Breaking down substances into their purest parts has long been one of biochemistry’s biggest challenges. It’s also an essential tool in understanding the function — and possible use — of a natural compound and one of the most important steps in drug development. In the 1930s, American chemist Lyman Craig, a researcher at The Rockefeller Institute for Medical Research, invented a method that proved able to break down the largest biological molecules into parts smaller than previous scientists had thought possible. For this work, and its contributions to basic and medical science, Dr. Craig was awarded the 1963 Albert Lasker Basic Medical Research Award.
Having spent most of his career studying the structures of alkaloids — a class of compounds that are very useful medically and very complex chemically — Dr. Craig had devised numerous methods for dealing with substances notorious for being difficult to pin down and pull apart. Microdistillation, sublimation, fractional crystallization and hydrogenation are just a few of his most innovative approaches. By the 1930s, pharmaceuticals were becoming more and more complex, increasing both the likelihood and the consequence of impure samples. During World War II, Dr. Craig was among many scientists conducting research on antimalarials, of which the military had urgent need. His primary aim was to devise a more perfect technique for isolating and verifying the purity of chemical compounds.
Dr. Craig’s first object of investigation during this time was quinacrine, a drug that had been used since the 1930s as both an antimalarial and a parasiticidal, and a significant challenge due to its molecular size and instability. For this task, he invented the technique known as countercurrent distribution (CCD).
In CCD, the compound to be separated is added to a mixture of two immiscible liquids known to dissolve substances of different molecular weights. The concoction is then added to an instrument made of numerous — up to a thousand — connected glass tubes, which moves automatically in a manner that first causes the two solvents to mix together, then allows them to separate naturally. The mix/separate process is then repeated in each successive tube. Because one of the liquids is light and one is heavy, they attract molecules of differing weight and are thus able to pull apart the larger compound into smaller and smaller component molecules. By the end of the process, the original compound has been taken apart like a jigsaw puzzle, and analysis of the two solvents can provide a highly detailed picture of its chemical composition.
Dr. Craig’s invention procured chemically pure samples of quinacrine as it was intended, but Dr. Craig applied it much further, contributing immensely to our knowledge of antibiotics. In the early 1940s, after his Rockefeller colleague René Dubos had identified the first naturally derived antibiotics — tyrocidine and gramicidin — Dr. Craig used his new invention to further break down the two compounds, eventually solving the entire amino acid sequence of tyrocidine. He also correctly identified the molecular weight of the hormone insulin and showed that other commonly used drugs thought to be pure preparations were in fact significantly mixed with other compounds, a problem that CCD not only identified but also solved.
CAREER
Born in Palmyra, Iowa, in 1906, Dr. Craig was educated at Iowa State University, receiving his Ph.D. in 1931. After postdoctoral research at The Johns Hopkins University, he joined The Rockefeller Institute in 1933 as a research assistant in chemical pharmacology. During World War II, the focus of his research switched to antimalarials, which were in high demand by the military. He became a member at Rockefeller in 1949 and remained there for the rest of his research career. Dr. Craig was a member of the National Academy of Sciences. In addition to the Lasker Award, he received the Fisher Award in Analytical Chemistry from the American Chemical Society and the Kolthoff Medal of the American Pharmaceutical Association. Dr. Craig died in 1974.