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Coordinating against malaria

Malaria-conference-6_15_GazetteIn December 1974, the last cases of smallpox in its deadliest form were confined to a Bangladesh slum. Public health workers were preparing the scourge’s coup de grâce, but were horrified when government bulldozers arrived, scattering 50,000 people across the countryside.

The ill-timed demolition of the slum spread the disease throughout the country, sparking outbreaks in several locations and extending the suffering and death from smallpox for another 10 months. The chapter illustrates the difficulty of ridding the world of a human disease, even one down to its last few cases, and how important it is that eradication efforts include whole societies.

A group of scientists, government officials, nonprofit leaders, malaria-control program directors, and others gathered at Harvard Business School last week sought to draw lessons from past eradication efforts as they embarked on a weeklong leadership program focused on eradicating another age-old scourge: malaria.

Though the program’s 56 participants have been involved in different aspects of the fight against malaria for years, Dyann Wirth, the Richard Pearson Strong Professor of Infectious Disease, chair of the Harvard T.H. Chan School of Public Health’s Department of Immunology and Infectious Diseases, and director of the Harvard Malaria Initiative, said that shifting officials’ focus from control and treatment of the disease to eradication requires shifting strategies as well.

“We want to give them the overview of the problem of malaria, all the way from the genes to the globe,” Wirth said. “Many of them work [on malaria]… and although most in the room probably have had this material at one point, they haven’t thought about it in this lens of elimination/eradication, which is quite different from treating symptomatic cases or preventing symptomatic cases.”

Smallpox stands as the only human disease successfully stamped out, so the intensive leadership program kicked off with a talk by Myron Levine, a University of Maryland professor who was a World Health Organization (WHO) consultant in Bangladesh during the final days battling smallpox’s most virulent strain, variola major. It would take another two years to eradicate a less deadly strain, variola minor, though there were laboratory-related cases in 1978.

Global anti-malaria efforts have made significant progress, Wirth said, with cases down 30 percent and deaths down 50 percent over the last 15 years. Even with that decline, however, malaria is far from on the ropes. In 2013 alone, there were an estimated 198,000,000 cases and 584,000 deaths, according to the WHO.

The leadership development program, called “Science of Eradication: Malaria 2015,” provided a broad overview, including the disease’s basic biology, challenges facing vaccine development, social determinants of transmission, economic advantages to eradication, the importance of communication, and ways to integrate eradication into existing control efforts.

The program is a partnership of organizations including Harvard, the Barcelona Institute for Global Health, and the Swiss Tropical and Public Health Institute, with funding from several other organizations.

Malaria may not become the second human disease to be wiped out. That’s because efforts targeting two other ailments, polio and guinea worm disease (which is caused by a tropical parasite), are on the verge of success, with the number of cases reduced to just a handful.

Elizabeth Juma, a research scientist with the Kenya Medical Research Institute, said malaria remains a major health problem there and is the biggest cause of death for children under 5. It’s widespread in the nation’s agricultural areas, making it an issue in agricultural production. Juma said she decided to attend the session to understand how the goal of elimination in Kenya would affect ongoing control efforts.

“The global goals have changed,” Juma said. “We now have to think of malaria elimination. [I decided to attend] to just find out … what should we do about a country such as ours, where this has been attempted in the past, and how best can we think about the endgame, which is elimination.”

Ndukwe Ukoha, a malaria specialist for the Health and Strategy Delivery Foundation, a Nigerian nonprofit that provides technical assistance to the government on health issues, said malaria is also a major public health concern in Nigeria. As Africa’s most populous country, with 184 million people, efforts to reduce malaria there will have an impact on the global disease burden, Ukoha said.

“We are presently controlling malaria in Nigeria, [but] we also need to look at new ways of doing things, new ways of developing more effective tools, because … presently there are issues around resistance and also health system issues,” Ukoha said. “So this kind of forum provides an avenue to talk about these, and even learn from countries where they have successfully achieved high success.”

By Alvin Powell, Harvard Staff Writer

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New tool identifies novel compound targeting causes of type 2 diabetes

Gokhan_Hotamisligil-copy1A new drug screening technology developed at the Harvard T.H. Chan School of Public Health has identified a new potential anti-diabetes compound—and a powerful way to quickly test whether other molecules can have a positive effect on a critical molecular pathway believed to be central to diseases ranging from diabetes to retinitis pigmentosa, cystic fibrosis, Huntington’s disease, and Alzheimer’s.

The study appears in the June 17, 2015 issue of Science Translational Medicine. (The animation at the top of the page depicts how dysfunction in the endoplasmic reticulum leads to diabetes.)

The compound, which the authors have called azoramide*, works by focusing on an organelle called the endoplasmic reticulum (ER). The ER is a tubular network within all cells where many key molecular building blocks of glucose metabolism, such as lipids and proteins, are synthesized. When someone is obese, the ER in metabolic tissues such as the liver, fat, and pancreas can no longer keep up with the demand for protein and lipid production. This results in ER stress which contributes to cellular dysfunction and the development of insulin resistance. Insulin resistance in turn makes it difficult for the body to process glucose —high blood sugar and type 2 diabetes result, as well as a cascade of other cellular malfunctions that can lead to heart and blood vessel damage.

“While we and others had previously discovered the central role that ER stress plays in diabetes and metabolic disease, efforts to translate that knowledge into clinically effective ways to improve ER function have had limited success so far,” says the study’s senior author, Gökhan S. Hotamisligil, chair of the Department of Genetics and Complex Diseases and the Sabri Ülker Center at Harvard T.H. Chan School of Public Health. Lead authors were current and former Hotamisligil lab members Suneng Fu, Abdullah Yalcin, and Grace Yankun Lee.

The study describes the development of two complementary assays that allow scientists to directly monitor ER function in live cellular systems in culture in the lab. This screening system enables measurement of the amount of chaperones, molecules that patrol and promote ER function, as well as the capacity of the ER to properly fold proteins into their three-dimensional shapes. Using this technique, they showed that azoramide uniquely improved both of these aspects of ER function. In further mechanistic work, they also demonstrated that azoramide could protect cells from death and dysfunction in multiple models of ER stress.

The researchers next tested whether azoramide would be effective in mouse models of obesity and type 2 diabetes, and determined that it greatly improved blood glucose levels by improving both the function of insulin-producing beta cells and increasing the ability of peripheral tissues to sense insulin. The next phase of this research would be to test this compound, or others that work in a similar manner, in human clinical trials.

In another aspect of the paper’s research the scientists determined that azoramide could potentially protect retinal cells from the genetic mutation that leads to ER stress and ultimately vision loss in one type of the disease retinitis pigmentosa.

“These results show the broad potential for azoramide or drugs with similar functions targeted at the endoplasmic reticulum,” said Hotamisligil. “ER dysfunction is implicated in many other disease processes such as cystic fibrosis, Huntington’s disease, and Alzheimer’s—which makes this novel screening strategy an exciting new tool that can be applied by multiple labs to discover new drug candidates for diseases that are linked to ER stress.”

Other Harvard Chan School authors included Ping Li, Jason Fan, Ana Paula Arruda, Benedicte M. Pers, Mustafa Yilmaz, and Kosei Eguchi.

*Azoramide is an existing compound , the complete name of which is N-{2-[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]ethyl} butanamide.

This work was supported in part by a grant from the Juvenile Diabetes Research Foundation (17-2012-346) to Hotamisligil.

“Phenotypic assays identify azoramide, a small molecule modulator of the unfolded protein response with anti-diabetic activity,” Suneng Fu, Abdullah Yalcin, Grace Y. Lee, Ping Li, Jason Fan, Ana Paula Arruda, Benedicte M. Pers, Mustafa Yilmaz, Kosei Eguchi, Gökhan S. Hotamisligil, Science Translational Medicine, June 17, 2015 DOI: 10.1126/scitranslmed.aaa9134

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Marge Dwyer

animation: Craig LaPlante

Chih-Hao Lee Promoted to Tenured Professor

Chi-Hao_Lee-copy1Please join the Harvard Chan community in warmly congratulating Chih-Hao Lee on his promotion to tenured professor in the Department of Genetics and Complex Diseases at the Harvard T.H. Chan School of Public Health.Dr. Lee has focused his research in the field of metabolic disease and lipid metabolism, and has succeeded in becoming a leading expert in understanding the connections between metabolism and inflammation, with numerous influential publications in the highest caliber journals. Dr. Lee was the first to demonstrate that Peroxisome proliferator-activated receptor -delta (PPAR-delta) modulates the inflammatory state of macrophages, thus identifying this receptor as a potential therapeutic target to limit cardiovascular disease. His focus on coordinated control of metabolism and inflammation through PPAR-delta biology and its nodal network represented a unique niche where he displayed thoughtful and focused leadership within a much broader field. Dr. Lee’s recent work addressing the interaction of the immune system and metabolism based on inter-organ signaling between the liver and skeletal muscle has established him as an innovator with a steep upward trajectory in both scholarly output and impact.

Dr. Lee received the BS degree in chemical engineering at National Tsing-Hua University, Taiwan, in 1989. After serving in the military, Dr. Lee went on to receive a PhD in Pharmacology from the University of Minnesota, Minneapolis in 1999. As a doctoral student, in 1998, Dr. Lee was presented with the Bacaner Research Award for excellence in creative research. Upon completion of his degree, he spent five years in postdoctoral training in Molecular Physiology at the Salk Institute for Biological Studies. In 2004 he joined the Harvard School of Public Health in the Department of Genetics and Complex Diseases as Assistant Professor. Dr. Lee received the William F. Milton Fund Award in 2005 and the Scientist Development Grant awarded by the American Heart Association in 2006. In 2010, Dr. Lee was promoted to Associate Professor of Genetics and Complex Diseases at the School. He was honored with the Mentoring Award by the graduating class of 2011. In 2012, Dr. Lee received the Armen H. Tashjian Jr. Award for Excellence in Endocrine Research.

On behalf of the School and the faculty, I congratulate Dr. Lee on his promotion and wish him continued success in his career at the Harvard T.H. Chan School of Public Health.

Best wishes,

David Hunter
Dean for Academic Affairs

A bench scientist with a passion for the environment

PeterWagner-470x313On a Friday afternoon in May, Peter Wagner was about to give his dissertation defense. Quan Lu, associate professor of environmental genetics and pathophysiology—introducing Peter before a group of about 50 of his fellow students, faculty, friends, and family—flashed an on-screen photo of Peter as a young boy with a snake draped around his neck. Then came photos of Peter outdoors—in mountains, near lakes, under blue skies.

The pictures showcased Peter’s deep interest in the environment, which—along with his background in bench science—led him in 2010 to Lu’s lab at Harvard T.H. Chan School of Public Health, where he studied the brain’s molecular response to lead exposure. This May, Peter will graduate with a PhD in biological sciences in public health.

“I consider Peter the ideal student. He’s smart, hardworking, and passionate about what he does,” said Lu.

Seminal moment

In 8th grade, as a reporter for his middle school newspaper at the International School of Brussels, in Belgium, Peter interviewed Jane Goodall—a world expert on chimpanzees and an ardent conservationist—who was visiting the school. “It was a magical and seminal moment in which the environment suddenly became very important to me,” he said. When Peter’s father, a U.S. diplomat, was transferred and the family moved to Germany, Peter found that his new school—the Berlin-Brandenburg International School—didn’t have an environmental club, so he started one himself.

Peter went on to study environmental biology at Columbia University in New York. While there, he discovered a penchant for lab work while working on his senior thesis, on bacteria in soil that can change the chemical form of arsenic, in the lab of Brian Mailloux. After graduation he spent two years in Finland—where his mother is from and where he was born—as a research assistant in the lab of Leena Peltonen-Palotie, a world-renowned geneticist, at the Institute for Molecular Medicine Finland in Helsinki. He learned much about population genetics and analytical methods. But he was looking for a way to combine his environmental background from Columbia with the genomics he learned in Finland—and that led him to Harvard Chan School.

“The School is probably the only place in the world where you can unify laboratory environmental exposures and human population genetics,” said Peter. He cited the value of being able to use data from the epidemiological studies managed by David Christiani, Elkan Blout Professor of Environmental Genetics, as well as the opportunity to participate in cutting-edge science in Lu’s lab.

Looking at lead

At his dissertation defense, Peter outlined some of the well-known negative effects of lead on children’s development, such as lower IQs, increases in ADHD, and increased antisocial or delinquent behavior. “Even low amounts of lead can cause these effects,” Peter said. Although the danger of lead is well known, it remains an environmental problem. In the U.S., for example, although lead in paint was banned in 1978, and lead in gasoline was mostly phased out in the 1980s, there is still lead in the environment. In urban areas in particular, lead-based paint flakes off windows and gets into household dust. In Guiyu, China, a town with a large electronic waste recycling plant, children living nearby have significantly higher blood lead levels than those living in a neighboring town.

Peter has researched the impact of lead on the brain from various angles. In the lab, he has looked at the genomic impact of lead on human neural stem cells in the brain. He has also looked at epidemiological data from 465 mother-child pairs participating in the ELEMENT (Early Life Exposure in Mexico to Environmental Toxicants) cohort in Mexico City, where people are exposed to lead from smog and lead glazes on dishes. Data from that cohort included lead levels in the children’s blood over time as well as information on their mental and psychomotor development.

Peter’s research suggests that some people have a genetic variant that actually helps protect them against lead’s harmful effects. This discovery, he said, “could help us better understand the body’s innate defenses to lead, and perhaps we could target those defenses so as to improve children’s outcomes when they’re exposed to lead.”

In the community—and beyond

During his time at Harvard Chan, Peter has been a coordinator for the Roxbury Prep Tutoring Program run by the School’s Office of Diversity and Inclusion. Through the program, Harvard Chan students tutor students at Roxbury Prep Charter School, a middle school in nearby Mission Hill, in math and science. “Everybody gets a lot out of it,” he said.

After graduation, Peter will work as a life sciences consultant at a small company in Boston. Now that he’s preparing to graduate, he offers a scientist’s perspective on the benefits of studying at the School. “Often times people think it’s strange that we do so much basic science at the School of Public Health, but it’s really a wonderful environment to do it in,” he said. “Everybody here wants to try and fix some kind of large public health problem. It’s so easy to get tunnel vision when you’re in a science lab and working at the bench. Being at a School where you’re looking at health problems from every angle imaginable really helps you keep a fresh perspective.”

— Karen Feldscher

 photo: Emily Cuccarese

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Tobias Walther chosen as HHMI Investigator

Tobias_WaltherCongratulations to Tobias Walter, who was chosen from a group of 894 eligible applicants to be one of 26 newly-minted Howard Hughes Medical Institute (HHMI) Investigators!  HHMI investigators will receive the flexible support necessary to move their research in creative new directions. The initiative represents an investment in basic biomedical research of $153 million over the next five years.

The scientists represent 19 institutions from across the United States. The new HHMI investigators – which include three current HHMI early career scientists — were selected for their individual scientific excellence.

HHMI will provide each investigator with his or her full salary, benefits, and a research budget over their initial five-year appointment. The Institute will also cover other expenses, including research space and the purchase of critical equipment. Their appointment may be renewed for additional five-year terms, each contingent on a successful scientific review.

HHMI encourages its investigators to push their research fields into new areas of inquiry. By employing scientists as HHMI investigators — rather than awarding them research grants — the Institute is guided by the principle of “people, not projects.” HHMI investigators have the freedom to explore and, if necessary, to change direction in their research. Moreover, they have support to follow their ideas through to fruition — even if that process takes many years.

Why Public Health? Selasi Dankwa

Selasi-DankwaIn our series “Why Public Health?” we ask Harvard T.H. Chan School of Public Health students and alumni to talk about what drew them to the field. Selasi Dankwa, PhD ’15, took an early interest in infectious diseases like malaria and cholera, a part of everyday life in her home country of Ghana. At Harvard Chan School, she studies the parasites that cause malaria infection. Now she envisions taking her skills and knowledge and returning to Ghana to “make a difference.”

See the video here: Why Public Health? Selasi Dankwa

Malaria parasite’s essential doorway into red blood cells illuminated

malaria Manoj

Malaria parasites infect red blood cells cultured from stem cells

Boston, MA – Researchers at Harvard T. H. Chan School of Public Health and the Broad Institute have identified a protein on the surface of human red blood cells that serves as an essential entry point for invasion by the malaria parasite. The presence of this protein, called CD55, was found to be critical to the Plasmodium falciparum parasite’s ability to attach itself to the red blood cell surface during invasion. This discovery opens up a promising new avenue for the development of therapies to treat and prevent malaria.

Plasmodium falciparum malaria parasites have evolved several key-like molecules to enter into human red blood cells through different door-like host receptors. Hence, if one red blood cell door is blocked, the parasite finds another way to enter,” said senior author Manoj Duraisingh, John LaPorte Given Professor of Immunology and Infectious Diseases at Harvard Chan. “We have now identified an essential host factor which when removed prevents all parasite strains from entering red blood cells.”

The five-year study was carried out in collaboration with labs at Harvard Medical School and the Broad Institute. It appears online May 7, 2015 in Science.

Severe malaria is one of the leading causes of mortality among children globally. During infection, parasites invade and replicate within red blood cells. With resistance to malaria drugs increasing, researchers are desperate to find new ways to prevent and treat the disease.

Lead author Elizabeth Egan, research fellow in the Department of Immunology and Infectious Diseases at Harvard Chan and instructor in pediatrics at Boston Children’s Hospital, and colleagues developed a new technique to tap into a relatively unexplored area — identifying characteristics of a host red blood cell that make it susceptible to the parasites. Red blood cells are difficult targets for such efforts as they lack a nucleus, which makes genetic manipulation impossible.

The researchers transformed stem cells into red blood cells, which allowed them to conduct a genetic screen for host determinants of P. falciparum infection. They found that malaria parasites failed to attach properly to the surface of red blood cells that lacked CD55. The protein was required for invasion in all tested strains of the parasite, including those developed in a laboratory as well as those isolated from patients, making it a primary candidate for intervention.

“The discovery of CD55 as an essential host factor for P. falciparum raises the intriguing possibility of host-directed therapeutics for malaria, as is used in HIV,” said Egan. “CD55 also gives us a hook with which to search for new parasite proteins important for invasion, which could serve as vaccine targets.”

This study was supported by a Gates Foundation Grand Challenges Exploration Award OPP1035276 (M.T.D.), National Institutes of Health (NIH) grant R01AI091787 (M.T.D.), a Pediatric Scientist Development Program Fellowship from the Eunice Kennedy Shriver National Institute of Child Health and Human Development K12-HD000850 (E.S.E), NIH grant K08 1K08AI103034-01A1 (E.S.E.), Boston Children’s Hospital Faculty Development Award (E.S.E.), NIH grant K01DK098285 (J.A.P.), and the Cambridge Biomedical Research Center, UK (M.P.W. and L.V.N.).

“A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum invasion,” Elizabeth S. Egan, Rays H.Y. Jiang, Mischka A. Moechtar, Natasha S. Barteneva, Michael P. Weekes, Luis V. Nobre, Steven P. Gygi, Joao A. Paulo, Charles Frantzreb, Yoshihiko Tani, Junko Takahashi, Seishi Watanabe, Jonathan Goldberg, Aditya S. Paul, Carlo Brugnara, David E. Root, Roger C. Wiegand, John G. Doench, Manoj T. Duraisingh, Science, online May 7, 2015

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Todd Datz

World Malaria Day forum explores public-private partnerships

Malaria ForumThe global community has made gains in fighting malaria, but those advances are tenuous and multi-sector partnerships are needed to eradicate the disease. That was the consensus among experts in the field who gathered at a forum co-hosted by Harvard’s Defeating Malaria initiative  on April 24 to mark World Malaria Day. The event, Partnerships for Malaria Elimination: Lessons and Opportunities, focused on the need to build partnerships between governments, academic researchers, and the private sector.

According to the World Health Organization, there were an estimated 198 million malaria cases in 2013 and an estimated 584,000 deaths. In a video message to the audience at the Joseph B. Martin Conference Center, Ray Chambers, the United Nation’s Secretary-General’s Special Envoy for Malaria, said that progress has been made in fighting the disease: Since 2000, there has been a 58% decrease in child deaths from malaria in Africa. Chambers said more gains are on the horizon.

“Today 55 countries are on target to reduce malaria incidences by 75% by the end of this year, and 26 countries are on a clear path towards elimination,” he said, adding that cooperation at multiple levels will make that possible. “Partnerships have helped drive innovation, improve measurement, and provide the management expertise that strengthens our work. They hold the key to new solutions and new technology.”

Dyann Wirth, Richard Pearson Strong Professor of Infectious Diseases and Chair, Department of Immunology and Infectious Diseases at Harvard T.H. Chan School of Public Health, said that type of holistic approach has driven the work of the Defeating Malaria initiative since its inception in 2011.

“We brought together individuals from across the spectrum of the malaria world, and across Harvard, trying to understand the fundamental aspects of this disease from its biology and transmission, all the way through the social, behavioral, and policy [components] to develop tools to attack the problem.”

Wirth moderated a panel that focused on the unique challenges of providing those tools and interventions in faith-based communities, where there can be tension between traditional healers and technologically focused medical personnel. Panelists discussed the efforts of the NetsforLife project, a partnership with the Episcopal Relief & Development organization, which has provided more than 22 million insecticide-treated mosquito nets across Africa.

Wirth said that the project is an effective convergence of a faith-based approach with a more business-oriented method, bringing a different approach to malaria control than organizations with a medical or health delivery background.  Wirth pointed out that it is a strategy that relies on cooperation and takes into account the multiple factors beyond medical treatment that can affect malaria control efforts.  She believes this community-based approach can help reduce the resistance to those new initiatives.  “Education and knowledge backed up by evidence allows people to see and actually evaluate [interventions] for themselves.”

In addition to implementation of malaria control measures, forum attendees also heard about various technological advances that could allow for more rapid diagnosis of the disease.

The Corporate Alliance for Malaria in Africa and GBCHealth co-sponsored the event.

Curtis Huttenhower wins top junior faculty award in bioinformatics

curtis-huttenhower-nicola-segata-release-copy1Curtis Huttenhower, associate professor of computational biology and bioinformatics, has been named winner of the 2015 Overton Prize from the International Society for Computational Biology. The prize recognizes early or mid-career scientists who are emerging leaders in computational biology and bioinformatics for their accomplishments in research, education, and service.

Huttenhower was chosen for his groundbreaking research on microbial communities, with a focus on the human microbiome. He has worked on developing novel computational tools to analyze the large, complex datasets associated with microbial communities and on the National Institutes of Health Microbiome Project. His research has provided new insights into how microbial communities impact human health and disease.

Huttenhower’s research potential has previously been recognized through two other awards: the Presidential Early Career Award for Scientists and Engineers, and a National Science Foundation Career Award.