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RESEARCH BRIEFSGenetic Computation Tells Man from Microbe
Scientists have developed a new mathematical tool that uses the process of elimination to unmask microbes lurking in human tissue. Led by MD-PhD student Griffin Weber, the researchers started with the 3.2 million sequences deposited at the public human expressed sequence tag (EST) database at the National Institutes of Health. These sequences come from hundreds of research labs and studies on thousands of healthy and diseased tissue samples. From there, it was a matter of subtraction by software. In a series of steps (illustrated above), the researchers eliminated duplicate sequences, sequences matched with the rough draft of the human genome completed last year, other known human sequences, and even the homologous mouse genome to account for undiscovered human genes. In the end, they were left with just over 65,000 candidate sequences, including cDNA from hepatitis B and C viruses, cytomegalovirus, Kaposi's sarcoma, herpesvirus, and Epstein-Barr virus. The eureka moment launching this study came one day while pathologist Matthew Meyerson, HMS assistant professor at the Dana-Farber Cancer Institute, was searching through databases of cDNA sequences from active genes for molecular pathways that are similar in bacteria and human tumors. He noticed bacterial sequences in the human database. No surprise there. By one estimate (based on bacteria counts in the colon or stool samples), microbes who call our bodies home outnumber human cells 10 to 1. Most of the bacteria, viruses, and other microbes are harmless or even beneficial. But others are suspected of being at the root of mysterious chronic diseases such as rheumatoid arthritis, type 1 diabetes, atherosclerosis, lupus, multiple sclerosis, and several types of cancer. Using a process of elimination, Meyerson believed, he might be able to detect and identify new infectious causes of cancer, autoimmune diseases, and inflammatory diseases. While this study, published in the February 2002 Nature Genetics, did not identify new pathogens, it successfully detected a specific type of human papillomavirus in cervical cells, where it is known to cause cancer. The researchers call their new in silico tool "computational subtraction method" and have applied for a patent.
Molecular Logjam May Underlie Huntington's, Parkinson's DiseasesThe proteasome is an organelle best likened to a meat grinder, drawing proteins into its maw, mincing them up, and extruding short peptides instead of hamburger. The proteolytic "knives" are tucked inside a barrel-like core particle. Though it is known that protein enters the core through an abutting regulatory unit--a hexameric ring of ATPases surrounding a central pore--little is understood about how this machine actually works. In a study published in the December 2001 Molecular Cell, postdoc Ami Navon working in the lab of Alfred Goldberg, HMS professor of cell biology, took apart the substrate-regulatory subunit interaction. Using a reporter protein with a rigid attachment in the form of a tightly folded protein domain, he demonstrated that the regulatory ATPase catalyzed the unfolding of the protein but that the appendage prevented the protein's entry into the barrel. Unfolding is therefore distinct from translocation and hydrolysis. In both the archaebacteria used in this study and in other forms of life, the degradation of cellular proteins is quite selective, and the proteasome is a nodal point for several critically important pathways. In eukaryotes, the proteasome degrades cyclins involved in cell cycle control, generates peptide antigens for presentation by MHC molecules, and destroys misfolded proteins. Recently, attention has focused on the proteasome's role in the late-onset neurodegenerative diseases characterized by intraneuronal aggregates of aberrant proteins. These proteins, though varying in function, all possess long repeats resulting from a "toxic gain-of-function" mutation. It is not known if the proteasomes frequently associated with such aggregates are active or trapped and nonfunctional. In light of this, it is interesting that Navon and Goldberg found that the appended, aberrant reporter molecule formed a stable complex with the ATPase that was slow to dissociate even in the presence of a large molar excess of another reporter protein. In short, the bulky protein jammed the disposal organelle, and kept it shut down. The authors write: "The conversion of substrate into inhibitor suggests an interesting new model for understanding the mechanism underlying certain human neurodegenerative diseases such as Huntington's disease, other poly-Q expansion diseases, and Parkinson's."
Dietary Pattern Sets Stage for Type 2 Diabetes in MenUp 35 percent in the last decade in the U.S., type 2 diabetes is on the increase worldwide, causing blindness, kidney failure, and even death. Because of migration patterns and the spread of Western culture--and along with it, processed foods, hamburgers, and fries--diet has long been suspected as a contributor to this rising ill tide. Yet this assumption has been hard to confirm. It is difficult to untangle the effects of diet from other risk factors. And investigators often focus on the contribution of individual dietary components--fiber, for example--omitting other foods that may contribute to the physiological changes accompanying deteriorating glucose metabolism. Now, in a comprehensive 12-year survey of more than 42,500 men, HSPH researchers have nailed down the link between type 2 diabetes and diet. In a study published in the Feb. 5 Annals of Internal Medicine, Frank Hu, HSPH assistant professor in the Department of Nutrition, and coworkers tracked the dietary and health habits of men between the ages of 40 and 75. The pattern that emerged after analyzing a 131-item food frequency questionnaire administered every four years was of two general categories of eater: the "prudent" types, who eat whole grains, fruits, vegetables, fish, and poultry, and the "Western" consumers of red meat, high-fat dairy products, fries, and desserts. Men with the latter diet were found to have a high risk for type 2 diabetes, especially when combined with obesity and a sedentary lifestyle. These men were also on average younger and more likely to smoke cigarettes. While all participants, selected from the Health Professionals Follow-up study, were healthy at the onset of the inquiry, 1,321 new cases of type 2 diabetes were diagnosed during the ensuing 12-year interval, adding to the 16 million Americans living with the disease. --Briefs above by Anne Mahon |
