Research Round Up

Did Evolution Give Us Inflammatory Disease?

Philip De Jager, MD, PhD

Researchers demonstrate that some variants in our genes that contribute to a person's risk for inflammatory diseases such as multiple sclerosis, Crohn's disease or rheumatoid arthritis, have been the target of natural selection over the course of human history.

 The research team, led by Philip De Jager, MD, PhD, of BWH's Department of Neurology, and Barbara Stranger, PhD, of the University of Chicago, looked at genome-wide association studies along with protein-protein interaction networks, as well as other data and found 21 places in the genome that bear a ‘signature' for both inflammatory disease susceptibility and natural selection.

Towfique Raj, PhD

 Towfique Raj, PhD, of BWH's Department of Neurology, is the lead author on this study. The study's findings suggest that, in the past, these variants rose in frequency in the human population to help protect humans against viruses, bacteria and other pathogens. But now in our modern world, the environment and exposure to pathogens has changed, and the genetic variants that were originally meant to protect us, now make an autoimmune reaction more likely. These results are consistent with the hygiene hypothesis in which our cleaner environment is thought to contribute to the increasing prevalence of inflammatory diseases.

 The study was published in the March 21, 2013 online issue of The American Journal of Human Genetics.

Protein-Protein Interactions Discovered Using Novel Method

Stephen Elledge, PhD

There are various methods that exist that help characterize protein-binding molecules.  Now a  BWH research team has added another one to the list by developing a new approach, known as PLATO, for mapping physical interactions between proteins and other molecules. PLATO, which stands for parallel analysis of translated open reading frames, combines in vitro display of full-length proteins with analysis by high-throughput DNA sequencing.

 The research team, led by Stephen Elledge, PhD, of the Division of Genetics in the Department of Medicine, used PLATO to perform various interaction screens against a normalized collection of 15,483 human complementary DNA (a type of DNA involved in the formation of proteins).

Elledge  and his team were able to identify proteins that interacted with LYN kinase (an enzyme involved in cell activation), as well as small-molecules known as gefitinib and dasatinib.

 "PLATO adds a new tool to our arsenal of methods for identifying direct interactions with proteins and should have a broad impact in drug target discovery and antibody-antigen discovery," said Elledge.

 The study was published in the March 17, 2013 online issue of Nature Biotechnology.

Snx3 Protein Essential to Blood Cell Formation

Barry Paw, MD, PhD

A research team led by Barry Paw, MD, PhD, with Caiyong Chen, PhD, of the BWH Division of Hematology, has found that a protein called Sorting Nexin 3 (Snx3), which is highly expressed in vertebrate hematopoietic (blood-forming) tissues is essential in red blood cell formation. Moreover, knocking out this protein's gene results in anemia and hemoglobin defects in zebrafish embryos and mouse cells and tissues.

Caiyong Chen, PhD

 The researchers observed that silencing of the Snx3 gene prevents the formation of the Snx3 protein which helps transport and recycle the iron uptake machinery in red blood cells. Furthermore, impairment of these processes leads to reduced assimilation and utilization of iron by the red blood cells.

According to the researchers, having identified the mechanisms of Snx3 will provide a genetic tool for further exploring red blood cell formation and iron metabolism disorders.

"The clinical significance of our work provides new areas of enhancing the delivery of iron to red cells with iron deficiency," said Paw.

 The study was published in the March 5, 2013 issue of Cell Metabolism.