As the recipient of the eighth annual Marshall S. Horwitz, M.D., Faculty Prize for Research Excellence, Dr. Pamela Stanley delivered the lecture "Glycans that Regulate Development and Notch Signaling" to more than 200 members of the Einstein community gathered in Robbins Auditorium on Monday, March 31, 2014. The lecture, which was followed by an award presentation and reception, had been long-anticipated after the initial event date in February was cancelled by one of this winter’s many snow storms.
To begin, Dr. Allen M. Spiegel, the Marilyn and Stanley M. Katz Dean at Einstein, welcomed those in attendance and imparted regards and congratulations to Dr. Stanley from her family in Australia. Dr. Vinayaka Prasad, chair of the award selection committee, then offered a brief history of the award that was established to honor both the memory of Dr. Marshall S. Horwitz, who died in 2005, and excellence in faculty research. Next, Dr. Stephen G. Baum shared memories of Dr. Horwitz when the two were young physician-scientists during the infancy of Einstein's infectious diseases division, and Dr. Arthur I. Skoultchi, chair of cell biology, introduced Dr. Stanley, calling her "a true pioneer in the field of glycobiology."
Following is a "question & answer" interview with Dr. Stanley that sheds light on her field and her research.
How would you define glycobiology, your research specialty?
Living cells possess individual sugar molecules or sugar polymers (glycans) that are physically attached to proteins and lipids. Glycobiology involves studying how these sugars and sugar compounds affect biological functions. This requires defining the full complement of glycans in all cell types and determining what happens in vivo when (1) glycan synthesis (the process known as glycosylation) is abnormal or (2) the placement of glycans on a molecule is altered.
Glycomics—the study of an organism's entire complement of sugar polymers attached to proteins or lipids—hasn't received the publicity given to other "omics" such as genomics and proteomics. Why do you think that is?
That's mainly because the ability to analyze glycans and to determine their structure hasn't yet been fully automated, nor can it be done at a single core facility. In addition, there are no simple ways to make significant amounts of defined glycans or to amplify glycans, as is routinely done for nucleic acids and proteins. Advances in mass spectrometry have benefited both glycomics and glycoproteomics, by helping identify the sites where glycans are attached to proteins. But it's still challenging to determine the precise structure of the different glycans on a given glycoprotein.
You've played a leading role in the Consortium for Functional Glycomics, an international group of 70 investigators that the NIH created in 2001 with a $37 million grant. Is the consortium still in existence, and what has it accomplished?
The Consortium for Functional Glycomics (CFG) was supported for 10 years by a non-renewable grant from the National Institute of General Medical Sciences. The consortium had several aims: to push forward the field of Glycobiology, to develop core facilities in faculty labs, to make reagents, to generate mouse models of glycosylation disorders, to advance bioinformatics and databases for glycans, and to develop technologies for analyzing glycans, glycan arrays and glyco-gene microarrays. Consortium members could apply for resources that were supplied at no charge. In this way the CFG supported basic research in Glycobiology in hundreds of labs around the world. In addition to several important findings arising from the CFG, its major impact was to allow scientists who otherwise wouldn't have done so to look for the functions of the glycans on their favorite virus or glycoprotein. The CFG continues on as the Functional Glycomics Gateway, which sponsors meetings, tutorials and databases.
Your research has focused on glycosylation, which involves a family of enzymes called glycosyltransferases. Some of these enzymes attach sugars to proteins and lipids to form glycoproteins and glycolipids, respectively, and others attach sugars to growing glycans. Arguably the most important glycoproteins and glycolipids are the cell-surface receptors that are present on virtually all types of cells and play crucial roles in cell signaling, the immune response and other important functions. Could you describe the way you've used mutant Chinese hamster ovary (CHO) cell lines to study how glycosyltransferases influence the structure and function of cell-surface receptors?
Over the years my lab has isolated a large panel of CHO mutant cells that synthesize altered glycans, due in each case to a mutation in a glycosyltransferase gene or a gene that influences glycan synthesis. These mutant lines are well-characterized genetically, biochemically and in terms of the glycans they express. Therefore, they are very useful for engineering the glycan portion of glycoproteins. We've used CHO mutants to identify roles for glycans in growth factor signaling and in Notch signaling. (Notch receptors are glycoproteins that play key roles in sending signals that control cell growth and determine cell fate during development.) Others have used our CHO mutants to produce therapeutic molecules (enzymes or antibodies) equipped with glycans that are tailor-made to improve the cell targeting or half-life of the therapeutic.
Health problems can result from defects in particular glycosyltransferases and other genes involved in glycan synthesis. More than 100 such disorders—all quite rare—have now been identified and are referred to as Congenital Disorders of Glycosylation. Have defective glycosyltransferases also been implicated in more common health problems?
Single nucleotide polymorphisms (SNPs) in a glycosyltransferase have been linked to multiple sclerosis and rheumatoid arthritis. (An SNP, also known as a point mutation, involves a change in a single nucleotide –A, T, C or G—in a DNA sequence.) As more SNPs are linked to disease, I expect that point mutations in glycosyltransferases will be associated with most common diseases, including mental disorders and congenital heart defects.
Is it possible to treat diseases by targeting certain glycans?
Influenza is the most common health problem treated by a drug that targets glycans. The influenza virus must attach to a specific sugar (sialic acid) to infect a cell. And for the virus to infect other cells, it must be released from the host cell by the viral enzyme neuraminidase, which cleaves off sialic acid from glycoproteins at the host-cell surface. Several drugs that inhibit neuraminidase are used to treat influenza patients. In addition, certain vaccines, such as the one against Haemophilus influenza type b--a bacterium that causes serious illness in children--are targeted against glycans. And much effort is now focused on producing an AIDS vaccine targeting glycans that are part of HIV.
As you know, a hot area of research these days is epigenetics—the study of methyl groups and other molecules that latch onto genes and influence whether they're expressed or not. Is there any evidence that these epigenetic "marks" exert important influences on the genes that code for glycosyltransferases?
Very few scientists have investigated this question. But when they have, they've indeed found epigenetic regulatory marks that regulate expression of glycosyltransferase genes. In fact, the promoter regions, splicing patterns and general regulation mechanisms controlling glycosyltranferase gene expression are poorly understood, as is regulation of glycosyltransferases by microRNAs. This is a fertile area for basic research.
Could you describe your recent discoveries involving the influence of glycans on cancer progression?
Dr. Stanley We were intrigued by the existence of a glycosyltransferase called MGAT3, which transfers a single sugar to a specific location in complex N-glycans and thereby alters the interactions of N-glycans with glycan binding proteins. We knocked out the Mgat3 gene in the mouse and found no obvious differences in growth or fertility compared with wild type mice. But when we challenged the mice by causing them to develop mammary tumors, we found that loss of MGAT3 allowed their tumors to grow more rapidly and to metastasize in greater numbers to the lung. Therefore, the normal function of MGAT3 in mammary gland and mammary tumors is to restrain cell proliferation. When we searched databases for expression of MGAT3 in human breast cancers, we found that higher expression correlates with longer survival without a relapse, as predicted by our experiments in mice.
Technology can be a "rate limiting factor" on progress in any scientific field. Can you think of a particular technological breakthrough that might greatly accelerate discoveries in your field of glycobiology?
Technological breakthroughs in mass spectrometry and imaging are most likely to accelerate discoveries in Glycobiology. We'd like to analyze cell membranes in a living tissue to identify the glycans on a signaling protein like Notch or on the Epidermal Growth Factor receptor, which is overexpressed in many types of cancer. That way we could monitor, in real time, changes in glycan structure due to metabolism or disease.
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