ray crystal structure of the bacterial ribosome, a feat that resulted in the 2009 Nobel Prize in Chemistry to Venkatraman Ramakrishnan, Thomas Steitz, and Ada Yonath.
Just as an individual scientist’s work can be eclipsed by later developments, so can an instrument. In the early 20th century analytical ultracentrifugation replaced viscosity measurements (essentially, resistance of a fluid to stirring) as the most accessible way to characterize proteins and nucleic acids. By the 1970s chromatography, electrophoresis, and various forms of spectroscopy relegated the Model E to basement storage locations, and the instrument is no longer commercially available. Beckman Coulter does provide a successor instrument called the ProteomeLab, which you could purchase for approximately a quarter million dollars. It’s small and modern in appearance, and more sophisticated in its analytical power, but not nearly as lovely as its predecessor, the behemoth and legendary Model E.
Thomas R. Tritton is president and CEO of CHF.