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The Fetal Hemoglobin Switch
Image Three years ago, current senior resident Vijay Sankaran and his mentor Stuart Orkin traced the fetal hemoglobin switch to a repressor, BCL11A, which turns off expression of gamma globin (and HbF), allowing beta globin (and HbA) to switch on. This seminal work, published in Proc Natl Acad Sci USA, Science and Nature, answered one of the most important questions in hematology in the past half century and created very important therapeutic possibilities for treating sickle cell disease and thalassemia. Vijay has continued to pursue this and related problems during his residency - working both here at Children's and across the river in Cambridge, where he is holds a Visiting Scientist position at the Broad Institute of Harvard and MIT. By following up on thalassemic patients with gene deletions that differ only slightly but lead to markedly different levels of fetal hemoglobin, Vijay tracked down the locus within DNA where BCL11A acts (N Engl J Med ). And, by following up on an old observation that some patients with trisomy 13 have high fetal hemoglobin levels, he was able to identify two micro-RNAs on chromosome 13 that regulate BCL11A via the Myb gene (Proc Natl Acad Sci USA). More recently, Vijay and his collaborators have shown that sickle cell disease in mice can be cured by silencing BCL11A and reactivating fetal hemoglobin expression (Science) and they have begun the search for small molecules that can cause such silencing and might be effective therapeutics. In other studies, which are yet to be published, Vijay has discovered a molecular clock that regulates the size and number of red cells, and he has found new genes responsible for Diamond-Blackfan anemia. He is embarking on a large scale study of the genetics of hematological disorders and a search to identify natural metabolites that might explain why patients with certain organic acidopathies have high fetal hemoglobins. Vijay is also a great doctor and teacher and was recently honored with an Outstanding Resident Teacher award from the third year Harvard Medical students.
Alex Kentsis develops urine test for appendicitis
Alex Kentsis As a medical student Alex Kentsis was interested in the structure of proteins, so during residency he decided to see if he could use the emerging science of proteomics to discover biomarkers for common diseases. He chose to focus on urine since it is easily obtained and asked whether any specific changes in the urine occur in patients with appendicitis. The result, published recently in the Annals of Emergency Medicine, and featured nationally in stories in Time Magazine, in the Los Angeles Times and on BBC News, showed that several proteins had a high predictive value and that one, leucine-rich alpha-2-glycoprotein (LRG), was particularly predictive. LRG was enriched more than 9-fold in the urine of patients with appendicitis and the amount correlated with the severity of the disease. Sensitivity and specificity approached 100% (the receiver operating characteristic area was 97%). LRG was highly concentrated in the inflamed appendices. It is normally expressed in differentiating neutrophils, liver, and the high endothelial venules of the mesentery, including the appendix, and functions in leukocyte activation and chemotaxis, which may explain its specificity. Notably, the test was positive even in some patients with early appendicitis who had normal CT and ultrasound imaging. Preliminary testing indicates that elevated levels of LRG are also easily detected in the urine of patients with appendicitis by western blotting, which means that it should be possible to develop a dipstick immunoassay for rapid testing.

The study was paid for by funds set aside for resident research. It was greatly facilitated by the state-of-the-art proteomics facility at Boston Children's Hospital and by the enthusiasm and cooperation of Hanno Steen, who runs that facility, and the emergency room staff. With the multiple different mass spectrometers available and the other protein fractionation equipment, Alex was able to survey over 2000 unique urine proteins to identify his biomarkers. With such a large protein palette, it seems inevitable that markers of other diseases will soon be found.

Alex Kentsis is currently a fellow in hematology/oncology at Boston Children's Hospital and the Dana-Farber Cancer Institute.

Paper - Discovery and Validation of Urine Markers of Acute Pediatric Appendicitis Using High-Accuracy Mass Spectrometry
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