Glycomics: Technologies Taming a Frontier Omics Field

It is a pleasure to welcome readers to this Special Issue dedicated to the field of glycomics. Given the essential role of glycans in defining phenotype an appreciation of glycomics is essential for developing a full understanding of complex biological systems. Importantly, recent technological and scientific advances, many of which are detailed in this issue, have dramatically advanced “glycomics” (Raman et al., 2005; Turnbull and Field, 2007) and increased our ability to ask sophisticated biological questions. Furthermore, translation of learnings from other omics areas, especially proteomics (through glycoproteomics) has enabled the field to progress rapidly. In our view, advancing omics, including glycomics, will promote increased understanding of biological phenomena and should enable multiple therapeutic and diagnostic applications, including biomarker discovery, target identification and definition, and even discovery of novel therapeutic modalities.

The glycome can be defined as the complete repertoire of glycan structures expressed by particular cells, tissues, organs, or organisms, and represent a highly structurally diverse class of molecules (Cummings, 2009). Importantly, in the biological context, glycans are one part of a family of conjugated biomolecules, including, for instance, glycoproteins, glycolipids, and proteoglycans, where typically both the glycan and the protein/lipid play important biological roles. For example, glycosylation of proteins alters their biological functions, and in some cases glycans themselves have intrinsic and independent functions (proteoglycans being a notable example of this class). This affords diverse opportunities for subtle regulation of biological processes at a higher level of complexity than DNA or proteins (Turnbull and Field, 2007), and this has underpinned the evolution of higher multicellular organisms. Furthermore, that glycans elicit function in the context of glycoconjugates highlights the interplay between the various omic disciplines.

Although the importance of glycobiology has been appreciated for some time, glycomics represents one of the more recently emerged omics disciplines. Historically, there have been a number of challenges associated with development of robust glycomics platforms, amenable to automation and high-throughput analysis. First, the structural complexity, and hence information content, of glycans is extremely diverse. This point encompasses multiple concepts, including diverse branching patterns, linkage information between monosaccharide units, and the presence of multiple isomeric and isobaric structures. Additionally, glycomics has traditionally lagged behind other omics areas due to the inherent difficulties in isolating and analyzing glycans, but this situation has changed rapidly as the specialist toolkit needed has been developed over the last decade and is now being applied in increasingly large-scale studies (Raman et al., 2005; Turnbull and Field, 2007). In this issue of OMICS a number of the articles focus on this important aspect and detail advances that have been made. For example, as in proteomics and metabolomics, mass spectrometry is proving to be an enabling technology for high-fidelity and high-throughput characterization of the glycome and glycoproteome (Bond and Kohler, 2007; North et al., 2009), and, in this issue, Zaia provides a thorough review of the methods currently in use, emphasizing the distinct aspects compared to proteins and other metabolites.

Because glycosylation is one of the major forms of posttranslational modifications of proteins, glycomics will become increasingly critical for extending our understanding of the functional proteome. The extreme complexity of glycans is leading to more systematic approaches for their categorisation and study. In this issue of OMICS we see two major examples of this; in particular, the definition of subglycomes for particular classes of functionally important glycan modifications. The first is exemplified by the sialome, which encompasses glycans modified with various types of sialic acids. Cohen and colleagues describe how these functionally important terminal modifications can be viewed in gycomics terms at various levels of complexity in a manner analogous to a forest canopy; the upshot is that holistic approaches are needed to understand the collective functions of complex glycans. The second example of a “subome” is the proteoglycome, which covers the subset of the proteome that is glycanated with highly complex glycosaminoglycan (GAG) polysaccharide chains that have important and dominant functions (Sasisekharan et al., 2006. Ly et al. describe this important ome, focusing on its structure and function, the unique challenges posed by GAG characterization, and a review of some of the analytical tools being employed to develop glycomics approaches for these unusual glycans.

With the increasing shift toward higher throughput, larger scale analyses in biological systems, glycomics has also benefited from the development of a variety of microarray-based methodologies applied to glycans (Liu et al., 2009; Zhi et al., 2008). In this issue, Voglmeir and colleagues review the use of microarray platforms for on-chip enzymatic glycosylation methodologies designed to generate more complex glycan structures for high-throughput studies, and Gupta et al. describe how diverse lectins (glycan-binding proteins) can be exploited in microarray platforms in glycomics applications to study glycoform variation.

Lectins have also been used as tools for enrichment of glycoproteins in glycoproteomic studies. However, a research article by Albert et al. exploits a glycomics approach to characterize the glycans attached to proteins after lectin affinity chromatography. The results provide a cautionary tale, because the global patterns were largely similar in bound and unbound fractions. This suggests that complex interactions of individual glycoforms of proteins with lectins, and that caution is needed in the application of lectins in biomarker discovery.

A further vital tool to exploit information from glycomics studies is synthetic chemistry (Seeberger and Werz, 2007; Turnbull and Linhardt, 2006). The latter is very complex for glycans, but significant advances are being made in a number of labs for streamlining the production of focused glycan libraries. Azzouz et al. describe how innovative chemistry is providing routes to structure–function insights into complex glycans in host–parasite interactions.

Development of dedicated bioinformatics resources to handle data from a wide variety of glycomics studies is also being tackled by a number of groups and international consortia (Raman et al., 2006). As an example of this, Yuki et al. describe in a research article a new Web-based resource called RINGS (Resource for Informatics of Glycomes at Soka), which is designed to offer data mining and algorithms for N-linked glycans freely to the glycomics community. Expansion of bioinformatics resources will clearly be critical to the future development of the field, and its integration with data from other omics studies.

Finally, we are beginning to see the fruit of larger scale glycomics approaches in exciting applications in biological systems, particularly in biomedicine. In a research article Sarratz et al. describe the study of glycoform variants of the prostate specific antigen (PSA), which is an important biomarker of prostate cancer. Using 2D electrophoresis, high-performance liquid chromatography (HPLC) glycan analysis and sequencing, and mass spectrometry, they demonstrate that variations in N-glycans could be important biomarkers of prostatic disease. This and other studies in this issue nicely highlight the real potential for breakthroughs based on new insights provided by glycomics strategies, including robust biomarkers (An et al., 2009), targets for the development of novel therapeutics (Shriver et al., 2004), and new synthetic chemistries Seeberger and Werz, 2007; Turnbull and Linhardt, 2006).

In the end, given the structural complexity of glycans and glycoconjugates, as well as the increasingly sophisticated biological processes that omics technology is enabling us to interrogate, it is likely that some are all of these approaches will prove important (Li and Richards, 2010). Of additional importance will be the development of one or more frameworks to enable integration of datasets from multiple techniques, including state-of-the-art techniques in HPLC, lectin array, NMR, and mass spectrometry—all of which are outlined here. Thus, although some methodologies will undoubtedly provide superior information content (depending on the question asked), dataset integration will likely be essential to bring glycomics “to the masses.” Additionally, because, as mentioned above, the glycome often needs to be interpreted with other omes, including the proteome and the lipidome, crossintegration of data from different omic disciplines will also be essential. In this way, we envision it will be possible to provide a robust, seamless platform that can enable us to address additional fundamental structure–activity questions of the glycome. In conclusion, although glycomics may still be a frontier omics field, we believe that it has a bright future in the postgenome era. We anticipate that the development and implementation of scientific advances, such as those described here, indicate that we are entering exciting, and potentially highly enlightening, times.