National Geographic Lee Goldstein, MD, PhD, psychiatry, neurology, ophthalmology Brain trauma from blast force...
By Lisa Brown
The identification of genetic variants that influence the structure of the brain may provide insight into the causes of variability in human brain development. The findings, which appear this week in the journal Nature, may also help determine the genetic processes that underlie neuropsychiatric diseases.
Portions of the human brain known as the subcortical regions are involved in functions associated with movement, learning, memory and motivation; alterations to the structure of these regions can lead to abnormal behavior and disease. To investigate how common genetic variants affect the structure of these brain regions, a worldwide group of researchers including those from Boston University School of Medicine (BUSM) analyzed genetic data and MRI scans collected from 30,717 individuals. They found a number of genetic variants that influence the volume of subcortical brain structures, and many of these variants seem to exert their effects through known developmental processes. One genetic variant found to be linked to changes in the volume of the hippocampus — a key region involved in learning and memory — is also known to be associated with schizophrenia.
The neurology working group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium is led by Sudha Seshadri, MD, a professor of neurology at BUSM and a senior investigator at the Framingham Heart Study. “This is another example of the wide range of new scientific discoveries that continue to emerge from the invaluable Framingham Heart Study cohort as well as the many diverse international collaborations BUSM researchers lead and participate in,” said Seshadri.
The study is a collaboration involving 30,000 participants and investigators from Australia, the U.S., Europe and Asia.
Deeper understanding of telomeres may lead to targeted cancer treatments
By a quirk of biology, every time an adult cell divides, a bit of DNA gets lopped off the end of the double helix. This seems like a recipe for disaster—imagine a crazed librarian ripping the last chapter off a book every time it got checked out. Soon, the book would be useless. So would truncated DNA, if not for structures called telomeres, long sequences of repetitive base pairs—the same meaningless TTAGGG over and over—that cap each end of our DNA. Every time a cell divides, it’s a bit of telomere that gets chopped off, rather than vital genes.
But biologists have long understood telomeres to be a double-edged sword. When they get too short, cells stop dividing. We see this as aging: hair turns gray, skin sags. But some cells are able to keep their telomeres long, effectively becoming immortal and dividing forever. Sometimes, the immortal cells become a cancer.
Now, scientists led by Rachel L. Flynn, a Boston University School of Medicine (MED) assistant professor of pharmacology and experimental therapeutics and medicine, have found a new way to kill certain cancers by targeting mechanisms of telomere elongation. The research, funded by the National Institutes of Health, the Foster Foundation, and the Karin Grunebaum Cancer Research Foundation, and published in the January 15, 2015, issue of Science, may lead to new therapies for certain rare and deadly cancers that often appear in children.
Cells that are able to lengthen their telomeres, and thereby divide indefinitely, use two known methods to do so. The more common is to use an enzyme called telomerase, which is active in embryonic stem cells but repressed as cells become specialized. The less common method, and the one Flynn studies, is called ALT, for alternative lengthening of telomeres. The ALT pathway is most prevalent in certain cancers, including pediatric osteosarcoma, a bone cancer, and glioblastoma, a type of brain cancer.
“In terms of the possible clinical applications, this research could be a game changer,” says Karen Antman, MD, provost of BU Medical Campus and dean of Boston University School of Medicine. “This exciting finding could allow us to target any cancer that uses the ALT pathway to maintain telomeres. Such cancers are often resistant to common treatment options and have a poor prognosis.”
The ALT pathway, though discovered almost two decades ago, is still poorly understood, says Flynn. “We know that ALT is a mechanism that relies on recombination—one telomere basically hijacks another and uses it to replicate and elongate itself,” she says. “But we didn’t know how the pathway was maintained until now.”
Flynn’s paper suggests how cancer cells may be able to maintain the ALT pathway—by depending on an enzyme called ATR kinase. This enzyme is what’s known as a “master regulator,” says Flynn. In a normal cell, it recognizes DNA damage when a cell is preparing to divide, and leads to either DNA repair or cell death. ALT cancer cells are constantly undergoing DNA repair at the telomere and are more reliant on ATR kinase activity than other cancer cells. Therefore, ATR promotes immortality by helping telomere elongation. Attack this enzyme, says Flynn, and you stop the cancer cell in its tracks.
“When you take ATR kinase out of the picture, it shuts down a whole chain of events,” says Flynn. “The cancer cell tries to promote telomere elongation, but it can’t, and the cell dies.”
There are several drugs already on the market that act as ATR kinase inhibitors, but none are used individually to treat these types of cancers. “The cool thing about these drugs is that the cancer cells actually die incredibly fast as opposed to just slowing down cell growth,” Flynn says. She also notes that since the drugs only affect cancer cells using the ALT pathway, normal cells should be left unharmed.
Flynn’s next step is to get the existing drugs into clinical testing for targeted use. She is working with a group at Massachusetts General Hospital who will test it on mice with glioblastomas. Eventually, she hopes, her work will lead to a new treatment for these deadly diseases.
“The dream is that this research will eventually give kids with devastating cancers an option for individualized treatment, something that will hopefully improve outcomes,” says Flynn.
This BU Today article was written by Barbara Moran. She can be reached at firstname.lastname@example.org.
A version of this story was originally published in BU Research.
Jan. 26 Exploring the Role of Social and Cultural Determinants Influencing Latino HIV and Substance Abuse Health Disparities
BU Medical Campus faculty, residents and PhD students are invited to a colloquium sponsored by the BU School of Social Work. Join Mario De La Rosa, PhD, Professor at Florida International University, Miami as he discusses “Exploring the Role of Social and Cultural Determinants Influencing Latino HIV and Substance Abuse Health Disparities” on Monday, Jan. 26 at 10:45 a.m. Dr. De La Rosa is a candidate for the inaugural Director of the Center for Innovation in Social Work and Health. A luncheon will immediately follow the colloquium, RSVP required by Jan. 22 to email@example.com
- “Exploring the Role of Social and Cultural Determinants Influencing Latino HIV and Substance Abuse Health Disparities”
- Mario De La Rosa, PhD, Professor at Florida International University, Miami
- Colloquium: Monday, Jan. 26, 10:45 a.m.
- Hiebert Lounge, BUSM Instructional Building
- Luncheon following colloquium, RSVP required by Jan. 22, firstname.lastname@example.org
Obesity-linked diabetes is a growing public health problem and contributes to cardiovascular disease, the most prevalent cause of death in the U.S. High plasma concentrations fatty acids derived from food intake and excess fat stores and high concentrations of glucose from diet are hallmarks of diabetes. Increasing attention has been directed to fatty acids and their multiple pathophysiological effects.
The plasma membrane receptor CD36 is a key protein that plays central roles in obesity and type 2 diabetes. It binds both fatty acids and oxidized low density lipoprotein (LDL), which has been implicated in promotion of atherosclerosis. However, the mechanistic roles of CD36 are complex and have remained elusive.
In a new study published in the Journal of Biological Chemistry, a research group led by James A. Hamilton, PhD, professor of Physiology, Biophysics and Radiology at Boston University School of Medicine, applied novel methods to detect binding of fatty acids to CD36 and their effect on internalization of oxidized LDL. Although other research groups have characterized a fatty acid binding site on CD36 and postulated CD36 to be a gatekeeper for fatty acid entry into cells, the Hamilton lab previously found that CD36 did not increase fatty acid translocation across the plasma membrane.
In the current study all of the common dietary fatty acid types (saturated, unsaturated, trans and polyunsaturated) were shown by a new assay to bind to CD36 at levels greater than expected for a single binding site characterized in previous studies. In cells with CD36 present in the plasma membrane, all of the fatty acids also enhanced oxidized LDL uptake, except for the fish oil fatty acid DHA. This current study adds to the possible mechanisms for fish oil benefits that are now widely recognized.
“Since obesity and type 2 diabetes are characterized by high plasma levels of fatty acids, the demonstrated enhancement of oxLDL uptake by increases in common dietary fatty acids may contribute to the pathophysiology of these diseases. Furthermore, our new results provided a link between fatty acids, CD36, and atherosclerosis and new drugs can be designed that target the exact mechanism more precisely.” added Hamilton.
The work was supported by a grant from the American Diabetes Association. The study’s co-authors are Anthony Jay, Alex Chen, Justin Hung, and Miguel Paz.
The Stanley L. Robbins Award for Excellence in Teaching is given each year at graduation to the outstanding educator at the BU School of Medicine (BUSM). The award was established in recognition of the excellence in teaching and devotion to students exemplified by Dr. Stanley L. Robbins, former Chair and Professor of Pathology at BUSM. This award serves to acknowledge the importance of teaching skills and commitment to students and education at BUSM.
This is a once in a lifetime award: previous awardees are not eligible. (See past recipients.) This year, BUSM faculty and students will nominate a Preclerkship faculty member. The award decision is made by a committee based on faculty and student nominations and input. Faculty may nominate themselves. Nominations will remain valid for three years.
Send nomination to:
- Rebecca Halley
- Administrative Manager
- Office of Academic Affairs, L-103
Nominations are due by March 1
Please include, in writing or via e-mail, the nominee’s name, department, how you know the nominee and a detailed justification for the nomination addressing the nominee’s exemplary skill, leadership, creativity, mentoring and other intangible aspects of the work needed to accomplish our teaching mission.
If you have any questions about the process, please contact Rebecca Halley at email@example.com.
BUSM faculty are encouraged to order 2015 commencement regalia before Friday, Feb. 27 through the Faculty Portal.
Commencement ceremonies are scheduled as:
- Graduate Medical Sciences (Master’s candidates): 10 a.m. Friday, May 15, Metcalf Hall in George Sherman Union
- School of Medicine (MD and GMS PhD candidates): 9 a.m. Saturday, May 16, Agganis Arena
- All-University Commencement: 1 p.m. Sunday, May 17, Nickerson Field
Please contact the Division of Graduate Medical Sciences (617-638-5255) or the School of Medicine’s Office of Student Affairs at (617-638-4166) with questions.
Emelia J. Benjamin, MD, ScM, professor of Medicine at BUSM, professor of Epidemiology at BU School of Public Health, co-Principal Investigator of the Framingham Heart Study and attending cardiologist at Boston Medical Center, has been selected as the recipient of the prestigious 2015 American Heart Association (AHA) Paul Dudley White Award.
The award, named in honor of one of Boston’s most revered cardiologists, Dr. Paul Dudley White, a founding father of the AHA, is given annually to a Massachusetts physician who has made a distinguished contribution to the Association’s mission of building healthier lives, free of cardiovascular disease and stroke. Benjamin will receive the award at the Boston AHA Heart Ball on May 2. Last year BUSM faculty member Dr. Gary Balady, received the award.
Benjamin is an associate editor for Circulation, and she also volunteers as vice chair of the Heart Disease and Stroke Statistics annual publication. She is a current member of the Council Operations and the Research committees, and past chair of the Functional Genomics and Translational Biology Council, and the Genomics & Translational Biology, Epidemiology and Observational/Epidemiology Research Study Section. In 2012 and 2013 she received the AHA’s Women in Cardiology and Functional Genomics and Translational Biology national mentoring awards, respectively.
Benjamin focuses on cardiovascular genetic epidemiology, and has made major contributions in the areas of atrial fibrillation, inflammation, vascular function and echocardiography.
Scott Duncan, MD, MPH, MBA, has been appointed chair of the department of orthopaedic surgery at Boston University School of Medicine (BUSM) and chief of orthopaedic surgery at Boston Medical Center (BMC), effective Jan. 1, 2015. Duncan comes to BUSM/BMC from Ochsner Health System in New Orleans, Louisiana, where he served as system chairman of the department of orthopaedic surgery, and section head of hand and upper extremity surgery.
“Dr. Duncan will be a strong faculty leader,” said Karen Antman, MD, provost of BU Medical Campus and dean of Boston University School of Medicine. “He is an accomplished surgical investigator with many years of experience in academic administration and research. Orthopaedic surgery will continue to grow and thrive clinically and academically under his guidance.”
Duncan is an international expert and thought leader in the areas of upper extremity trauma; revision carpal tunnel surgery; small joint arthroplasty; and reconstructive surgery of the wrist, forearm, elbow and shoulder. He frequently presents at medical schools and conferences around the world on topics such as: shoulder arthroscopy, hand trauma, thumb injuries, and utilizing iPads and iPhones in an orthopaedic surgery practice. Duncan has served as an international visiting professor of orthopaedic surgery, most recently at the Medical College of Peru in Lima.
“Dr. Duncan is a true leader in his field, and has demonstrated a clear commitment to his patients, his research and to educating tomorrow’s physicians,” said Kate Walsh, president and CEO of Boston Medical Center. “He will be an integral member of the BMC team, and we are confident that his leadership and clinical skills will benefit both our patients and our staff.”
Duncan graduated college at Harvard University. He earned his medical degree and his master’s of public health in epidemiology at the University of Washington (UW) Schools of Medicine and Public Health. He also received his master’s in business administration, health care management, at the University of Texas, Southwestern Medical Center. He completed his residency in orthopaedic surgery at the Campbell Clinic, University of Tennessee, and a fellowship in hand and upper extremity surgery and microsurgery at the Hospital for Special Surgery at Cornell University Medical College. Duncan also is a member of the American Academy of Orthopaedic Surgeons, the American Association for Hand Surgery, and the American Association of Orthopaedic Executives, among other professional organizations.
Jan. 22 Celebrate the Legacy of Martin Luther King, Jr., ” The Enduring Legacy and Lessons of MLK: From Birmingham to Ferguson”
All members of the BU Medical Campus are invited to a special presentation commemorating the legacy of Rev. Martin Luther King, Jr.
Kermit A. Crawford, PhD is a forensic psychologist and associate professor of Psychiatry at BU School of Medicine. He is the Executive Director of the Massachusetts Marathon Bombing Victims/Survivors Resiliency Center and the Director of the Center for Multicultural Mental Health, providing leadership across the nation in the aftermath of disasters, ranging from Sept. 11, 2001, to the Boston Marathon bombings.
Crawford has been honored with a doctorate from Boston College, as well as a doctoral degree of humane letters from the Massachusetts School of Professional Psychology. He has a variety of peer-reviewed publications and book chapters, and is the recipient of the Commissioner’s Excellence Award, the 2012 Excellence in Diversity Training Award from APPIC, the 2012 American Psychological Association’s Minority Fellowship Program James Jones Lifetime Achievement Award and the 2014 Culturally and Linguistically Appropriate Services Individual Award. He also has made presentations on culturally competent practices in mental health at several acclaimed national organizations.
Following Dr. Crawford’s presentation, a musical performance sponsored by the Boston University Medical Campus Arts Program, will feature BMC patient Joseph Payne (vocals) and Moisès Fernández Via (piano).
Celebrate the Legacy of Martin Luther King, Jr.
- Speaker: Kermit A. Crawford, PhD
- Topic: The Enduring Legacy and Lessons of MLK: From Birmingham to Ferguson
- Date: Thursday, Jan. 22
- Time: 12:30-1:30 p.m.
- Location: Keefer Auditorium
This event is brought to you by BUSM Office of Diversity and Multicultural Affairs in collaboration with BU Goldman School of Dental Medicine Office of Diversity, BU School of Public Health, BMC Human Resources Department and the BMC Minority Recruitment Program.
Boston University School of Medicine’s Dr. Deborah Anderson and her colleagues are challenging dogma about the transmission of the human immunodeficiency virus type 1 (HIV-1). Most research has focused on infection by free viral particles, while this group proposes that HIV is also transmitted by infected cells. While inside cells, HIV is protected from antibodies and other antiviral factors, and cell-to-cell virus transmission occurs very efficiently through intercellular synapses.
The Journal of Infectious Diseases (JID) has devoted their December supplement to this important and understudied topic. The 10 articles, four from researchers at BUSM, present the case for cell-associated HIV transmission as an important element contributing to the HIV epidemic.
Anderson chides fellow researchers for not using cell-associated HIV in their transmission models: “The failure of several recent vaccine and microbicide clinical trials to prevent HIV transmission may be due in part to this oversight.”
Approximately 75 million people in the world have been infected with HIV-1 since the epidemic started over 30 years ago, mostly through sexual contact and maternal-to-child transmission. A series of vaccine and microbicide clinical trials to prevent HIV transmission have been unsuccessful, and scientists are returning to the drawing board to devise new approaches. The JID supplement advocates for new strategies that target HIV-infected cells in mucosal secretions.
The publication presents evidence that HIV-infected cells populate genital secretions from HIV-infected men and women as well as breast milk, and genetic evidence suggesting that cell-associated HIV transmission occurs in people. Various models for studying cell-associated HIV transmission and molecular targets for intervention are also presented. Finally, the efficacy of current HIV prevention strategies against cell-associated HIV transmission and opportunities for further development are described.
The collaborative team of BUSM researchers includes Drs. Deborah Anderson, Joseph Politch and Jai Marathe from the Departments of OB/GYN and Medicine, Manish Sagar from the Department of Medicine and Rahm Gummuluru from the Department of Microbiology.
They hope that these articles will help to inform and invigorate the HIV prevention field and contribute to the development of more effective vaccine, treatment, and microbicide strategies for HIV prevention.