Sialic Acid Acetylesterase Gene Variants
This page expands on a study by Kua et al. (2004) in which the authors compare the popular press to the “scientific press.” Here, we will extend their analysis to a particular case study. The page highlights the differences between the reports of new scientific discoveries published in the popular press and published in the scientific community. Both of these media convey similar information but are geared to a different audiences. In general, popular press articles assume the reader has no previous scientific knowledge. As such, these articles attempt to limit scientific jargon and present the information in its scientific context. They often represent claims simply as facts with little information on the logic that led to such conclusions. Scientific articles, however, assume the reader has an in depth background knowledge of the subject. These articles attempt to convince the reader that their hypothesis or claim is valid through scientific data. These articles describe the methodologies used to investigate the issue and outline the logical steps that lead to their conclusion or claim.
The case study for this webpage is an investigation of sialic acid acetylesterase gene mutations published in Nature on June 16th, 2010 and reported online in Wired Magazine’s Science section on the same date. Sialic acid acetylesterase (SIAE) is an enzyme that regulates B-cells. B-cells are a critical component of the human immune system as they manufacture antibodies against harmful bacteria and viruses. SIAE was first linked to autoimmune disorders in mice.
In order to investigate if SIAE was linked to autoimmune disorders in humans (like the mice previously mentioned), the researchers compared SIAE alleles of 923 people with common autoimmune disorders to the SIAE alleles of 648 unafflicted people. All of the subjects of this study were from European origin as to minimize potential variants from different human populations. The functionality of SIAE alleles was determined by adding the wt SIAE gene to laboratory T cells. This gene was mutated through site directed mutagenesis to correspond with the observed alleles. Finally, the SIAE enzyme was isolated though immunoprecipitation and analyzed on western blots (Surolia et al. 2010). Examples of the results are reproduced below.
The figure above is an SIAE enzyme analysis of three SIAE alleles (N33S, C196F, Q309P) from subjects with an autoimmune disorder and a wild type SIAE allele (WT) (Surolia et al. 2010). To the left is a western blot. “Lysate” refers to proteins that would have been inside the cells. “Supernatant” refers to proteins in the culture outside of the cell. As you can see, C196F and Q309P are present inside the cells, but are not present in traceable levels in the surrounding culture (the bands at the bottom are loading lanes to verify the gels were loaded correctly). However, N33S appears to be present outside the cell in higher levels than the control. To the far right (the last graph) is a quantitative analysis of this data. As you can predict from the gel, N33S has a substantially larger ratio of enzyme outside the cell to enzyme inside the cell (when compared to the wild type). All of the protein samples from the lysate were analyzed for esterase activity. These results are produced in the middle. “Mock” refers to cells not transfected with any SIAE gene, so they should so no activity. N33S appears to be over-active. C196F and Q309P show no activity.
The figure above is the same as the previous figure, but are of SIAE alleles in individuals without an autoimmune deficiency. What is interesting here is like the C196F and Q309P variants, R314H is not expressed in traceable levels outside the cell, but R314H is from a patient without an autoimmune deficiency. These observations show evidence of a gene that has been mutated and changed its protein’s functionality in a way similar to an autoimmune patient. However, the individual with this gene does not have an autoimmune deficiency. Keep this idea in mind, we will come back to it later.
The results of all of these experiments are summarized in the table below.
As we established before, we have evidence of mutations affecting the functionality of a protein in a similar way, but producing an overall different phenotype in individuals (having or not having an autoimmune disorder). One interpretation of this data would be this gene is not actually linked to an autoimmune disorder in humans, as it is in mice. However, of the 923 people with autoimmune disorders, 24 of them had defective SIAE alleles, while only 2 of the 648 unafflicted people had defective SIAE alleles. Based on this information it seems autoimmune disorders and SIAE alleles might somehow be linked (Table 2). This data brings us to another conclusion, mentioned by the authors, that the SIAE gene is one of several genes that together can cause an autoimmune disorder. Maybe the person with R314H had other normal genes that kept them from having an autoimmune disorder, while the people with C196F and Q309P did not. Regardless, the significance of this study (though not explicitly stated) is that rare variations and combinations of multiple rare genes throughout one’s genome contribute to an individuals susceptibility to certain disorders (Surolia et al. 2010).
The Wired article focuses on the significance and context of the Nature paper. It begins by stating it has been difficult to “explain genetic underpinnings of diseases that clearly have a hereditary component” simply through genomic analysis (Kiem 2010). The author recalls that in genome-wide association studies, gene links are established to complex diseases that account for only 5 percent of the heritability of such genes, as documented in population-based studies. Multiple rare gene variants, like the SIAE mutations, could account for this “missing heritability.” The article cites one of the Nature authors as saying, “The SIAE gene alone doesn’t cause the disease, but likely works in tandem with other, as-yet-unidentified rare variants.” This statement is followed by a quote from scientist not associated with the study, “...many diseases are determined by a lot of different rare variants.” The article concludes by admitting variants are not the only possible cause of this “missing heritability,” but are a likely candidate (Kiem 2010).
Popular Press vs Scientific Publication
Ultimately, both articles convey the same message: multiple rare genes are likely to explain why certain hereditary diseases are difficult to identify genetically. The Nature study does not explicitly state this conclusion, but hints it by stating, “Our results provide important support for a role for rare variation in predisposition to autoimmune diseases...” (Surolia et al. 2010). The Wired article highlights this message and explains the scientific context of the Nature article.
- Change in Focus
- The Nature study focuses on proving SIAE mutations are linked to autoimmune disorders. The Wired article focuses on the overall context or implications of SIAE mutations being one of several genes that cause autoimmune disorders.
- The papers should not have the same focus; they are targeted to different readers. The Wired article effectively explains the significance of a new scientific discovery in a way that a non-specialist could understand. However, the article focuses so much on the significance and implications, that the actual discovery of the SIAE mutations becomes sidelined.
- Change in Evidence for Claims
- The Nature study provides persuading data in the form of tables, graphs, and images to support the claim that SIAE mutations are linked to autoimmune disorders.
- The Wired article does not adequately support to the claim that SIAE mutations are linked to autoimmune disorders. It simply states, “The SIAE gene, which cause immune cells to go haywire during autoimmune disease,” as if it is fact (Kiem 2010). The paper cites that 24 of 923 autoimmune deficient people had a mutated copy of this gene, while 2 of 648 of unaffected people had a mutated copy. These claims are further backed by the statement, “When the mutations were recreated in laboratory cell cultures, the researchers confirmed that the SIAE variants produced altered forms of their enzymes” (Kiem 2010). The article expects the reader to accept that SIAE mutations are linked to autoimmune disorders simply because the claim was published scientific study. All the other evidence in this article is in the form of quotes from various experts that support assertions on the significance of the discovery.
- Change in Methods Providing Evidence
- The Nature study tells the specific methods used to generate the evidence. It details that SIAE alleles were sequenced. The wt SIAE gene was added to laboratory T cells. This gene was mutated through site directed mutagenesis to correspond with the observed alleles. Finally, the SIAE enzyme was isolated though immunoprecipitation (Surolia et al. 2010).
- The Wired article says, “Pillai’s team analyzed every single DNA unit of every SIAE gene” (Kiem 2010). This statement by itself to be extremely unsatisfactory. It is not really a method, but is the closest thing to one in the paper. For all we know, the researchers sequenced the SIAE gene and calculated the GC content. Furthermore, there is no mention of the method behind how the “mutations were recreated in laboratory cells” (Kiem 2010). There are no substantial methods described to validate any of the evidence.
As Kua et al. (2004) note, the transmission of scientific knowledge and discovery to the masses is a very difficult task as many people lack the contextual knowledge to understand the importance of such findings. In order to convey this knowledge, the popular press must translate the scientific language and jargon into plain language while presenting information to support claims and convey the context (Kua et al. 2004). This Wired article excels in emphasizing and explaining the context of the research in plain language. However, the article fails to effectively communicate the methods and evidence that led to the overall conclusion (that many genes together control autoimmune deficiencies). This lack of communication is a big issue as it encourages readers to accept something as fact simply because scientific methods say it is fact. The media must give the reader the ability to “question the nature of scientific processes,” because through questioning, scientific inquiry becomes better (Kua et al. 2004).
Kiem B. Rare Gene Glitch a Clue to Genomics Mystery. Wired Science [Internet]. 2010 Jun 16 [cited 2011 Jan 23] Available from: http://www.wired.com/wiredscience/2010/06/rare-variants/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed:+wired/index+(Wired:+Index+3+(Top+Stories+2))&utm_content=Google+Reader
Kua E, Reder M, Grossel MJ. Science in the News: A Study of Reporting Genomics. Public Understanding of Science. 2004;13:309–322.
Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, MacDonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature [Internet]. 2010 Jun 16 [cited 2011 Jan 23];446: 243–247. Available from: doi:10.1038/nature09115.