300 Longwood Avenue Boston, MA 02115 (617) 355-6000 Research: Timeline: Recent Advances 2007 Cardiac surgeons Drs. Virna Sales and John Mayer create living, growing heart valves using tissue engineering techniques in an animal model. Their work raises the possibility that children with congenital heart disease could receive replacement valves and other heart structures that grow with them, eliminating the need for repeat operations. [press release] Researchers led by Dr. Bernhard Kuhn demonstrate a way to get injured heart tissue to regrow and regain pumping ability. In an animal model, Kuhn and colleagues used a naturally-occurring compound called periostin to stimulate growth pathways that are normally switched off in heart cells after embryonic development. [press release] Dr. Morris White and colleagues show that reducing insulin signaling specifically in the brain can prolong lifespan in mammals, providing a molecular explanation for the value of exercise and eating in moderation. Mice whose insulin signaling was reduced only in the brain lived longer and were more active in old age, retaining youthful metabolic cycles and protective levels of anti-oxidant enzymes. [press release] Dr. Lois Smith and colleagues show that increasing intake of omega-3 fatty acids, found in popular fish-oil supplements, may protect against blindness resulting from abnormal blood vessel growth in the eye. In an animal model of retinopathy, a mere 2 percent change in dietary omega-3 intake was sufficient to decrease disease severity by 50 percent. [press release] High-volume drug screening in zebrafish reveals a new way to increase stem cells in blood, suggesting a possible treatment to help patients recover immune function more quickly after chemotherapy or bone marrow transplant. Dr. Leonard Zon and colleagues show that a stable analog of prostaglandin can enhance the blood-forming system - the first induction of stem-cell production by a small-molecule drug. [press release] Dr. Stuart Orkin and colleagues show that difficult-to-treat myeloproliferative syndromes, which can progress to leukemia, are rooted not in errant blood stem cells, as previously thought, but in the cells' surrounding environment. The new understanding helps explain why normal blood stem cells transplanted into patients with myeloproliferative syndromes sometimes become diseased themselves, and may pave the way to novel therapies. [press release] Dr. Deborah Waber and colleagues report the first data to emerge from the National Institutes of Health MRI Study of Normal Brain Development, a large, population-based study begun in 1999. The findings offer a first glimpse at the effects of gender, age and income on cognitive performance in a broad population of healthy children, and provide a comprehensive reference for future research and clinical practice. [press release] A team led by Dr. Gabriel Corfas provides the best evidence to date that defects in the brain's white matter are a key contributor to schizophrenia, showing that two of the dozen or more genes previously linked with schizophrenia - neuregulin 1 and erbB4 - induce pathologic changes in the white matter that unbalance the dopamine system. The new understanding of schizophrenia raises the possibility of early diagnosis and perhaps preventive treatment. [press release] Dr. David Fisher finds that the cancer-suppressing protein p53 is doubly protective when it comes to melanoma: it not only guards against cancer-causing DNA damage from the sun, but also kick-starts the tanning process, spurring production of skin-darkening melanin. The discovery might someday be applied to help prevent skin cancer, even in people unable to tan well. [press release] 2006 Lab space at the Proteomics Center Children's opens a state-of-the-art Proteomics Center, enabling researchers and clinicians to conduct large-scale, systematic studies of proteins and protein actions and interactions in the body. Michael Greenberg, PhD, and colleagues demonstrate that newly-recognized genetic elements called microRNAs, which suppress gene activity, have a role in the developing nervous system. They show that one microRNA fine-tunes the development of synapses, the points of communication between brain cells that underlie learning and memory. Dale Umetsu, MD, PhD, Omid Akbari, PhD, and colleagues report that a newly recognized type of immune cell, NKT, may play an important role in causing asthma, even in the absence of conventional T-helper cells. Moreover, NKT cells respond to a different class of antigens than are currently recognized to trigger asthma. A report in The Lancet describes good outcomes in seven children with spina bifida who received laboratory-grown bladders, the first complete tissue-engineered organs to be implanted in human patients. Dr. Larry Benowitz, PhD, and colleagues discover a naturally occurring growth factor called oncomodulin that stimulates regeneration in injured optic nerves, raising the possibility of treating blindness due to optic-nerve damage and the hope of achieving similar regeneration in the spinal cord and brain. 2005 gp120, a protein on HIV's surface that binds to a cell's CD4 receptor. Stephen Harrison, PhD, and colleagues show how a key part of the human immunodeficiency virus (HIV) changes shape, triggering other changes that allow the AIDS virus to enter and infect cells. The findings offer clues that could lead to new vaccine and treatment approaches. Richard Malley, MD, and colleagues discover that natural protection against Streptococcus pneumoniae infection occurs through an immune mechanism that may be independent of the current Prevnar vaccine. This mechanism, once better understood, could possibly exploited for an improved, more broadly protective whole-cell vaccine. Marco Ramoni, PhD, and collaborators create a novel method for predicting stroke risk in patients with sickle cell anemia, by combining large-scale genetic analysis with Bayesian networks, a method of "mining" information that combines artificial intelligence and statistics. The model shows that genetic differences in 12 genes interact with fetal hemoglobin level to modulate the risk of stroke, with an overall predictive accuracy of 98 percent. In the best-documented effort to date, Felix Engel, PhD, and Mark Keating, MD, successfully get adult heart-muscle cells to divide and multiply in mammals, the first step in regenerating heart tissue. They are now investigating whether their technique can improve heart function in animal models of cardiac injury. Raif Geha, MD, discovers a gene mutation that accounts for many cases of immune deficiency, in particular two syndromes known as immunoglobulin A (IgA) deficiency and Common Variable Immunodeficiency (CVID) that make people highly susceptible to infections. The finding is expected to yield a new diagnostic test for these conditions, which often go unrecognized. 2004 Jane Newburger, MD, MPH, receives a $20 million grant from the National Heart Lung and Blood Institute to study tetralogy of Fallot and speed up the process of translating research into clinical care. Bruce Yankner, MD, PhD, and colleagues uncover a pattern of gene activity in the aging human brain that may contribute to age-related cognitive decline.The findings indicate the possibility of preserving brain function by preventing damage to these critical genes. Frances Jensen, MD, and colleagues show that an existing drug, topiramate, may protect newborns from brain injury and long-term neurologic problems caused by excitotoxicity, or over-activation of neurons. The findings have implication for the prevention of cerebral palsy and epilepsy. Stem cell researcher George Daley, MD, PhD, is awarded one of the nine inaugural Pioneer Awards from the National Institutes of Health. The award aids scientists who were deemed to have the potential to make major breakthroughs in the improvement of human health. Children's receives more than $10 million from the National Institutes of Health to study a potentially life-threatening complication of smallpox immunization known as eczema vaccinatum (EV). The goal is to reduce the risk of EV and develop a safer smallpox vaccine. Children's launches a multidisciplinary study of autism that will seek to define its genetic and biochemical causes. The study, involving the Developmental Medicine Center, the Program in Genomics, the Program in Neurobiology, and the Children's Hospital Informatics Program (CHIP), is expected to yield greater biological understanding of autistic spectrum disorders, better diagnostic and prognostic techniques, and possibly new treatments. 2003 Fred Alt, PhD, and colleagues discover the disruption of a gene known as H2AX can disrupt the machinery that senses and fixes broken DNA, thereby setting the stage for cancer to develop. In mice, loss of H2AX led to an increase in lymphomas and solid tumors because errors in the genetic code were not always repaired correctly. The finding has implications for understanding the origin of human cancers, since a large number of human tumors contain alterations in the region of chromosome 11 where the H2AX gene is located. Leonard Zon, MD, and colleagues isolate a gene responsible for making blood stem cells. The gene, called cdx4, establishes the location of blood cell formation in the developing embryo by altering the expression of HOX genes, which are involved in making the body plan. The discovery could lead to a method for growing blood stem cells in the laboratory for patients with severe congenital anemias or those needing bone marrow transplants for cancer. Researchers at Children's, Brigham and Women's Hospital, Harvard Medical School, and the University of Massachusetts Medical School discover a specific receptor on cells that opens the door to the SARS virus, allowing the virus to bind, enter and replicate. Researchers hope this will be a major advance in the diagnosis and treatment of SARS. George Daley, MD, PhD, and colleagues report creating a continuously growing line of embryonic germ cells, primitive cells that mature to become sperm or eggs. They also created male reproductive cells capable of fertilizing an egg to form an early embryo. These achievements may lead to a better understanding how reproductive cells form, and ways of 'reprogramming' specialized cells to become more like embryonic stem cells. 2002 Scott Pomeroy, MD, PhD, and Todd Golub, MD, use microarray gene expression profiling to identify different types of brain tumors and predict clinical outcomes. This allows radiation and chemotherapy to be tailored to kill cancer cells while leaving healthy tissue alone. Children's endocrinologists David Ludwig, MD, PhD, and Mark Pereira, PhD, MPH, describe dietary factors that influence glucose metabolism and insulin regulation and contribute to Type 2 diabetes. Children's is recognized by the National Association of Children's Hospitals and the American Academy of Pediatrics as a national model in terrorism preparedness. The following year, it is awarded $700,000 by the Agency for Healthcare Research and Quality to establish the Center for Biopreparedness, which is developing best-practice management techniques for biological, chemical or radiation events affecting children and their caregivers. 2001 Sara Vargas, MD, and Antonio Perez-Atayde, MD, identify an aggressive new type of cancer that affects the upper respiratory tract in young patients. Louis Kunkel, PhD, and colleagues from Beth Israel Deaconess Medical Center identify a region on chromosome 4 that is associated with exceptionally long life. Individuals with these special genes live healthy lives beyond 100 years. Children's clinicians care for a patient with life-threatening heart disease, making him the world's first hemophiliac to be placed on extracorporeal membrane oxygenation and only the second to undergo a heart transplant. Lois Smith, MD, PhD, demonstrates that insulin-like growth factor 1 is critical to blood vessel growth in the eye. She also finds that retinopathy of prematurity, a disease that can cause blindness in premature infants, may be due to the loss of IFG-1 from the amniotic fluid when babies are born weeks early. Children's opens the nation's first pediatric palliative care inpatient room in a hospital, which allows families of terminally ill children to stay together in a homelike setting while the child receives end-of-life care. 2000 Timothy Browder, MD, demonstrates in mice that lower, more frequent doses of chemotherapy target the endothelial cells that line the vascular bed of a tumor, showing that chemotherapy can be anti-angiogenic. Craig Gerard, MD, PhD, identifies a candidate receptor responsible for many symptoms of bronchial asthma, a finding that could lead to the development of medications that inhibit the secretion of mucus that causes broncho-constriction. 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