Glycobiology Research at NIH
The term “glycobiology” was first used in 1988 to indicate the blending of carbohydrate chemistry and biochemistry, with an understanding of glycans at the cellular and molecular level. Glycans, also known as saccharides and carbohydrates, are sugar molecules that cloak the surface of all cells and festoon many proteins, lipids, and other molecules. Scientists now know that glycans are inextricably linked to nearly every facet of cellular biology and implicated in conditions from cancer to neurodegenerative diseases and type 2 diabetes. NIH has a rich history of glycobiology research. Here are some of the early and current glycobiology investigators. This list is by no means comprehensive.
Glycans are complex biomolecules made from sugars. Glycans are an important part of biology and can impact how our cells or proteins work.
Early Glycobiology Researchers at NIH
Claude Hudson (1881–1952): Hudson has been called the father of American carbohydrate chemistry and was chief of the Laboratory of Chemistry at NIH from 1929 to 1951. He is commonly remembered for “Hudson’s rules” governing the optical rotation of sugars and was the first one to observe the relationship between the chemical structure of sugars and rotation of polarized light.
Hewitt G. Fletcher (1917–1973): Fletcher joined NIH in 1944 in Hudson’s laboratory. After Hudson retired, Fletcher served as chief of the Section of Carbohydrates at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) from 1951 to 1973. He trained many other scientists during his time at NIH who continue to record that their years at NIH were the most formative ones. His research mostly focused on stereochemistry of sugars and separation techniques.
George Gilbert Ashwell (1916–2014): Ashwell joined NIH in 1950 and was chief of the Laboratory of Biochemistry and Metabolism in the National Institute of Arthritis and Metabolic Diseases (NIAMD, now NIDDK) from 1967 until his retirement in 1997. He is world-renowned for co-discovering the asialoglycoprotein receptor in the liver, also referred to as the Ashwell-Morell receptor. Researchers worldwide use the basis of Ashwell’s work to deliver drugs specifically to the liver and the receptor also plays a key role in limiting the aggregation of platelets in life-threatening complications of infection. He received the Karl Meyer award in 1993.
Cornelis Glaudemans (1932–2018): Known for his work on shigella single-shot vaccine, Glaudemans came to NIH in 1962 as a postdoctoral fellow. In 1965 he joined NIH as an independent investigator and collaborated with the National Cancer Institute (NCI) on molecular interactions governed by sugar molecules between myeloma antibodies and bacterial antigens. He succeeded Fletcher to become the chief of the Section on Carbohydrates in 1973 and retired in 1998.
Pavol (Paul) Kovac (1938–present): Kovac joined NIH in 1983 and succeeded Glaudemans as chief of NIDDK’s Section of Carbohydrates. His primary focus is the synthesis of complex carbohydrates and the development of conjugate vaccines for bacterial diseases such as anthrax, cholera, and shigellosis by using synthetic and bacterial sugar antigens.
Victor Ginsburg (1930–2003): Ginsburg came to NIH as a postdoctoral fellow at NIAMD (now NIDDK) in 1956 and became chief of the Laboratory of Structural Biology in 1986. He is well known for his discovery of guanosine-diphosphate-fucose in 1958, and his research led to the understanding of the biochemical basis of blood groups in human beings.
Elizabeth Neufeld (1928–present): Neufeld joined NIH as a postdoctoral fellow at the National Institute of Arthritis, Metabolism and Digestive Diseases (NIAMDD, now NIDDK) in 1963. Her research focused on the genetic basis of metabolic disease and in 1977, she became the first woman NIH scientist to be elected to the National Academy of Sciences. She discovered the mechanisms behind lysosomal storage disorders such as Hurler syndrome, in which complex sugars cannot be stored or metabolized properly resulting in stunted physical and mental growth, vision and hearing problems, and death. She won the Albert Lasker Clinical Medical Research Award in 1982 for her work and left NIH in 1984 for the University of California at Los Angeles (Los Angeles).
Roscoe Brady (1923–2016): Brady joined NIH in 1954 and spent 50 years at the National Institute of Neurological Disorders and Stroke. Brady demonstrated the metabolic causes of lipid storage diseases including Gaucher disease, Niemann-Pick disease, Fabry disease, and Tay-Sachs disease. Along with his students and collaborators he is known for his contributions to the understanding of hereditary diseases, the development of effective genetic counseling procedures, and pioneering the first enzyme-replacement therapy for these conditions.
Vincent Hascall (1940–present): Hascall is known for his work on heavily glycosylated proteins known as proteoglycans, which are an important component of connective tissue in the body. He was chief of the Proteoglycan Chemistry Section at the National Institute of Dental and Craniofacial Research (NIDCR) and received the Karl Meyer award in 1992. In 1994 he left NIH to join the Department of Biomedical Engineering at the Cleveland Clinic Foundation (Cleveland, Ohio).
Stuart Kornfeld (1936–present): Both Kornfeld and his wife, Rosalind Kornfeld, trained with Ginsburg at NIAMD as postdoctoral fellows from 1963 to 1965. He won the Karl Meyer award in 1999 and is known for his work describing pathways involved in oligosaccharide biosynthesis, processing, and maturation, which are critical actions in mediating proper folding and transport of proteins. He and his wife began independent laboratories at Washington University School of Medicine (Saint Louis). Kornfeld has mentored many successful researchers in the field of glycobiology.
Snapshot of Selected Current NIH Glycobiology Investigators
John Hanover (senior investigator and chief, Laboratory of Cell and Molecular Biology, NIDDK) has dedicated nearly 40 years to glycobiology research and has made significant contributions to the field. Read more about him in this issue of The NIH Catalyst.
Joseph Barchi Jr. (senior scientist, Chemical Biology Laboratory, NCI) is developing nanoparticles to deliver immunogenic glycopeptides from tumor-associated mucin proteins as vaccines to elicit potent anticancer immune responses. His group also focuses on developing inhibitors of specific protein-carbohydrate interactions involved in tumor metastasis.
Jeff Gildersleeve (senior investigator, NCI) is researching how antibodies to carbohydrates are generated, what they do, and how they can be used to improve cancer care. His group focuses on developing and studying carbohydrate-binding monoclonal antibodies and understanding the roles of serum antiglycan antibodies for cancer treatment, especially immunotherapies.
Nadine Samara (Stadtman investigator, Structural Biochemistry Unit, NIDCR) is characterizing how O-glycosyltransferases (enzymes that add glycans to proteins) synthesize the polysaccharides that influence host-microbe interactions in the oral cavity and play an important role in health and disease. [https://irp.nih.gov/pi/nadine-samara]
Kelly Ten Hagen (senior investigator, Developmental Glycobiology Section, NIDCR) is studying how glycosyltransferases influence basic biological processes such as organ development and function and how to better understand how aberrations contribute to disease. Her lab has a specific interest in defining the way glycosyltransferases influence matrix composition and cell adhesion. The Ten Hagen lab has defined novel roles for O-glycosylation in secretion and secretory vesicle formation.
Lawrence Tabak (acting NIH director; senior investigator, Section on Biological Chemistry, NIDCR) studies the functions and biosynthesis of O-glycans, which are carbohydrate side chains that heavily decorate mucin-glycoproteins. Mucins contribute to the formation of extracellular matrix or to the gel-like mucus coat that envelops mucosal surfaces of the body, thereby forming the most exterior face of the innate immune system.
Carole Bewley (senior investigator and chief, Laboratory of Bioorganic Chemistry, NIDDK) and Peter D. Kwong [senior investigator and chief, Structural Biology Section, Vaccine Research Center (VRC), National Institute of Allergy and Infectious Disease (NIAID)] as well as many others at the VRC have revealed the importance of HIV glycans. The more commonly acquired influenza virus is also decorated with glycans. These sugars affect receptor binding and immune response as described by several NIH scientists by creating a physical barrier over the virus and preventing antibody neutralization.
Pamela Marino (senior scientific program manager, NIH Common Fund Glycoscience Program) started at NIH in 1986 as a postdoctoral fellow in Ira Pastan’s lab (NCI). She then went to the FDA and ran her own lab, which focused on studies of multidrug-resistant tuberculosis. In 1994, she returned to NIH at the National Institute of General Medical Sciences as a health science administrator. Marino is known to virtually all in the glycobiology field because of her vision and advocacy for the field and its researchers and students, as well as the mentorship she provides to the community. She was the driving force behind the establishment of the highly successful Consortium for Functional Glycomics, which established resources for doing glycomics research and made them freely available to the broader scientific community. She now serves as a coordinator for the Common Fund’s Glycoscience Program and chairs the GlycoBiology Scientific Interest Group, which has developed a network between intramural and extramural researchers to forge glycobiology research with cancer, immunology, virology, vaccines, and biochemistry. Additionally, she has initiated courses, workshops, collaborations, and scientific meetings and posters sessions and reestablished an annual NIH and FDA Glycosciences Research Day. She has received numerous career achievement awards, including the Society for Glycobiology’s 2021 Distinguished Service Award.
Edward Alan Berger (senior investigator, NIAID) studies how the glycoprotein-containing envelope surrounding a virus mediates interaction with cell membrane receptors, allowing the virus to infect a cell. His group has focused on HIV but in recent years has expanded studies to other viruses with a particular present emphasis on Kaposi sarcoma-associated herpesvirus.
William Gahl (senior investigator, Medical Genetics Branch, National Human Genome Research Institute) studies rare disorders and discovers new diseases as part of NIH’s Undiagnosed Diseases Program. His group has an interest in congenital disorders of glycosylation (CDG) and identified the second and third known patients in the world with CDG type IIb.
Herbert Geller (senior scientist, Developmental Neurobiology Section, National Heart, Lung, and Blood Institute) studies the role of proteoglycans in the control of neural development and neuronal regeneration after injury in the brain and spinal cord. A major focus is the role that sulfation of proteoglycan glycosaminoglycan sugar chains plays in signal transduction.
Dave Roberts (senior investigator, Laboratory of Pathology, NCI) researches the extracellular matrix, and in particular, the protein thrombospondin-1, which signals a response through its receptor CD47 that regulates tumor growth. CD47 is glycan-modified, and Robert’s lab is focusing on understanding this pathway to enhance immunotherapy for treating cancer.