Case Studies

Dana-Farber Cancer Institute

Unleashing the Potential of the Immune System

On September 4, 2014, the Food and Drug Administration approved a new type of immunotherapy drug that will provide a much-needed option for patients with advanced or inoperable melanoma who no longer respond to other drugs – including the well-established immunotherapy agent ipilimumab (Yervoy).

The newly approved drug, pembrolizumab, will be marketed under the name  Keytruda. Based on impressive results in clinical trials at Dana-Farber Cancer Institute and elsewhere, the FDA had designated pembrolizumab a “breakthrough therapy” and placed it on a fast track for approval.

“This drug is exciting because of its really striking response rate and good indications that these responses are durable” for a least a year, says Patrick Ott, MD, PhD, clinical director of the Center for Immuno-Oncology at Dana-Farber.  “And it is very well tolerated, with very manageable side effects,” he adds.

Both Keytruda and Yervoy unleash the search-and-destroy power of the body’s immune system against cancer cells. These drugs, as well as others in clinical trials, are arriving on the crest of a new wave of immunotherapy research in which Dana-Farber scientists have played a prominent role.

The approval of Keytruda marks a first in the United States for a new class of immunotherapy drugs that block the PD-1 protein, which is commandeered by melanoma and other cancers to avoid attack by the body’s immune system.

PD-1 works with a pair of partner molecules, PD-L1 and PD-L2, to protect normal cells from being mistakenly harmed by immune soldier cells. Many cancers exploit this PD-1 pathway to hide from the immune system, but the PD-1/PD-L1 relationship was unknown until it was discovered at Dana-Farber Cancer Institute in 2004 by Gordon Freeman, PhD, (above) and colleagues engaged in basic research.

This discovery launched an entire field of immunotherapy research, which is now poised to open up a whole new era of targeted treatments with fewer side effects. PD-1 inhibitor drugs are in the pipeline for a wide range of cancers including lung, kidney, neurologic, sarcoma, head and neck, lymphoma, multiple myeloma, and assorted blood cancers, all of which are in clinical or pre-clinical trials at Dana-Farber.

Basic research, which leads to this kind of game-changing discovery in cancer science and medicine, is among the institutional priorities made possible at Dana-Farber Cancer Institute through the unrestricted gifts of the Monell Foundation.

Learn more about Dana-Farber’s pioneering research into the PD-1 immune pathway.

Harvard T.H. Chan School of Public Health

HSPH pairs with refugee public health students to create a healthier Burma

The thatched bamboo huts sprawling up the side of a mountain near Thailand’s border with Burma could at first be mistaken for a tranquil rural village. Surrounded by a lush forest, Umpiem Mai hums with life. Roosters dodge motorbikes whizzing by on the carless streets. Laughing children play ball in front of a market where women in colorful skirts balance babies on their hips as they shop for vegetables. It is a community of more than 13,000 people, densely packed and tightly knit. A wooden pole operated by hand is raised and lowered for entering cars. The only permanent structure is the main road, and even that is just partially paved.

The people who live in Umpiem Mai and in the eight other camps along the border are Burmese refugees, mainly from Karen state, who have fled turmoil in the eastern part of their homeland and are seeking asylum from sectarian violence. Decades of civil war in Burma have created one of the most protracted refugee crises in modern history. Some people have lived in the camps for nearly 30 years and an entire generation has known no other life.

The end of military rule in Burma (also known as Myanmar) in 2011 signaled new hope that a resolution was in sight. But even if ceasefires hold between the Burmese government and ethnic minority groups, the conflict has left a legacy of devastation that will linger for years. While some predict that the Thai border camps (which are separate from the refugee camps housing another persecuted minority, the Burmese Rohingya Muslims) will close within the next three years, the future of the 130,000 people who call them home remains uncertain.

Students at Harvard School of Public Health who are training for humanitarian careers often study life in refugee camps, but few have seen these settlements in person. Fewer still have the opportunity to work with refugees as colleagues and get to know them. In January 2014, eight HSPH students traveled to Umpiem Mai for the School’s first experiment with a “twinning” class in a refugee camp. For three weeks, they studied alongside 21 refugee students at the camp’s Public Health Institute (PHI) and developed a joint research project that would be carried out remotely during the first half of the spring semester.

Shyness evolves to sharing.

The selection process for students participating in such a unique experience had to be thorough, says Parveen Parmar, MPH ’10, who designed and led the course and is associate director of the Brigham and Women’s Hospital International Emergency Medicine Fellowship and an associate faculty member at Harvard Humanitarian Initiative. Gregg Greenough, assistant professor in the Department of Global Health and Population, also served as an instructor. Parmar looked for students with the spirit and experience to deal with squat toilets and other austere realities of fieldwork.

But more important, “Understanding how to work with colleagues in a respectful and egalitarian way when they don’t speak your language and have different skill sets and backgrounds—that’s not something a lot of researchers do well, even very experienced researchers,” Parmar says. “The students appreciated that they weren’t the experts in this situation. This was intended as an equal exchange.”

While the PHI students were initially shy around the HSPH newcomers, barriers broke down during the daily meals the group shared at the camp. “They opened up about their lives from the first day,” says Corey Peak, SM ’14. “I heard about students who had left their families behind to get an education. Some had crossed over a landmined border to come here because there were no other opportunities. They wanted to share their stories and hear ours, too. And to understand that while we may be different, we’re all just people.”

Formidable needs, few training opportunities.

The HSPH students traveled to the camp each morning in the back of a truck after spending the night at a nearby home in a Hmong village. Daily lectures by faculty members from both institutions covered water and sanitation, women and children’s health, and tools used to develop and assess public health programs—skills the PHI students will need after they graduate and join the region’s public health workforce. With one of the highest rates of maternal death in the world, along with high rates of malnutrition and drug-resistant malaria, the public health needs are formidable and the opportunities for training are few.

The twinning course grew out of Parmar’s work with Community Partners International, a nongovernmental organization that has operated the camp’s Public Health Institute for the past two years in collaboration with the Karen Refugee Committee Education Entity and the Karen Department of Health and Welfare. It was offered by the Humanitarian Academy at Harvard through HSPH’s Department of Global Health and Population.

Parmar plans to develop an evaluation component for the course next year, so that its success can be demonstrated and eventually replicated elsewhere. “The ideal situation would be for refugee students to access education back home,” she says. “But in the absence of that opportunity, programs like this are a great way to ensure that a group of well-trained individuals can carry out the necessary services to rebuild when peace does return to their homeland.”

The Public Health Institute provides students with internships in the region that often lead to permanent placements. Students graduate from the program motivated to give back to their damaged communities.

Help vs. self-reliance: Striking a balance.

Today, the idea of closing the camp and repatriating the refugees is gaining political traction in Thailand. International donors are turning their attention to other hot spots, and agencies that provide camp services have seen their funding cut. Monthly rice and charcoal rations have in turn fallen. The key question—how to strike a balance between providing for refugees’ needs and fostering their self-reliance—has no easy answer.

“Understanding how to work with colleagues in a respectful and egalitarian way when they don’t speak your language and have different skill sets and backgrounds–that’s not something a lot of researchers do well, even very experienced researchers.” – Parveen Parmar, MPH ’10, associate faculty member, Harvard Humanitarian Initiative

During the course, students met with the NGOs and community-based organizations that deliver public health services to the camp and divided into teams to develop a research project to support their work. The aim was to create a snapshot of health-related practices, such as rubbish management and condom use, to help the organizations decide how to best allocate dwindling resources.

Soap and charcoal.

Peak, an infectious disease epidemiologist, noticed right away that many toilets in public places such as schools and government offices did not provide soap, in part because money for soap had been cut. For many refugees not accustomed to having soap, its absence didn’t seem worrisome— but from a public health perspective, individual cleanliness was paramount to preventing the spread of infection. So Peak worked with his PHI colleagues to document hand-washing capabilities in every public toilet in camp. Back in Boston, he stayed in touch remotely with his team as they systematically gathered data—contending with a 12-hour time difference and spotty Internet service in the camp. Meanwhile, the students continued meeting each week for joint lectures (delivered through videoconferencing) and drew up a comprehensive map of the camp’s sanitary facilities.

At this year’s graduation, HSPH members of the twinning course received the James H. Ware Award for Achievement in the Practice of Public Health. (From left) Corey Peak, SM ’14; Kelsey Gleason, SM ’14; Jean Nepomuceno, MPH ’14; Rachel Whelan, SM ’14; Julia Hellman, MPH ’14; Courtney Cox, SM ’14; Parveen Parmar, instructor and Harvard Humanitarian Initiative associate faculty member. Not pictured: Phillip Summers, MPH ’14, and Jami King, SM ’15.

Kelsey Gleason, SM ’14, worked in a group that investigated how fuel usage could be made more efficient and less risky to health—results that will be shared with refugees during classes at the camp. But as Gleason conceded self-deprecatingly, another of her ideas did not pan out. After studying fuel usage for household cookstoves, she had determined that it would be healthier if the stoves were raised higher so that the women who did the cooking did not have to lean over the stoves. An American Refugee Committee representative pointed out, however, that this small change would pose a fire hazard. Building materials in the camp are highly flammable and have erupted in serious fires over the years. For Gleason, it was a lesson in humility. There also were lessons in another virtue that can be hard to master for high-achieving Harvard students: patience. “Every time I got frustrated by a communication issue, I realized it was my fault,” Gleason says.

“In the camp, there were weird oscillations between things that were exciting and new and things that would bring home the reality of how hard life is there,” says Peak. “You’d see beautiful kids being kids, playing games that you recognize, next to people scraping by. The emotional highs and lows were very close. It was hard—but I learned so much.”

The course was an equal exchange of passion and expertise, Peak adds. Unlike typical fieldwork, which might employ locals simply to collect data, the course made PHI students full collaborators. “They were invested in the study and plugged us into the community,” says Peak. “I saw them gain in confidence just during the three weeks we were there. I think they are well equipped to make a difference for health, both in the camps and back in Burma.”

In their own words: Stories from refugee students.

The Harvard teachers explained that in public health, “prevention is better than cure.” I really like that meaning. My ambition is to become a good health worker. When l was living in my village in Burma, I saw many pregnant women die from postpartum hemorrhage problems. I saw many children delivered by village midwives come out yellow on the whole body—and three days later, the newborn died. So I feel very sad and I want to give education about family planning, hygiene, and washing methods to control disease.
— Kyi War Khaing, 20

In 1997, the Burmese military attacked our Karen people, killed them, burned our house. At that time, my parents could not do anything for us. We didn’t have shelter or enough food to eat, so we moved to the refugee camp.… When the Harvard students arrived, I was very excited to see them. They were patient and explained the lesson when we didn’t understand. They have a good relationship with us.
— Naw Eh Tu Lo K’mwee, 23

When I was a child, I wanted to become a doctor and my parents encouraged me. My family and villagers often had to escape from the military. I had to finish my school in the jungle because of the military. When I was eleven and a grade four student, there was a day that I have never forgotten. The troops came to my village and burned all the houses in the village and killed the villagers. Since that day, I fled to Thailand and a refugee camp to continue my education. I graduated high school with high motivation and strong courage from my parents.… I decided to study public health because you can help many people at the same time. [In the HSPH course] I learned how to manage and how to be a leader. Now we are using public health training in our internship. We figure out root causes of diseases and work with different stakeholders to set up sustainable public health projects. I hope one day public health will succeed.
— Saw Tei Htoo, 22

When I was 10 years old, I told my parents, ‘I want to go to school.’ But we didn’t have the money. Almost all the children in my village could not pay the school fee, so we had only primary school. I faced many problems: no food, no umbrella, also no shoes because my parents are poor. In 2002, I moved to the refugee camp and had the opportunity to continue my studies.… I chose the public health program so I can promote health and give education to the public about prevention.
— Saw Maung Pay, 28

I learned at PHI that if we spend 1,000 baht, we can cure only one person—but we can prevent many people from becoming sick and injured.
— Naw Hsa K’ Pru Paw, 22
— Amy Roeder is assistant editor of Harvard Public Health

Monell Chemical Senses Center

A leader in scientific discovery, the Monell Chemical Senses Center expands our fundamental understanding of taste and smell – the chemical senses – through research, training, and communication.

The Center’s cutting–edge research identifies the underlying mechanisms of taste and smell and probes their involvement in appetite, nutrition, and disease to benefit human health and well-being.

In its role as a nonprofit, Monell provides a comprehensive resource for information and serves as an unbiased authority on the science of taste and smell.

In the 1960s, very little was understood about the essential mechanisms and functions of what were then thought to be the “minor senses” – taste and smell. In 1967, the Ambrose Monell Foundation contributed $1 million to establish a multidisciplinary scientific institute dedicated to basic research on these senses.

Almost 50 years later, the Monell Center’s research has dramatically increased scientific understanding of taste, smell, and chemesthesis (the third chemical sense, which mediates ‘chemical feel,’ such as the cooling of menthol, the tingle of carbonation or the burn of chili peppers). The Center’s scientific discoveries contribute significantly to a growing awareness of the central role that these senses play in human health.

The Monell Foundation continues to strongly and consistently support the Center’s basic and clinical research mission, maintaining its role as a fundamental driving force in the Monell Center’s growth and development.

From the start, Monell’s science has been based on an explicit multidisciplinary approach. This is by necessity, as a comprehensive understanding of these senses requires multiple disciplines and methodologies:

The senses of taste and smell detect chemical stimuli from food, from other organisms, and from the environment. Chemical information then is transduced by biological structures into nerve impulses. The neural information is in turn processed by the brain to form sensations and perceptions that can alter behavior and ultimately, human health.

To unravel these complex interwoven processes, the Center is structured to encourage collaboration among scientists from diverse backgrounds. The Monell Center has no departmental organization; offices and laboratories are not segregated by discipline; and most importantly, the staff is imbued with the ideal of multidisciplinary interaction.

Research involves both internal interactions and an international network of colleagues from academic, government, and corporate research facilities, bringing extraordinary depth to Monell’s science.

Representative disciplines: Interaction brings insight, advances discovery

• physiology
• sensory psychology
• organic chemistry
• cognitive neuroscience
• biochemistry
• molecular biology
• neurobiology
• immunology
• genetics
• biophysics
• cell biology
• developmental psychobiology

The Monell Center’s ‘product’ is fundamental scientific knowledge. Research findings are communicated through journal publications and presentations at academic and educational conferences. The Center’s scientists have contributed thousands of scientific journal articles and book chapters to advance scientific understanding of taste and smell.

Monell research also is regularly cited in the international news media. The Center’s studies often have relevance to health and quality of life, providing novel insights to improve lives in many ways.

The Monell Center has helped to define the science of taste and smell. Monell’s world-class scientists are at the forefront of inquiry across varied levels of investigation.

Among the Center’s unique areas of expertise:

• Human sensory testing across the lifespan using innovative psychophysical and physiological techniques 
• Integration of human sensory perception with molecular biology
• Pioneering techniques to biopsy and maintain living human taste and smell receptor cells for human species-specific study
• Experiential, physiological and genetic determinants of flavor and food preferences across the lifespan
• Stem cell biology to regenerate dysfunctional taste and smell receptor cells
• Focus on taste and smell receptors in extra-oral sites and their relation to health
• Odor communication in health and disease

The Center’s research advances fundamental knowledge of taste and smell. In the process, Monell’s scientific findings also uncover solutions to pressing problems related to health, the environment and more. Monell scientists helped to identify the sweet taste receptor, a breakthrough that paved the way to current inquiries into how to stimulate, manipulate, enhance, inhibit, and create synergy of sweet taste. In other areas, ongoing Monell research is:

• Demonstrating the key role of prenatal and early postnatal experience in shaping life-long taste, odor, and flavor preferences.
• Utilizing advanced stem cell biology techniques to regenerate smell receptors and develop treatments for smell loss.
• Analyzing the genetics of taste to identify the salt taste receptor, knowledge needed to develop effective salt enhancers and modifiers and help reduce sodium consumption.
• Identifying how body odors can be used for the early non-invasive detection and diagnosis of cancer, infectious disease, and tissue damage.
• Determining how genetic variation in taste and smell receptors influences flavor perception, food choice, nutrition, and health across the lifespan.
• Pioneering studies of odortypes, genetically-determined olfactory markers of individual identity.
• Revealing how short and long-term exposure to air-borne chemicals alter sensory perception and health.
• Probing the mechanism and function of taste and smell receptors located outside the mouth and nose.

Although Monell encourages an interdisciplinary approach, its research can be divided for descriptive purposes into six overlapping programs:

• The Program in Sensation and Perception is at the forefront in developing and using accurate human sensory measures to explore taste and smell perception across the lifespan, from prenatal to infancy to childhood to the aging. Much of the research speaks directly to questions related to palatability and the development of food preferences.
• The Program in Neuroscience and Molecular Biology is a world leader in the use of human sensory tissue to investigate the underlying mechanisms of taste and smell. Molecular genetic studies identify heritable influences on chemosensory detection and perception, both in the mouth and in extra-oral sites throughout the body. Other work focuses on identifying taste and smell receptor cells and how these specialized cells encode information.
• The Program in Environmental and Occupational Health studies the response of humans to environmental odors and irritants, such as those emitted by industry and agriculture. Its scientists determine the effects of exposure to air-borne chemicals on human perception, cognition and physiology.
• The Nutrition and Metabolism Program studies the physiology and biochemistry of appetite, which is closely linked to taste and smell. The research is clarifying the role that taste and smell play in the development and maintenance of hypertension, obesity, diabetes, and other food-related diseases.
• The Program in Health and Well-Being concentrates on how humans respond to tastes and odors from a clinical perspective, with a focus on taste and smell disorders. A new initiative focuses on identifying the causes of anosmia – smell loss – with the ultimate goal of identifying new treatments for this invisible disability that affects millions worldwide. Other studies explore noninvasive disease detection using changes in human body odors.
• The Program in Chemical Ecology and Communication explores the production of odors by animals and humans for communication and reproductive purposes. Research with the USDA seeks to identify non-lethal methods to control animal pest species that threaten agricultural and aquatic food crops.

An integral part of Monell’s mission involves preparation of the next generation of scientists:

• Monell’s strong post-doctoral program attracts talented young scientists from a wide range of disciplines. Approximately 20 post-doctoral fellows are trained at the Center each year. Monell fellows go on to contribute to scientific advancement through work in academia, industry and government.
• The Center’s highly successful Monell Science Apprenticeship Program (MSAP) for high school and college students is now entering its 34th year. The program aims to stimulate interest in STEM careers among demographic groups underrepresented in science, including females, racial and ethnic minorities, and the economically disadvantaged. MSAP enrolls approximately 25 students each summer.

Originally established as a division of the University of Pennsylvania, the Monell Center separated from Penn ten years later to become an independent nonprofit research institute. Today, the Center’s major source of funding comes from competitive government research grants, primarily through the National Institutes of Health. Other sources of funding include corporate sponsorship, individual philanthropy, and foundations.

The Monell Foundation is the Center’s largest private supporter, contributing valuable assistance across the breadth of the Center’s operation, from the recruitment of preeminent scientists to the creation of new laboratories.

Since its inception, the Monell Center has been at the vanguard of successful academic-industry partnerships. The Center was established as a joint venture involving academic, government, and industry scientists, at a time when such collaborations were rare.

Today, over 40 companies from around the world help support Monell’s basic research through the Center’s Corporate Sponsorship program. Companies that support Monell are involved in a diverse range of enterprises, ranging from foods and beverages to fragrances to personal care products, pharmaceuticals, industrial chemicals, pet care products and more.

Annual support from corporate sponsors is unrestricted, permitting the Center to initiate new programs and fund junior scientists as they begin their careers. In return, sponsors receive access to research expertise and unbiased cutting-edge scientific information via educational and consulting opportunities.

The Monell Center is led by Director and President Robert F. Margolskee, MD, PhD. A pioneer in the use of molecular biology to study cellular mechanisms of taste, Dr. Margolskee has been responsible for major advances in the field of taste biology. Most recently, his research has focused on the mechanisms and functions of taste receptors located in the gastrointestinal tract and other organs throughout the body. These extra-oral receptors are increasingly implicated in regulation of food intake, nutrition, metabolism, and hormone release.

The Center’s third Director, Dr. Margolskee succeeded Gary K. Beauchamp, PhD, who led the Center from 1990 to 2014. A world-renowned expert on taste and smell possessing broad expertise across a variety of disciplines, Dr. Beauchamp also serves on the Board of the Ambrose Monell Foundation .

Indicative of its deep commitment to the Center, a member of the Ambrose Monell Foundation has always been a part of the Center’s governance. Currently, Ambrose K. Monell sits on the Monell Center Board of Directors.

In addition, many eminent scientists, government leaders, academicians and business executives have served the Center on the Board and as members of advisory committees. Dwight Riskey, PhD, retired Senior Vice President, Consumer & Customer Insights at PepsiCo and current principal of Riskey Business Solutions, LLC, serves as Board Chair.

The Future
Early in the Center’s history, founding Director Morley Kare said, “Monell itself is a scientific experiment.” The results of this experiment have surpassed hopes and expectations. From a fledgling organization, Monell has grown to be a major force in scientific research.

Monell discoveries increase fundamental understanding of taste and smell to address critical present-day issues, including:

• nutrition and diet
• obesity and metabolic disease
• population regulation
• disease detection
• pediatric health
• homeland security
• environmental chemical exposure

Other organizations and individuals conduct outstanding basic and clinical research on taste and olfaction. However, no other institution or group of scientists has the depth and breadth of Monell’s multidisciplinary approach.

There still is much to learn about these primal senses that influence our lives in so many powerful ways. Looking to the future, the Monell Center will continue to pursue its groundbreaking exploration of taste and smell, building knowledge and providing opportunities to improve the lives of human and other animal species.