Category Archives: Uncategorized

Research Project by Dr. Quan Lu receives support through the Blavatnik Biomedical Accelerator

Quan-Lu-copy1One of the research projects of Dr. Quan Lu, Associate Professor of Environmental Genetics and Pathophysiology, at the Harvard T.H. Chan School of Public Health, will receive support through the Blavatnik Biomedical Accelerator during the next year. His is one of twelve Harvard based projects to receive funding from this organization. Dr. Lu’s research will address the challenges associated with delivering new treatments to the tissues that need them the most by testing the ability of natural microvesicles known as ARMMs to deliver large therapeutic proteins to cells. Dr. Lu and the other projects reflect the diversity of translational biomedical research at Harvard.

To see the original article with more details of all the projects being supported by the Blavatnik Biomedical Accelerator, please click here.

 

No traffic jams in asthmatic cells

Jeffrey_Fredberg-copy1An unexpected new discovery—that, in people with asthma, the cells that line the airways in the lungs are unusually shaped and “scramble around like there’s a fire drill going on”—suggests intriguing new avenues both for basic biological research and for therapeutic interventions to fight the disease. The findings could also have important ramifications for research in other areas—notably, cancer—where the same kinds of cells play a major role.

Until now, scientists thought that epithelial cells—which line the lung’s airways as well as major cavities of the body and most organs—just sat there motionless like tiles covering the floor, or like cars jammed in traffic, said Jeffrey Fredberg, professor of bioengineering and physiology at Harvard T.H. Chan School of Public Health and one of the senior authors of the study, which was published online August 3, 2015 in Nature Materials. But the study showed that, in asthma, the opposite is true.

Images show human bronchial epithelial cells obtained from a normal donor (left) and an asthmatic donor (right).

Images show human bronchial epithelial cells obtained from a normal donor (left) and an asthmatic donor (right).

The physics of biology

The researchers decided to look at the detailed shape and movement of cells from the asthmatic airway because, according to Fredberg, a growing body of research is showing that physical forces change how cells form, grow, and behave. Given this knowledge—and the fact that no one knows what causes asthma, which afflicts more than 300 million people worldwide—it made sense to look at the shape and movement of epithelial cells, which many scientists think play a key role in the disease.

The study included lead authors Jin-Ah Park and Jae Hun Kim, research scientists in the Department of Environmental Health who study asthma, and Jeffrey M. Drazen, a pulmonologist and professor in the Department of Environmental Health, who studies “mechanotransduction” in asthma—how the bronchial constriction of asthma might trigger cell changes in the epithelium. The study also included mathematical physicists James Butler, senior lecturer on physiology in the Department of Environmental Health, and M. Lisa Manning and Max Bi at Syracuse University, as well as other colleagues from Harvard Chan School and other Harvard institutions.

 

To analyze cell movement, the researchers took time-lapse images of epithelial cells. They also produced videos that show quite vividly the differences between normal cells and asthmatic cells. The videos, shown above, show that the normal cells are nearly pentagon-shaped and are jammed—they hardly move at all—while the asthmatic cells become more spindle shaped and are unjammed—they constantly move and swirl.

To analyze the mechanical forces at work, the researchers placed layers of epithelial cells—either from normal airways or asthmatic airways—on a soft gel surface that simulates the degree of stiffness of the lung. As the cells moved, their push-pull motion caused movement in the gel as well. This gel movement then enabled the researchers to infer the mechanical forces at work among the cells.

Next steps

Now that it’s known that epithelial cells in asthmatic airways are oddly shaped and are not jammed, scientists have to figure out why it’s happening—whether it’s asthma causing the cells to unjam, or if it’s the unjamming of these cells that causes asthma.

“It’s a very big question to figure out why this particular cell shape and movement is happening,” said Park. “We know that asthma is related to genes, environment, and the interaction between the two, but asthma remains poorly understood.”

Whatever the reason, knowing more about how these cells jam and unjam is important, said Fredberg, because epithelial cells play a prominent role not just in asthma, but in all processes involving cell growth and movement—including organ development, wound healing, and, importantly, cancer. The new findings about epithelial cells open the door to new possibilities for developing drugs to fight asthma as well as other diseases—and to new research questions.

“Trying to define how cells behave, how they exert forces on each other, and how that changes what they do are big open questions,” said Fredberg. “Researchers all over the world are looking more and more at these questions. It’s very exciting.”

Karen Feldscher

— images courtesy Jeffrey Fredberg and Jin-Ah Park

For original article please click here.

Unraveling the mystery of sepsis

Rose_Lester_for-webSepsis kills more than 500,000 Americans each year, but in some ways it remains a mystery to both researchers and doctors. Lester Kobzik, professor in the Department of Environmental Health, and Rose Filoramo PhD ’17 are working together to unravel this medical mystery. (One-on-One podcast series, 7:28)

Please click here to listen to this podcast in your browser. Alternatively, you may download the podcast in mp3 format by right-clicking here (Mac: control-clicking)

Pedro Molina Selected as one of HHMI International Student Research Fellows

Pedro MolinaPedro Alberto Lamothe Molina, a BPH student in the laboratory of Dr. Bruce Walker, was selected as one of HHMI’s International Student Research Fellows. This program supports international students during their third to fifth years of graduate school in the United States, with awardees receiving $43,000 during each year of the fellowship.

To read more about the HHMI fellowship and this year’s recipients, click here.

Congrats Pedro!

 

 

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

To see original article click here

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

To see the original article click here

For more information:
Marge Dwyer

mhdwyer@hsph.harvard.edu
617.432.8416

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

To see original article click here

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.