Image courtesy Indus Hospital, Karachi, Pakistan

The Sentinel Project on Pediatric Drug-Resistant Tuberculosis, a new global partnership of researchers, caregivers and advocates that aims to develop and deploy evidence-based strategies to prevent child deaths from this treatable disease, released their first joint report on March 20, 2012. The report, Being Brave: Stories of Children with Drug-Resistant Tuberculosis, commemorates World TB Day, March 24.

In October 2011, the Department of Global Health and Social Medicine at Harvard Medical School joined forces with the National Institute for Research in Tuberculosis (Chennai, India) to convene and host this partnership. Since then, more than 140 individuals in more than 30 countries have begun to collaborate on joint research and advocacy projects.

Mercedes Becerra is one of the founders of the Sentinel Project. An HMS Associate Professor of Global Health and Social Medicine and a senior TB specialist at Partners in Health, Becerra has researched the epidemiology and treatment of TB in Lima, Peru for nearly two decades. Building on a large NIH-funded study there of the epidemiology of drug-resistant TB, and with support from Harvard University’s David Rockefeller Center for Latin American Studies, Becerra and collaborators in Lima are piloting and evaluating an intervention that aims to improve detection and treatment of children with drug-resistant tuberculosis. This will lay the groundwork for a multi-site prospective study that Becerra plans to pursue with collaborators in the Sentinel Project network in countries including Peru, India, Colombia, Pakistan, Ethiopia, Lesotho and South Africa.

This year, which marks the 40^th anniversary of the first world TB day and the 140^th anniversary of Robert Koch’s discovery of Mycobacterium tuberculosis, the bacteria which causes tuberculosis, World TB Day focuses on the impact of the illness on children.

The collection of stories released today highlights the devastating impact of drug-resistant TB on children. Even in successful cases, diagnosis and treatment of drug-resistant TB in children is lengthy and difficult. Diagnostic tools are often inaccurate and can take months to determine resistance. Without pediatric formulations of most drugs, treatment is difficult to administer.

“Thousands of children around the world die each year from this treatable disease,” says Becerra. “Our goal is zero deaths. With coordinated clinical and translational research efforts and strong community partnerships, that goal is well within our reach.”

-Jake Miller

Regina Benjamin, Surgeon General of the United States, addresses a standing-room only crowd at a panel discussion on America’s first National Prevention Strategy. Photo: Jake Miller.

Panel of community health innovators share insights

Regina Benjamin, US Surgeon General, led a panel discussion on the National Prevention Strategy, the nation’s first overarching plan to incorporate preventive health care measures into our national health policy and practice. The prevention strategy is a key element of the Affordable Care health care reform initiative.

“Health does not occur in the doctor’s office alone,” Benjamin said. “If we really want to reform health care in this country we need to prevent people from getting sick in the first place.”

The March 21 event, which occurred at a packed  auditorium at Harvard Medical School, was organized by Doctors for America and co-sponsored by the HMS Center for Primary Care and several other partner organizations.

Researchers from Harvard Medical School and Massachusetts General Hospital have developed a magnetic nanoparticle-based MRI technique for predicting whether—and when—subjects with a genetic predisposition for diabetes will develop the disease.  While done initially in mice, preliminary data show that the platform can be used in people as well, so far to distinguish patients that do or do not have pancreas inflammation.

“This research is about predicting Type-1 diabetes, and using that predictive power to figure out what is different between those who get it and those who don’t get it,” said Diane Mathis, Morton Grove-Rasmussen Professor of Immunohematology in the Department of Microbiology and Immunobiology and, along with Christophe Benoist, Morton Grove-Rasmussen Professor of Immunohematology, co-senior author of the paper. The results were published online in Nature Immunology on Feb. 26, 2012.

Non-invasive visualization of a mouse by Magnetic Resonance Imaging with a 4.7-Tesla microimaging system. Courtesy Wenxian Fu.

According to first author Wenxian Fu, a research fellow in the Mathis-Benoist lab, the group was surprised that the diagnostic window—from six to 10 weeks of age— was so early, and so brief. This shows that the progression of the disease, at least in this animal model, is determined very early in life, and that diabetes does not require an additional trigger such as a secondary infection or environmental stress, as some theoretical conceptions of diabetes have proposed.

What’s more, the researchers were able to leverage this diagnostic information to prevent diabetes in mice predisposed to it.

Invisible differences

Even within a population of genetically identical mice, all of which are predisposed to develop Type 1 diabetes, there is great variability in the course of the disease. Some 30 percent never develop diabetes; among those that do, it might develop in the first months of life, or not until six months.

Until now, when researchers wanted to study the fundamental biochemical and biophysical development of diabetes, they had to assume that all of the subjects in their study were at similar stages in the progression of the disease, even though, in reality, nearly a third of the animals would never even develop the disease—and there was no way to know which animals were part of that group. This uncertainty adds significant noise to the data.

Using the techniques developed by Mathis and Benoist’s group in a ten year collaboration with the laboratory of Ralph Weissleder, HMS professor of systems biology and radiology at MGH, Fu discovered that he could not only predict which mice would develop diabetes, but how soon.

“There’s a nice correlation between the intensity of the signal and how quickly they will develop diabetes,” Fu said.

The researchers are hopeful that the scanning method will allow scientists to study with greater accuracy and uniformity the developmental stages of this disease.

Setting their sights on inflammation

The mice in the study were injected with magnetic nanoparticles designed to accumulate only in inflamed tissues, where they are then visible by MRI. The team performed full-body scans of the subjects, but focused their attention on inflammation in the pancreas.

Fu and collaborators performed periodic scans over the course of 18 weeks, then waited until the mice were 40 weeks old to monitor for signs of diabetes. Looking at the data retrospectively, they saw a clear pattern: In mice that developed diabetes, there was increased inflammation in the pancreas between the ages of six and 10 weeks. Outside of this window, there was no difference in MRI signal between the two groups.

“It’s important to note that we could not have made this discovery without a non-invasive scanning technique, because otherwise the mice would need to be sacrificed before knowing whether they go on to develop the disease,” said, Benoist.

Once they could predict which mice would and would not become diabetic, they performed biochemical and gene expression analyses of the mice, separating cohorts of diabetic and non-diabetic mice. They identified a number of markers that correlate with diabetes development.

The researchers speculate that [in many of these cases,] increased expression of a particular gene in non-diabetic subjects conveys protection from diabetes. One of the pathways they examined was a receptor called CRIg, a molecule involved in various innate immune system activities. Injecting engineered CRIg-related molecules into mice predisposed to diabetes inhibited disease development, demonstrating the important role this pathway plays in the disease.

In an earlier study, the collaborative team confirmed that the same scanning techniques could be used to measure pancreatic inflammation in human subjects, and were able to separate non-diabetics from diabetics. The great value of this new ability is that it will permit a rapid assessment of the influence of drugs designed to clear the pancreatic inflammation. “We could use our MRI technique to get real-time data on the effectiveness of new drug therapies,” Mathis said. “The way we work now, we have to wait and wait to see if therapies are having any benefit to the patients.”

Mathis said that their technique also has the potential to be a useful tool for performing long term, longitudinal studies of the progression of diabetes in humans. Current methods of imaging the pancreas, such as high-radiation PET scans, are too dangerous to use for repeated scans.
This research was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation and the American Diabetes Association.

—Jake Miller

For more information, students may contact Christophe Benoist or Diane Mathis at cbdm@hms.harvard.edu.

Rather than hitting the ski slopes or simply basking in the lull between semesters, close to 50 Harvard undergraduates spent a week of their winter break attending a new course titled “Introduction to Clinical/Translational Research,”  offered by Harvard Catalyst | The Harvard Clinical & Translational Science Center.

Designed to introduce students to the growing field of translational research, course sessions illuminated the process by which laboratory discoveries become patient treatments. Topics included the history of clinical and translational research, trial design methods, ethics, and drug and device development, with case studies and discussion woven throughout.

Lee Nadler, HMS dean for clinical and translational research, explains the "bench to bedside" trajectory. Photo by Kerry Foley

Elliott Antman, HMS associate dean for clinical and translational research and Jim Ware, HSPH associate dean for clinical and translational science at Harvard School of Public Health, designed the course to inspire the next generation of translational researchers. “It’s important for us to encourage budding researchers to pursue this critical field,” said Antman. “There’s clearly a desire among undergraduate students to learn more about clinical and translational research opportunities.” According to Ware, “It was extremely rewarding to teach these talented and enthusiastic undergraduates.”

The four-day survey course also provided students the opportunity to interact with Harvard faculty and industry leaders. Students sought career advice and listened to stories from HMS leaders such as Jeffrey Flier, dean of the faculty of medicine at HMS, Lee Nadler, director of Harvard Catalyst and dean for clinical and translational science, and William Chin, executive dean for research at HMS.

Ashley Bach, a sophomore at Harvard College, said, “It was such a privilege to hear from leaders in the field.”  For Bach, the course confirmed that translational research is the avenue to connect her interests in science and global/public health.  Bach is concentrating her studies in neurobiology in the mind, brain, and behavior track and pursuing a secondary field in global health and health policy, hoping to incorporate translational research.

For those who were unable to attend over winter break, videos are available on Harvard Catalyst’s Education Video Library, an archive of past postgraduate education offerings.

The Education Video Library is a free resource that can be accessed by anyone with an HMS eCommons ID or Harvard PIN. It is designed as a tool for undergraduates interested in pursuing the field of clinical and translational research, recent graduates who want to accelerate their research, or Harvard employees with an interest in a broad spectrum of research topics ranging from research design and biostatistics to leadership advice and negotiation tactics. New courses are regularly added.

For some, courses get better with repeated viewings. “I could watch his lecture again and again and glean something different every time,” said Frank Maldonado, a junior at Harvard College, referring to a session by pharmaceutical leader Joshua Boger. Maldonado is studying neurobiology and working in the laboratory of Gabriel Kreiman, HMS assistant professor of ophthalmology at Children’s Hospital Boston.

To view the course “Introduction to Clinical and Translational Research,” go through the Education Video Library at Harvard Catalyst’s Postgraduate Education program website. Videos from the course can be found in the Undergraduate Offerings category under Special Events.

–Sara Galyon

Thomas S. Kupper. Image courtesy of Brigham and Women's Hospital

Now, a study by a Brigham and Women’s Hospital (BWH) research team led by Xiaodong Jiang, a research in dermatology, and Thomas S. Kupper, Chair of the BWH Department of Dermatology and the Thomas B. Fitzpatrick Professor of Dermatology at Harvard Medical School, has used a model involving a vaccinia virus infection of the skin to answer important questions about how these newly discovered cells protect us.

The study was published online in February 29, 2012 in Nature.

Jiang and Kupper used skin infection with vaccinia virus to study the relative roles of central memory T cells (T cells that circulate in the bloodstream) and resident memory T cells in protective immunity. They found that after infection, disease-specific T cells were rapidly recruited not only to the infected site, but also to all areas of skin.

They further showed that multiple additional infections at future time points led to an accumulation of even more of these resident memory T cells in the skin, and that these cells remained in the skin for long periods of time.

Finally, Jiang and Kupper showed, for the first time, that resident memory T cells were the most important protective immune cells in fighting infection-much more important than central memory T cells, which were ineffective at rapid immune protection by themselves.

“This work suggests a fundamental reassessment of how vaccines are both constructed and delivered,” said Kupper. “These results have altered the way we think about the immune system and vaccination for infectious diseases.”

Adapted from Brigham and Women’s Hospital press release.

iStock Photo

The study, funded by a 5-year, $3 million grant from the National Institute on Disability and Rehabilitation Research, involved 184 patients at 11 clinical trial sites in three countries. The patients involved were receiving inpatient rehabilitation and were in a vegetative or minimally conscious state between four and 16 weeks after traumatic brain injury. During the four-week treatment period, recovery was significantly faster among patients who were administered amantadine than those in the placebo group.

Study leader Joseph T. Giacino, HMS associate professor of physical medicine and rehabilitation and director of rehabilitation neuropsychology at Spaulding Rehabilitation Hospital, said, “The results of this study provide convincing evidence that it is possible to increase the speed of recovery from severe traumatic brain injury when treatment is initiated within four months of onset. These findings engender optimism for a medical condition that is often viewed as untreatable.”

For the full release, visit the website of Spaulding Rehabilitation Hospital.

Amy Wagers. Photo by B.D. Colen

The appointment is supported by a second significant gift from the Glenn Foundation for Medical Research to Harvard Medical School. Harvard was one of the first institutions to receive funding from the foundation, whose mission is to grow a community of top researchers in the world dedicated to studying the mechanisms of aging in an effort to extend the healthy productive years of life.

“I’m excited about collaborating with my colleagues at the Glenn Labs,” Wagers said. “Understanding the mechanics of aging is at the core of so many biological phenomena and crucial for our understanding of both health and disease. I’m delighted that the Foundation has provided me this fantastic opportunity to work more closely with some of the world’s best scientists is the aging field.”

“Amy is an extraordinarily talented scientist,” said William Chin, HMS executive dean for research. “Her work in the area of stem cells speaks for itself. Thanks to the Foundation’s support she will no doubt contribute exciting research to Harvard Medical School’s efforts in the biology of aging with a focus on muscle”

Work in the Wagers lab focuses on mechanisms that regulate the migration, expansion, and regenerative potential of blood- and muscle-forming stem cells, work relevant to conditions from leukemia to muscular dystrophy. She has investigated why the regenerative potential of stem cells typically declines with age, impairing the ability of aged tissues to recover after injury.  As a member of the Glenn Labs, Wagers and her team will pursue a new lead focused on age-related changes in blood-circulating cells and factors and novel strategies to reverse age-related loss of stem cell activity and restore robust regenerative function.

Wagers joined the HMS faculty in 2004, after completing her PhD in immunology and microbial pathogenesis at Northwestern University and a postdoctoral fellowship in the laboratory of Irving Weissman at Stanford School of Medicine. She is a recipient of the Burroughs Wellcome Fund Career Award in the Biomedical Sciences, the W.M. Keck Distinguished Young Scholars Award, the Smith Family New Investigator Award, and an Early Career Scientist Award from the Howard Hughes Medical Institute.

The Harvard Medical School Center for Primary Care today announced the formation of an Academic Innovations Collaborative that will provide more than $10 million in resources over two years to nine Harvard Medical School affiliated hospital-based primary care teaching practices and eight affiliated community health practice partners. The Center will award more than $5 million in grants to the selected affiliates who will directly match the funds, totaling more than $10 million.

The goal is to create a platform for training future health care leaders by transforming Harvard-affiliated primary care teaching practices through innovation in four key areas: team-based primary care, management and prevention of chronic illnesses, management of patients with multiple illnesses, and patient empowerment and behavior change.

Photo by Joel Haskell

“It is well known, and has been well documented, that primary care in the United States is in crisis,” said David Bates, one of three co-interim directors of the Center for Primary Care. “If the U.S. is to have higher quality care at lower costs, primary care models will have to change, and this initiative provides the local grantees the chance to innovate solutions.”

The grantees are:

• Bowdoin Street Health Center, Healthcare Associates, The Dimock Center (Beth Israel Deaconess Medical Center affiliates)
• Brookside Community Health Center, The Phyllis Jen Center for Primary Care, Southern Jamaica Plain Health Center (Brigham & Women’s Hospital affiliates)
• Malden Family Medicine Center, Primary Care Center, Somerville Hospital Primary Care, Windsor Street Health Center (Cambridge Health Alliance affiliates)
• Children’s Hospital Primary Care Center, Martha Eliot Health Center (Children’s Hospital Boston affiliates)
• Primary Care Center, The Sagov Center for Family Medicine (Mount Auburn Hospital affiliates)
• Chelsea Health Center Adult Medicine and Pediatrics, Internal Medicine Associates, Mass General Pediatrics (Massachusetts General Hospital affiliates)

These practices serve a broad mix of patients, many of whom live in low-income communities in Boston and involve a variety of primary care disciplines including internal medicine, pediatrics and family medicine.

More than 275,000 patients will benefit from this investment. Through the Collaborative, these Harvard-affiliated clinical sites will join forces to develop best practices for transforming systems of care, improving value in health care, and creating a stronger platform for health care education.

These grants also will highlight the benefits of interdisciplinary teamwork in which patients, doctors, nurses, social workers, pharmacists and other allied health professionals learn from and support each other in innovative ways to improve patient care.

“Harvard Medical School, the Center for Primary Care and Harvard’s affiliated clinical entities share a mutual commitment to transforming care delivery within their networks to benefit patients, clinicians, trainees and society,” said Jeffrey Flier, dean of the faculty of medicine at Harvard Medical School.

“A partnership of this scope is without precedent in our community and could provide solutions to our country’s most pressing health care problems, solutions that we hope will make our state health care system, and ultimately our national health care system, among the best in the world,” said Center for Primary Care Interim Co-Director Russell Phillips.

“This collaboration is designed to engage medical students, trainees and affiliated medical faculty and staff as leaders in care redesign,” said Andrew Ellner, interim co-director. “It is as much an educational innovation as it is an effort to help catalyze change in primary care delivery on a broad scale.”

Despite increasing demands on primary care and the development of new practice models nationally, the pace of change has been incremental. The stress imposed by cost pressures, rapid changes in payment models and cuts to federal funding for research at academic medical centers has made it difficult to provide the needed resources and attention to primary care. The Center’s initiative will help expedite transformation as well as build strong connections between affiliated community health centers and community practices.

“This collaborative is a tremendous opportunity for the Center to fortify relationships between academic hospital-based practices and community health centers,” said Myechia Minter-Jordan, chief medical officer at The Dimock Center. “We know that community health is at the nexus of truly transformative health care. These grants will provide Harvard Medical School faculty, trainees and staff with unique opportunities to learn from innovative community health environments.”

To view the complete list of grantees and more information, visit: http://primarycare.hms.harvard.edu/what-we-do/program-primary-care-innovation/academic-innovations-collaborative

Harvard Medical School Center for Primary Care’s mission is to transform care by embracing service, wellness, patient and community empowerment, and innovation in systems for care and training at Harvard, academic health centers, and beyond. For more information visit http://primarycare.hms.harvard.edu/

Magnetic fields span the globe, but few organisms can sense them. In fact, how these few magnetically-aware organisms, such as butterflies and bees, gain their magnetism remains one of biology’s unsolved mysteries.

Now, using the tools of synthetic biology, researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School have induced magnetism to a non-magnetic organism: yeast. And because they used a common cell pathway, the findings suggests that such magnetism could be achieved in many types of cells for a variety of industrial, medical and research applications. The findings appear in the Feb. 28 issue of PLoS Biology.

“Magnetism in nature is a unique and mysterious biological function that very few living systems exploit,” said principal investigator Pam Silver, the Elliott T. And Onie H. Adams Professor of Biochemistry and Systems Biology at HMS. “So while magnetic yeast may sound like a curiosity, it’s actually a highly significant first step toward harnessing this natural phenomenon and applying it to all sorts of important practical purposes.”

Silver’s team took an engineering approach. First author Keiji Nishida, research fellow in systems biology at HMS, first grew yeast in a medium containing iron. The yeast cells took in the element and stored it inside cellular containers called vacuoles. By placing a magnet under the culture, Nishida saw that the yeast cells had become slightly magnetic.

“We used the design, build, test cycle of engineers,” said Silver, who is also a core faculty member at the Wyss Institute. “It worked, but we wanted to make it better. That’s where we employ synthetic biology.”

The tools of synthetic biology manipulate natural biological instructions, such as genes or cellular signals. Since the instructions that make up the resulting biological organism are not found together in nature, the new biology is considered “synthetic.”

To improve the magnetized yeast, Nishida employed two tools of synthetic biology: He introduced one protein, ferritin, which joins with iron and prevents it from becoming toxic to the cell. He also knocked down the expression of another protein, ccc1, which carries the iron into the cell’s vacuoles. “The cells we built ended up forming magnetic iron crystals in their mitochondria, not a place yeast normally put iron,” Nishida said. They also exhibited approximately three-fold higher levels of magnetism than wild-types supplemented with iron.

Silver and Nishida also searched for genes that might contribute to magnetism. They screened collections of yeast with different genes knocked out for mutants that affect magnetism. They focused on iron homeostasis genes, which regulate how cells store iron, and oxidative stress genes, which regulate how cells use iron.

They zeroed in on one gene: TCO89. Increased levels dialed up magnetism, while decreased levels dialed it down. Further experiments showed that, to achieve increased magnetism, the TCO89 protein must interact with TORC1, a protein complex that regulates cell metabolism. TORC1 is highly conserved, meaning its form and function is similar from yeast to more advanced, and even human cells. “This suggests that other cells might potentially be similarly magnetized,” Silver said.

Such a capability could have many applications. In an industrial setting, magnetization could be a means of isolating cells during a process. “There’s often a need to suck out cells that are making a product or contaminating a bioprocessor,” Silver said.

Tissue engineers could guide cells magnetically to layer themselves on a scaffold. And with the application of additional synthetic biology tools, clinicians may one day use cells engineered to respond to a magnetic field by growing or healing, or implant magnetic stem cells that can be tracked with magnetic resonance imaging.

“This study is an example of the facility with which you can engineer biology,” said Silver, who imagines that a similar approach could be used to mimic other unusual natural phenomena. “Biology is where organic chemistry was about 80 years ago. Now we know enough about biology that it could take over from chemistry.”

The synthetic yeast may also aid in the study of magnetism in nature. Although Nishida and Silver may not be able to study naturally magnetic bacteria directly — it doesn’t do well in the lab — “we have our own private evolvable system,” Silver said. “It may or may not be artificial, but it is a starting point that allows us to study the evolvability of the phenomenon.”

—Elizabeth Dougherty

Rwanda and Harvard Medical School have teamed up to empower a new generation of health leaders to bridge the gap between knowledge and practice in global health care delivery.

On Feb. 19, 41 faculty and students from Burundi, Haiti, Rwanda, and the United States gathered at the Rwinkwavu Hospital Training Center to launch an immersive five-day course in global health delivery, led by HMS faculty in conjunction with the Ministry of Health of Rwanda.

Joia Mukerjee, Associate Professor of Global Health and Social Medicine at HMS and Sabin Nsanzimana, Head of HIV AIDS, STIs and other Blood Borne Infections Division/ Rwanda Bio-Medical Center at the inaugural Global Health Delivery course. Photo by Claire Wagner.

Dr. Agnès Binagwaho, Rwanda’s minister of health and a senior lecturer at Harvard Medical School, called the course an example of “authentic and effective capacity building for the health sector, meant to break the vicious cycle of poverty and disease.”

The course, Global Health Delivery in Rwanda, utilizes a novel educational framework to address the global burden of disease and its complex inter-related social determinants. In a rigorous and stimulating scholarly environment, participants will:

• analyze case studies from around the world that detail the design, operations and outcomes of projects to improve health care delivery in resource-poor settings;
• engage in deep discussions about how epidemiology, culture, economics, and politics inform the design and performance of global public health programs; and
• conduct field visits to health care delivery sites in rural Kayonza District to observe and analyze management principles.

“To build a discipline of global health, research universities need to work with the real experts: those who deliver services,” said Paul Farmer, Koloktrones University Professor at Harvard, chair of the HMS Department of Global Health and Social Medicine and a member of the course faculty. “It’s an honor to teach and also to learn here in Rwanda.”

The course will be offered twice per year, with the goal of enrolling all central-level leaders in the Ministry of Health, as well as program managers and students from around the world. New case studies will be developed to disseminate innovations in Rwanda’s health sector and cultivate Rwandan leaders in the emerging discipline of global health delivery.

“I am thrilled to learn about a new way of conceptualizing service delivery,” said Jean de Dieu Ngirabega, director general of clinical services in Rwanda’s health ministry and a student in the course.

The non-governmental organization Partners In Health / Inshuti Mu Buzima, which collaborates closely with the HMS Department of Global Health and Social Medicine, provided logistical support and funding for the pilot version of the course.

—Department of Global Health and Social Medicine