George Gilbert 'Gil' Ashwell (1916 – 2014)

Editor’s note: George Gilbert “Gil” Ashwell, a National Institutes of Health glycobiologist who won the ASBMB–Merck Award for outstanding contributions to biochemistry and molecular biology in 1984, died in late June in Bethesda, Md. He was 97. In recognition of his contributions and to draw attention to two seminal publications in the Journal of Biological Chemistry, the journal in 2006 published a “Classic” article about his life and work. Here, we’ve republished that JBC “Classic” article (edited for length, clarity and style).

G. Gilbert Ashwell  

George Gilbert “Gil” Ashwell was a recipient of the prestigious Gairdner Foundation Prize, the Alexander von Humboldt Foundation Senior Scientist Award and the Society for Glycobiology’s Karl Meyer Award. He was a member of the National Academy of Sciences and, in 1984, was named NIH Institute Scholar, a title created to recognize his scientific achievements.

Hepatic carbohydrate binding proteins and glycoprotein catabolism

G. Gilbert Ashwell was born in Jersey City, N.J., in 1916. He attended the University of Illinois, where he earned his B.A. in 1938 and his M.S. in 1941. Ashwell then went to Columbia University and received his M.D. in 1948. After graduating, he remained at Columbia as a research fellow for two years.

In 1950, Ashwell joined the National Institute of Arthritis, Metabolism and Digestive Diseases at the National Institutes of Health. The institute later split into the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases, where Ashwell remained.

Ashwell is perhaps best known for his work with Anatol G. Morell. They proposed that membrane lectins remove senescent circulating glycoproteins and discovered one of the earliest known carbohydrate receptors.

Ashwell met Morell when he was on sabbatical leave at Columbia University in 1965. Morell, who was at the Albert Einstein College of Medicine in the Bronx, was interested in devising a method for labeling serum glycoproteins to study the role of ceruloplasmin in Wilson disease. Together, Ashwell and Morell devised a labeling prodcedure that involved enzymatic removal of the glycoprotein’s terminal sialic acid residue, thereby exposing galactose, which was then treated with galactose oxidase and tritiated borohydride, resulting in the incorporation of tritium into the protein. 

When they injected their radioactive ceruloplasmin into rabbits, Ashwell and Morell noticed that the asialoglycoproteins rapidly disappeared from the serum and appeared in parenchymal cells in the liver. Further investigations showed that this phenomenon occurred with a variety of naturally occurring plasma glycoproteins and that the plasma membranes of the liver were the primary site of binding for the circulating glycoproteins.

This led to the hypothesis that the exposure of terminal, nonreducing galactosyl residues by the removal of sialic acid provides a means by which the liver recognizes and removes the defective molecules from circulation as part of their normal catabolic pathway. As described in their 1974 Journal of Biological Chemistry article, Ashwell and Morell eventually isolated the asialoglycoprotein binding protein from rabbit liver using an affinity column composed of asialoorosomucoid covalently linked to Sepharose 4B.

Several years later, Ashwell and Toshisuke Kawasaki isolated an avian hepatic binding protein that was specific for terminal N-acetylglucosamine residues on glycoproteins. This is the subject of a 1977 JBC paper. They compared the avian and rabbit proteins and found that they had many properties in common, such as similar carbohydrate constituents and a requirement for calcium.

However, the two proteins also differed in many ways. For example, the avian protein, in contrast with the mammalian protein, exhibited only minimal binding activity for asialoglycoproteins but interacted strongly with agalactoglycoproteins. The structures of the two proteins also differed. The rabbit protein consisted of two different subunits that were 48,000 and 40,000 daltons. The avian protein contained a single subunit with an estimated molecular weight of 26,000. 

Ashwell’s work on hepatic binding proteins has served as a stimulus for the identification of a host of carbohydrate-specific receptors on various cell surfaces and has inaugurated the current concept of a cellular lectin.