Rafael Ortega, MD, the associate dean of Diversity and Multicultural Affairs, has...
In a scientific discovery that has significant implications for HIV vaccine development, collaborators at the Boston University School of Medicine (BUSM) and Duke University School of Medicine have uncovered novel properties of special HIV antibodies. The paper, published in Cell Host and Microbe, describes how some HIV antibodies experience an unusual type of mutation, a phenomenon that allows them to neutralize many different strains of HIV. These antibodies are called “broadly neutralizing antibodies,” or BNAbs.
Antibodies develop from immune cells known as B cells. When B cells are confronted with foreign elements (known as antigens), some of them experience a high rate of mutations resulting in the substitution of an amino acid within the antibody for another. B cells whose antibodies carry variations that allow them to bind tightly with antigens proliferate, whereas those that do not die off. Thus, the immune system is able to adapt constantly by utilizing its own very fast version of evolution. More rarely, the antibodies will experience more dramatic changes than single amino acid substitutions. When whole strings of amino acids are inserted or deleted, this is known as an indel. Less than four percent of human antibodies contain indels; in BNAbs this figure is more than 50 percent. Only a small subset of HIV-infected individuals produce BNAbs.
Comparing the antibody genes of HIV infected and non-infected individuals, scientists discovered that HIV infected individuals had 27 percent more insertions and 23 percent more deletions than non-infected individuals. They also found this elevated rate of mutation persisted in all HIV-infected individuals, regardless of their ability to produce BNAbs. Most importantly, this high rate of indels was due to an overall increase in mutation frequency rather than something special associated with HIV itself, or unusual characteristics of the people who are able to make BNAbs. “This result suggests that a BNAb-eliciting vaccine is possible after all,” explained lead and corresponding author Thomas B. Kepler, PhD, professor of microbiology at BUSM. “More than 80 percent of indels were found in genetic regions responsible for binding to the HIV virus,” he added.
Since the BNAb indels don’t result from special characteristics of the people who make them, the researchers suspected that the indels may be important for the antibody function. They studied one particular BNAb called CH31, which has a very large indel, to see what role these indels might have played in the acquisition of broad neutralizing activity. They found that the indel was the key event in the development of CH31. According to the researchers just putting the indel into antibodies that did not originally have it, increased its effectiveness eight-fold; taking it away from ones that did have it initially, made them much worse. “When tested on their ability to broadly neutralize HIV, only those CH31 antibodies with indels were able to accomplish the task,” said Kepler.
Barton Haynes, MD, director of the Duke Human Vaccine Institute and senior author noted, The more we understand about the unusual pathway the BNAbs take to develop, the better chance we will have in inducing them. This news study unravels a particularly complex BNAb pathway.” The great hope in the quest to prevent HIV-1 is the development of a single vaccine that can cover multiple forms of HIV-1. A vaccine that works by eliciting BNAbs is a major goal, and this new work suggest that strategies for such a vaccine should focus on speeding up the antibody evolution that occurs after every immunization. The study suggests that such a strategy could work in everyone, not just a lucky few.
Other institutions involved in this study included the National Institute for Communicable Diseases, Sandringham, Johannesburg, South Africa; the Center for AIDS Program of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa; the Vaccine Research Center, NIAID, NIH, Bethesda, MD and Stanford University Medical Center, Stanford, CA
Funding for this study was provided by the National Institutes of Allergy and Infectious Diseases.
In some women abnormally high levels of a common and pervasive chemical may lead to adverse effects in their offspring. The study, published recently in the Journal of Clinical Endocrinology & Metabolism, is the first of its kind to shed light on the possible harmful side effects of perchlorate in mothers and their children.
Using data from the Controlled Antenatal Thyroid Study (CATS) cohort, researchers at Boston University School of Medicine (BUSM) and Cardiff University studied the effect of perchlorate, an environmental contaminant found in many foods and in some drinking water supplies, and its effects on children born to mothers with above average levels of this substance in their system. They studied 487 mother-child pairs from women with underactive thyroid glands and in the 50 women with the highest levels of perchlorate in their body, their offspring had below average IQ levels when compared to other children.
“The reason people really care about perchlorate is because it is ubiquitous. It’s everywhere,” said Elizabeth Pearce, MD, MSc, associate professor of medicine at BUSM. “Prior studies have already shown perchlorate, at low levels, can be found in each and every one of us.”
Perchlorate is a compound known to affect the thyroid gland, an organ needed to help regulate hormone levels in humans. According to Pearce previous studies have attempted to implicate this anti-thyroid activity in pregnant mothers as a possible cause of hypothyroidism, or an underactive thyroid gland. Hypothyroidism in newborns and children can lead to an array of unwelcome side effects, including below average intelligence.
Funding for the original CATS study was provided by the Wellcome Trust and Compagnia de San Paulo, Turin.
Researchers from Boston University School of Medicine (BUSM) report that two rare variants in the AKAP9 gene significantly increase the risk of Alzheimer’s disease (AD) in African-Americans.
This previously unknown association furthers the understanding of the role of genetic factors in the development of AD, according to the researchers, whose findings appear in Alzheimer’s & Dementia.
AD is the most frequent age-related dementia affecting 5.4 million Americans including 13 percent of people age 65 and older and more than 40 percent of people age 85 and older. Up to 75 percent of AD cases are thought to have a genetic basis; however the specific genes involved likely differ between ethnic populations. The most well-known AD risk gene, APOE4, does not play as strong a role in AD risk in African Americans as it does in Caucasians, despite the fact that a higher proportion of African Americans than Caucasians are afflicted with this disorder.
By analyzing the DNA sequence for all genes from participants of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and Genetic and Environmental Risk Factors for Alzheimer’s Disease among African Americans (GenerAAtions) Study, researchers identified two genetic variants in AKAP9 unique to African Americans that are enriched in individuals with AD. They then confirmed this association in several thousand other African American subjects in the Alzheimer Disease Genetics Consortium dataset. Carriers of either of these AKAP9 variants have a respective 2.8 and 3.6 times greater risk of developing AD.
According to the researchers AKAP9 encodes a protein with multiple forms, One of these, AKAP450, is expressed in the brain and responsible for microtubule anchoring and organization. Another protein, tau, which is responsible for microtubule functioning is well known to be the key constituent of neurofibrillary tangles that accumulate in AD brains.
“While further work is needed to clarify the causal link between these AKAP9 variants and AD, “this study indicates a new potential disease mechanism in the quest for a better understanding of AD, particularly in African Americans,” explained senior author Lindsay Farrer, PhD, Chief of Biomedical Genetics and professor of medicine, neurology, ophthalmology, epidemiology and biostatistics at BUSM. “Moreover, this is the first authentic example of rare genetic variants conferring a high risk of AD in African Americans,” he added.
Funding for this study was provided by the National Institute on Aging (R01-AG025259, R01-AG09029, P30-AG13846, and U01-032984).
Read the full study in Alzheimer’s & Dementia.
A recently completed renovation on the 11th floor of the Alumni Medical Library now provides a state-of-the-art, 220 seat testing center. The testing center is among the first of its kind, and will serve to both facilitate the administration of exams while at the same time enhancing the quality of study space for BUMC students.
Renovations include a new ceiling with improved sound-proofing qualities, energy-efficient lighting, new carpeting and flooring, newly painted walls, new chairs and tables with power outlets at every seat, and club seating and cube tables in the hallway outside the floor-to-ceiling glass walls of the testing center. The heating and air conditioning system was upgraded, and a more powerful wireless system is provided throughout the testing center, as well as some wired network connections.
The testing center is equipped with a video monitoring system and an audio system for proctor announcements. During exams, proctors will have video monitoring controls to observe activity throughout the space via iPad. The testing center serves a dual-purpose as student study space when not reserved for exams.
Medical Library Computing & Systems offices are located on L-11, and staff will provide on-site technical support for student laptops and laptop loaners during exams. A new state-of-the-art computer classroom with 26 PCs will also serve as a public computing lab when classes and exams are not scheduled. A coffee/vending lounge includes additional club seating, group study tables, PCs, a scanner and print release station. The elevator lobby was renovated and a new LCD monitor and signage have been installed throughout the floor.
On Monday, Aug. 4, members of the BUSM Class of 2018 received their white coats on Talbot Green. View the pics on Facebook.
Researchers at Boston University School of Medicine (BUSM) have uncovered important clues about a biochemical pathway in the brain that may one day expand treatment options for cognitive deficits seen in schizophrenia. The study, published online in the journal Molecular Pharmacology, was led by faculty members David H. Farb, PhD, Terrell T. Gibbs, PhD, and Shelley J. Russek, PhD in the department of pharmacology & experimental therapeutics at BUSM.
Patients with schizophrenia suffer from a life-long condition that can produce cognitive deficits, delusions, disordered thinking, and breaks with reality. A number of treatments are available for the treatment of schizophrenia, but many patients do not respond to these therapies or experience side effects that limit their use. There is no current treatment for the cognitive deficits experienced in schizophrenia.
The healthy brain is made up of billions of cells including the primary signaling cells called neurons, that are responsible for managing everything the body does: including movement, eating behavior, and memory formation. These neurons acts like a miniature computer and are controlled by substances called neurotransmitters that, like bits in a computer chip, may be “turned on” or “turned off” depending on the specific signals being integrated. Neurotransmitters latch onto a cell via a specific receptor, like a key fits into a lock.
In schizophrenia, it is thought that certain neurons don’t “turn on” as well when exposed to a certain neurotransmitter, the amino acid glutamate, may not be sensed by one of its key receptors (the NMDA receptor) whose diminished function may be the possible culprit for these sluggish cells. It is thought that this deficit can at least partially be responsible for symptoms seen in schizophrenics.
Currently the therapeutic means for making these cells more “sensitive” to glutamate can be toxic to the brain.
In this study, researchers discovered that another, naturally occurring steroid within the brain, known as PregS, may be able to bypass this toxic effect, and “turn on” neuron communication safely through a novel mechanism. The implication is that a deficit in the amount of this novel steroid may underlie deficits in signaling and that stimulation using therapeutics that elevate its levels in the brain may decrease or eradicate some of the debilitating symptoms seen in schizophrenia.
Although still in the early stages, further research in this area may be instrumental in the identification and development of treatments not only for schizophrenia, but also for other neurological conditions, such as age-related decreases in memory and learning ability.
Jasmine Chobanian remembered as a patron of the arts and a humanitarian.
Jasmine Chobanian, who was regarded as the “First Lady” of Boston University during the many years that her husband Aram V. Chobanian, MD, served in University leadership, both as dean of the School of Medicine and the ninth president of Boston University (2003–2005), died last Friday after a brief illness.
“Jasmine was our beloved first lady of the Medical Campus,” says Karen Antman, provost of the Medical Campus and dean of the School of Medicine. “She was a smart, savvy, warm person who started out life in the technical sciences but clearly also was deeply committed to the arts. We on the Medical Campus will miss her.”
Jasmine Chobanian was a much-loved patron of the arts and a humanitarian. She served on the board of trustees of Boston Ballet and was active in efforts to provide aid to the people of Armenia. In November 2005 the University’s Women’s Council announced the establishment of the Jasmine Chobanian Scholarship Fund and sponsored a gala honoring Chobanian for her many contributions to the University. Boston Ballet dancers Melanie Atkins, Pavel Gurevich, Roman Rykine, and Larissa Ponomarkenko performed selections from The Nutcracker, and then-provost David Campbell sang four lieder, accompanied by his wife, pianist Claude Hobson.
“Jasmine was a vivacious and caring emissary for Boston University, as she supported Aram in his roles as longtime dean of the School of Medicine and then president of Boston University,” says President Robert A. Brown. “The University has lost a true friend.”
A graduate of Brown University, Chobanian was a talented painter, and studied with Conger Metcalf at the Boston Museum School, now the School of the Museum of Fine Arts, Boston. She worked for many years as a researcher at Thorndike Memorial Laboratories at Boston City Hospital. Chobanian is being remembered by friends as someone who lived life to the fullest: a world traveler, voracious reader, fascinating raconteur, nature lover, bird watcher, and sports fan.
Caroline Apovian, professor of medicine and pediatrics at the School of Medicine, says Chobanian “was at the center of the movement on the Medical Campus to unite the arts and the sciences. She encouraged many of the faculty and students to pursue their creativity, specifically in music, but also in the other arts as well. She will be deeply missed by many.”
Robert Witzburg, associate dean and director of admissions at the School of Medicine says Jasmine Chobanian was a remarkably warm and caring person. “She had her own presence at BUSM and the University, quite independent of her prominent husband, Aram,” says Witzburg. “Her smile would light up a room, and she had that rarest of attributes: the ability to respect everyone she met and to instantly put them at ease. All of us who were privileged to know Jasmine will miss her dearly.”
Jasmine Chobanian was born in Pawtucket, R.I., the daughter of the late Charles and Zabel (Russian) Goorigian. She is survived by her husband of 59 years, Aram V. Chobanian (Hon’06), president emeritus of BU, and their children, Karin Chobanian Torrice of Natick, Mass., Lisa Chobanian Ramboeck of Bronxville, N.Y., and Aram Chobanian, Jr. of Brookline, Mass. She is also survived by her grandchildren, Marc and Vanessa Torrice; her sisters Nectar Lennox of Cumberland, R.I., and Marie Vartanian of Agawam, Mass.; and her sister-in-law, Ruth Chobanian of Cambridge, Mass., as well as a large number of nieces, nephews, and friends.
Funeral arrangements are being made through the Bedrosian Funeral Home, 558 Mt. Auburn Street, Watertown, Mass. A wake will be held at St. Stephen’s Armenian Church, 38 Elton Avenue, Watertown, Mass., tomorrow, Tuesday, July 29, from 4 p.m. to 8 p.m. Funeral services will take place on Wednesday, July 30, at 11 a.m. at St. Stephen’s Armenian Church. Burial services will be private.
In lieu of flowers, contributions may be made to the Chobanian Scholarship Fund at Boston University School of Medicine, c/o Development Office, 72 East Concord St., L219, Boston, MA 02118; St. Stephen’s Armenian Church; or The Fund for Armenian Relief, 630 Second Ave., New York, NY 10016. A memorial service to celebrate her life will be held in September at a date and place to be announced.
This BU Today story was written by Art Jahnke.
BUSM’s Domenic A. Ciraulo, MD, was appointed as the chairman of the National Institute of Alcohol Abuse and Alcoholism (NIAAA) study section AA-3, which reviews all grant applications requesting funding for clinical studies of treatments for alcoholism and health services research on alcoholism. He has been funded by NIAAA for more than 18 years, serving as a Principal Investigator at the BUSM site for the COMBINE study, PI on his own R01 grants, and mentor for a number of K awards.
Ciraulo is the chairman of the department of psychiatry at BUSM and chief of psychiatry at Boston Medical Center. He is internationally recognized as an expert in medication development and clinical trial methodology in alcoholism and addiction therapies. His research in alcoholism and addiction focuses on medication development, the interaction of psychosocial therapy and medication therapy, neuroimaging, and clinical psychopharmacology.
He has served on several national committees, including FDA advisory panels, NIH scientific review groups, and the American Psychiatry Association’s Council on Addiction Psychiatry. He is Associate Editor of the Journal of Clinical Psychopharmacology and serves on the editorial board of the American Journal of Drug and Alcohol Abuse. Ciraulo has authored or co-authored more than one hundred fifty papers and book chapters and co-edited five books. He graduated from Georgetown University School of Medicine in 1975, was a psychiatric resident at the Institute of Living from 1975-77, and Chief Resident of the Somatic Therapies Unit, Clinical Fellow Harvard Medical School, Massachusetts Mental Health Center from 1977-78.
Researchers from Boston University School of Medicine (BUSM) report variants in a new gene, PLXNA4, which may increase the risk of developing Alzheimer’s disease (AD). The discovery of this novel genetic association may lead to new drug treatment options that target PLXNA4 specifically. These findings appear in the Annals of Neurology.
AD is the most frequent age-related dementia affecting 5.4 million Americans including 13 percent of people age 65 and older, and more than 40 percent of people age 85 and older. Genetic factors account for much of the risk for developing AD with heritability estimates between 60 percent and 80 percent. However much of the genetic basis for the disease is unexplained. Less than 50 percent of the genetic contribution to AD is supported by known common genetic variations.
Using data from the Framingham Heart Study, the researchers obtained strong evidence of an association with several single nucleotide polymorphism in PLXNA4, a gene which had not been previously linked to AD. They then confirmed this finding in a larger dataset from the Alzheimer’s Disease Genetics Consortium and other datasets. Next, they performed a series of experiments in models that pinpointed the mechanism by which this gene affects AD risk. “Importantly, this is one of few single studies which go from gene finding to mechanism,” explained corresponding author Lindsay Farrer, PhD, Chief of Biomedical Genetics and professor of medicine, neurology, ophthalmology, epidemiology and biostatistics at BUSM.
According to the researchers a form of the protein encoded by this gene promotes formation of neurofibrillary tangles consisting of decomposed tau protein, one of the two pathological hallmarks of the disease. “We showed that PLXNA4 affects the processing of tau as it relates to neurofibrillary tangles, the primary marker of AD. Most drugs that have been developed or that are in development for treating AD are intended to reduce the toxic form of beta-amyloid, a sticky substance that accumulates in the brain of persons with AD, and none have been very effective. Only a few drugs have targeted the tau pathway,” added Farrer.
This study was supported by grants from the National Institute on Aging (R01-AG025259, P30-AG13846, R01-AG0001, U24-AG021886, U24-AG26395, R01-AG041797 and P50-AG005138), the Alzheimer Association, the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (#A110742), and the Evans Center for Interdisciplinary Biomedical Research (ECIBR) ARC on “Protein Trafficking and Neurodegenerative Disease” at Boston University.
To view the complete findings of the study, PLXNA4 is Associated with Alzheimer Disease and Modulates Tau Phosphorylation.
How can engaged patients improve health care?
BUSM’s Suzanne Mitchell, MD, and other expert panelists tackled the question during a recent TEDMED#GreatChallenges discussion, “Examining the Case for Patient Activation Measures.”
Research indicates clinical sites using the Patient Activation Measure (PAM) — a tool developed by researchers at the University of Oregon to measure patients’ knowledge, skills and confidence for managing their health — save between $260 and $3,700 per patient annually. The benefits of patient engagement extend far beyond the scope of revenue reports by promoting better communication between patients and providers.
“We’re trying to figure out how to personalize people’s care, because one size doesn’t fit all,” said Dr. Mitchell, bringing valuable insight from the clinical perspective to the discussion. “I think we can see the PAM used as a way of personalizing care, as a way of informing patients where they’re at and what they need. It could also be used as an assessment of whether a particular intervention has worked successfully to increase a person’s level of or their ability to engage in managing their own health care.”
Sustainable patient engagement is increasingly important to health care providers and administrators. To read more about the current discussion, visit George Washington University’s School of Public Health blog.