Around the world, hundreds of women infected with the Zika virus have given birth to children suffering from microcephaly or other brain defects, as the virus attacks key cells responsible for generating neurons and building the brain as the embryo develops.
Studies have suggested that Zika enters these cells, called neural progenitor cells or NPCs, by grabbing onto a specific protein called AXL on the cell surface. Now scientists at the Harvard Stem Cell Institute (HSCI) and Novartis have shown that this is not the only route of infection for NPCs.
The scientists demonstrated that the Zika virus infected NPCs even when the cells did not produce the AXL surface receptor protein that is widely thought to be the main vehicle of entry for the virus.
“Our finding really recalibrates this field of research, because it tells us we still have to go and find out how Zika is getting into these cells,” said Kevin Eggan, principal faculty member at HSCI, professor of stem cell and regenerative biology at Harvard University’s Faculty of Arts and Sciences and Harvard Medical School, and co-corresponding author on a paper reporting the research in Cell Stem Cell.
“It’s very important for the research community to learn that targeting the AXL protein alone will not defend against Zika,” agreed Ajamete Kaykas, co-corresponding author and a senior investigator in neuroscience at the Novartis Institutes for Biomedical Research (NIBR).
Previous studies have shown that blocking expression of the AXL receptor protein does defend against the virus in a number of human cell types. Given that the protein is highly expressed on the surface of NPCs, many labs have been working on the hypothesis that AXL is the entry point for Zika in the developing brain.
“We were thinking that the knocked-out NPCs devoid of AXL wouldn’t get infected,” said Max Salick, a NIBR postdoctoral researcher and co-first author on the paper. “But we saw these cells getting infected just as much as normal cells.”
Working in a facility dedicated to infectious disease research, the scientists exposed two-dimensional cell cultures of AXL-knockout human NPCs to the Zika virus. They followed up by exposing three-dimensional mini-brain “organoids” containing such NPCs to the virus. In both cases, cells clearly displayed Zika infection. This finding was supported by an earlier study that knocked out AXL in the brains of mice.
“We knew that organoids are great models for microcephaly and other conditions that show up very early in development and have a very pronounced effect,” said Kaykas. “For the first few months, the organoids do a really good job in recapitulating normal brain development.”
Historically, human NPCs have been difficult to study in the lab because it would be impossible to obtain samples without damaging brain tissue. With the advancements in induced pluripotent stem cell (iPS cell) technology, a cell reprogramming process that allows researchers to coax any cell in the body back into a stem cell-like state, researchers can now generate these previously inaccessible human tissues in a petri dish.
The team was able to produce human iPS cells and then, using gene-editing technology, modify the cells to knock out AXL expression, said Michael Wells, a Harvard postdoctoral researcher in the Eggan Lab and co-first author. The scientists pushed the iPS cells to become NPCs, building the two-dimensional and three-dimensional models that were infected with Zika.
The Harvard and NIBR collaborators started working with the virus in mid-April 2016, only six months before they published their findings. This unusual speed of research reflects the urgency of Zika’s global challenge, as the virus has spread to more than 70 countries and territories.
“At the genesis of the project, my wife was pregnant,” Eggan remarked. “One can’t read the newspapers without being concerned.”
The collaboration grew out of interactions at the Broad Institute of Harvard and MIT’s Stanley Center for Psychiatric Research, where Eggan directs the stem cell program. His lab already had developed cell culture systems for studying NPCs in motor neuron and psychiatric diseases. The team at Novartis had created brain organoids for research on tuberous sclerosis complex and other genetic neural disorders.
“Zika seemed to be a big issue where we could have an impact, and we all shared that interest,” Eggan said. “It’s been great to have this public/private collaboration.”
The researchers are studying other receptor proteins that may be open to Zika infection in hopes that their basic research eventually will help in the quest to develop vaccines or other drugs that defend against the virus.
Adapted from a Harvard Stem Cell Institute news release.
Delivering effective interventions to patients who need them remains one of the greatest hurdles facing medicine and public health, despite significant global health resources and many known solutions. The Global Health Delivery Project at Harvard (GHD) brings together and trains ministry leaders, care providers, educators, researchers, and students to bridge that gap.
Participants in the project’s Global Health Delivery Summer Intensive (GHDI) program spend three weeks at Harvard in July, enrolling in three courses that take place at the Harvard Chan School of Public Health, where they learn how to understand epidemiology and manage programs to strengthen health systems and delivery structures.
These three courses are also part of a separate Master of Medical Sciences in Global Health Delivery (MMSc-GHD) degree-program offered through Harvard Medical School.
GHD is a joint initiative of Harvard Medical School, Harvard Business School, and Brigham and Women’s Hospital launched eight years ago by current World Bank President Jim Kim, Partners In Health co-founder and Kolokotrones University Professor Paul Farmer, and Michael Porter, the Bishop William Lawrence University Professor at the Harvard Business School. GHD welcomed 52 mid-career global health professionals from 27 countries to this summer’s intensive training session.
The goal of the program is to improve how care is delivered and health organizations are managed around the world.
“We’ve recognized for years that transnational inequities in health are explained not by a lack of solutions to prevent and treat disease, but by the failure to deliver them to those in greatest need,” said Farmer, who is also and head of the HMS Department of Global Health and Social Medicine.
“Improving health care delivery requires training new leaders in the complex work of implementation. GHDI is doing just that, and will continue to do so for professionals around the world.”
"At the World Bank, we realize that one of the most pressing issues to solve is global health delivery,” Kim said. “It's a fundamental problem in development, and GHDI seeks to address the delivery issue from different angles. I'm moved and inspired by how the program has taken off. It was just a dream when it started, and it's incredible to have expanded to three courses and a cohort of more than 50 students.”
Since 2009 the program has trained more than 250 practitioners who make real world impact. This year’s cohort includes:
- Maxi Raymonville, executive director of the University Hospital in Mirebalais, Haiti
- Ntombifuthi Dennis, prevention manager for Swaziland’s National AIDS Council
- Vera Mussah, program manager for performance-based financing for the Liberian Ministry of Health
David Golan, HMS dean for basic science and graduate education, notes, “The students who enroll in GHDI are an impressive group of leaders. They come to Harvard to learn, but they also bring a wealth of experience and knowledge and invariably teach one another, building enduring collaborative relationships. Their passion and dedication to improving health throughout the world is palpable.”
- Nicholas Muraguri (2011), head of Kenya’s national AIDS commission at the time, later director of an international effort to eliminate HIV among children, and now the director of medical services for Kenya
- Lorenzo Dorr (2012), senior program manager at Last Mile Health, a key leader in Liberia’s Ebola outbreak
- Benjamin Grant (2014), another senior program manager at Last Mile Health, who oversaw Ebola preparedness trainings across one of the country’s 15 counties
Dorr and Grant acknowledge GHDI as a “great opportunity for senior level management training” that helped them with the outbreak response.
“We know so much that could help so many, but making sure the right people have that knowledge and can implement it is critical to improving care,” said Rebecca Weintraub, Faculty Director of the GHD and HMS assistant professor of global health and social medicine. Weintraub is also co-director of the GHDI along with Joseph Rhatigan, HMS associate professor of global health and social medicine.
This story is adapted from a GHD news release.
Philanthropists Ronda Stryker and her husband, William Johnston, have pledged $20 million to the Harvard Medical School Department of Global Health and Social Medicine over the next five years.
This generous gift will support senior and junior faculty, research fellows and students in their work to provide equitable health care around the world, HMS leaders said.
“I believe that, in my lifetime, we can create a movement and effect real change in billions of people’s lives around the world, particularly women and children who often bear the brunt of the lack of access to health care,” said Ronda Stryker, director of the Stryker Corporation and a member of the Harvard Medical School Board of Fellows and Advisory Council on Global Health and Service.
“A significant investment in HMS to support current and future leaders in global health, under Paul Farmer’s leadership, will change things for the better. It comes down to kindness to humanity, and if Harvard Medical School can teach and train others to replicate the work Paul and his team do every day, the world will be better for it,” she said.
HMS Dean Jeffrey S. Flier, said he is deeply grateful to Stryker and Johnston for their generosity and for their meaningful commitment to global health and to advancing the vision of Paul Farmer.
“This remarkable gift will enable our faculty within the Department of Global Health and Social Medicine to continue to improve the lives of people throughout the world while also supporting the next generation of global health leaders,” Flier said.
The gift, which is the largest in the department’s history, will
- establish the Ronda Stryker and William Johnston Professorship in Global Health;
- bolster the careers of junior faculty and fellows by supporting research in fields such as HIV and Ebola and by creating an annual forum in which researchers can receive mentorship and build community;
- enable students from around the world to enroll in the HMS Master of Medical Sciences in Global Health Delivery program;
- support the development and execution of projects in the HMS Global Health Research Core that inform patient care; and
- enhance HMS research and advocacy efforts in global surgery.
“This gift gives us the ability to solidify our foundation of collaborative research, care delivery and education for global health equity, while also providing crucial flexibility to respond to the needs of the communities we serve, as defined by the people within them,” said Paul Farmer, chair of the HMS Department of Global Health and Social Medicine and Kolokotrones University Professor at Harvard.
Farmer said the gift will also allow the department to continue offering need-blind admission to students in the MMSc program in global health delivery.
One recent student provides a tangible example of the importance of the kind of flexibility the gift will allow, department leadership said. When Mohamed Bailor Barrie applied to the program, he intended to pursue a research project focused on tuberculosis. Between the time of his acceptance and the beginning of the program, Ebola erupted in his native Sierra Leone.
Barrie shifted the focus of his work to delivering clinical care to those affected and to furthering the understanding of Ebola, not just as an isolated biomedical phenomenon but in the context of history, economics and culture.
The HMS Research Core in Global Health was also able to direct its efforts toward West Africa when cases of Ebola were on the rise. Working with partners in Sierra Leone, the Research Core drew on established relationships with caregivers in rural Ebola treatment units to field test a new rapid Ebola diagnostic that could become a crucial tool in the battle against the virus.
Farmer emphasizes the importance of looking at the many facets of global health not as competitors for scarce resources, but as crucial, interlocking parts of a whole that reinforce one another.
“Research and training don’t take away from care delivery, they make it better,” Farmer said. “The connective tissue that allows all of these different elements to work together is philanthropy, and this gift will be truly transformational.”
Harvard Medical School scientists have found a compound that in laboratory dishes blocks the dengue virus in two ways, raising hopes for a future drug whose dual activity could suppress the otherwise likely emergence of drug resistance.
Spread by mosquitoes, dengue belongs to the same family of viruses as Zika, whose emerging strain has just been linked by the U.S. Centers for Disease Control and Prevention to severe birth defects. Like Zika, dengue virus has no antiviral drugs to prevent illness or stop its spread.
Dengue virus infects more than 300 million people a year worldwide, causing no symptoms in some people but flu-like misery or dangerous hemorrhagic fevers in others.
“Dengue’s been an understudied virus.”—Priscilla Yang
The compound found by Yang’s team, GNF-2, keeps the dengue virus from infiltrating and overwhelming cells in the body. It does this by blocking its known kinase target inside the cell and by also inhibiting a viral target found on the surface of the virus. Yang considers the discovery of GNF-2 to be serendipitous.
“We had screened a library of known kinase inhibitors and had a ‘problem compound’ where we could not explain all the antiviral activity that we were seeing based on just the effect it had on the host kinase it normally targets,” Yang said.
That instance of serendipity was followed by years of experiments in collaboration with scientists across HMS, in particular, Stephen Harrison and Nathanael Gray, both professors in the Department of Biological Chemistry and Molecular Pharmacology. The dengue work was carried out through one of three Centers for Excellence in Translational Research at HMS, a National Institutes of Health effort designed to move discoveries about emerging infections closer to clinical applications in diagnosis, treatment and prevention.
“The compound was inhibiting the virus by targeting the host kinase, but then somehow it also was binding to the surface of the virion, and then preventing entry of the virus,” Yang said. “That’s not at all what we thought we would find when we did the original kinase inhibitor screen.”
GNF-2 had surfaced in a chemical screen Yang’s lab performed in 2007, one compound among many showing some activity against dengue virus. Viruses invade host cells and replicate there, so jamming one or both processes could mean relieving the symptoms of infection and preventing transmission of the virus.
Yang said they zeroed in on host factors as antiviral targets because it seemed likely that related viruses would rely on the same or similar host factors to replicate. If they found a compound that worked against one virus, they surmised, it might work against others in the same family. Cellular kinases seemed likely to be required by the virus because they regulate most cellular processes.
Yang also hoped that finding a way to help the host cell repel the virus would overcome the virus’ ability to thwart antiviral drugs. Viruses evolve so frequently that their elements are moving targets for antiviral drugs. Tamiflu, for example, has lost much of its efficacy in the years since it was aimed against influenza, Yang said. By comparison, combination therapies, such as those used against HIV, can be successful because they fight the virus on more than one front.
In the case of dengue and other understudied and emerging viruses, resources to develop the kinds of drug combinations that have proven effective against HIV and hepatitis C virus may not be available. In these cases, a single drug that acts by targeting multiple viral processes simultaneously may provide an alternate way to suppress resistance.
“Dengue’s been an understudied virus,” Yang said. “Everything changed when the NIH made it a priority pathogen because the number of severe infections where people get very sick has been increasing. Like Zika right now or Ebola a few years back, it’s hard to predict when that will happen and where that will happen and the scale of how many people will be affected.”
This work was supported by a Harvard Medical School Faculty Development Grant, an Armenise-Harvard Junior Faculty Grant and NIH Grants R01 CA130876, R01 AI076442, R01 AI095499, R56 AI095499, U19 AI109740, U54 AI057159 and a Catalyst grant from the Harvard Clinical and Translational Science Center (NIH UL1TR001102).
More than 5 billion people worldwide lack access to essential surgical care, but an international group of surgeons, anesthesiologists, journalists, advocates and business and biotechnology leaders have outlined a plan to bring safe, affordable surgical care to the men, women and children who need it most.
“Building surgical systems that work for everyone is affordable and achievable,” said co- first author Josh Ng-Kamstra, a Paul Farmer Global Surgery Research Fellow at Harvard Medical School and a general surgery resident at the University of Toronto. “It’s also essential if we are to meet the global goals of ending poverty, improving health, ensuring gender equality and creating economic growth.”
The paper, which appears in the inaugural issue of the BMJ Global Health, outlines a series of actions that universities, hospitals, surgeons, biotech companies and the media in wealthy countries can pursue to improve access to surgery worldwide.
The effort builds on a landmark 2015 report by the Lancet Commission on Global Surgery. The commission found that nearly a third of the global disease burden can be attributed to surgically treatable conditions. For billions of people in low- and middle-income countries, a lack of infrastructure, insufficient numbers of trained surgeons and anesthesiologists, and the prohibitive costs of receiving care prevent people from receiving the care they need. The commission estimated that 143 million additional surgical procedures are needed each year to save lives and prevent disability. But the case for action isn’t just humanitarian: Investing in surgery would save developing countries approximately $12.3 trillion in lost GDP by 2030.
As Jim Yong Kim, president of the World Bank Group, said in his address to the Lancet Commission in May 2015, “The stakes are high, because failing to fix this problem will have a substantial impact on people’s lives, well-being and even their economic health going forward.”
The current publication highlights a series of actionable recommendations that those in high-income countries can take to enhance the world’s capacity to deliver surgical and anesthesia care. Specifically, the paper calls for:
- Colleges and academic medical centers to develop global partnerships for training and ongoing professional development and to support research efforts in quality, safety and outcomes measurement
- High-income country surgery and anesthesia trainees to develop long-term clinical and research relationships with colleagues in low- and middle-income countries
- Academic surgeons and journals to support research by surgeons in low- and middle-income countries and eliminate barriers to publishing and disseminating research in the communities where it was conducted
- Global health funders to aggressively invest in strengthening health systems with a specific focus on surgery as a critical component of universal health care coverage
- The biomedical devices industry to design and manufacture user-centered equipment appropriate for resource-limited environments and train health professionals and biomedical equipment technicians in low- and middle-income countries
- Press and advocacy groups to develop public support by telling the stories of those affected by surgical disease, and to independently investigate the state of surgery around the world
"The goal is universal access to safe, affordable surgical and anesthesia care when needed," said co-author John Meara, the Steven C. and Carmella R. Kletjian Professor of Global Health and Social Medicine in the field of Global Surgery and director of the Program in Global Surgery and Social Change at HMS, Plastic Surgeon-in-Chief at Boston Children's Hospital, and co-chair of the Lancet Commission on Global Surgery. "This reports demonstrates a common policy agenda between major actors and provides a road map for maximizing benefit to surgical patients worldwide."
While the authors highlight the role of individuals and institutions in wealthy nations in the current paper, they also emphasize the important role of health professionals and policymakers who live and work in low- and middle income countries, noting that unilateral action by high-income country groups without an ethos of partnership is unlikely to bring about sustainable change. Instead, the authors wrote, high-income country resources can be brought into the service of local interests, building sustainable health systems and providing a durable solution for the world’s poor.
“We’re thrilled to be launching this paper at such a crucial time for global surgery,” said Paul Farmer, Kolokotrones University Professor at HMS, co-founder of Partners In Health and a Lancet Commissioner. “We have an opportunity to turn surgery from the ‘neglected stepchild of global health’ to a centerpiece in national health systems, averting death and disability for millions.”
This story is adapted from a multi-institution news release.
An outbreak of multidrug resistant tuberculosis (MDR-TB) in Papua New Guinea may well become a replay of the disastrously delayed response to the West African Ebola pandemic, says Jennifer Furin, Harvard Medical School lecturer on global health and social medicine, in a commentary she co-authored with Helen Cox, senior lecturer in the Division of Medical Microbiology at the University of Cape Town, South Africa. The commentary was published in Lancet Respiratory Medicine on March 23 to coincide with World TB Day, which is today, March 24.
Harvard Medicine News spoke to Furin to learn more about the situation in the island province of Daru, just north of Australia in the southwestern Pacific.
HMN: What’s happening on Daru?
JF: Currently, on Daru Island in Papua New Guinea, there is a significant and ongoing outbreak of MDR-TB. It is spreading throughout the country and could possibly move to Australia.
HMN: How does it compare to other outbreaks globally?
JF: Conservative estimates show that 1 percent of the population of Daru is sick with MDR-TB. This translates to about 150 cases per year in a population of 15,000. As a point of comparison, an outbreak on nearby Chuuk Island, one that the CDC was able to get under control, had 26 cases in a population of 108,000.
In one community in South Africa, Khayelitsha, there are about 200 MDR-TB cases a year, with a population of about 400,000 and an HIV prevalence above 20 percent.
Since Daru has almost no HIV—which greatly increases the risk of contracting MDR-TB—the number of cases there is even more staggering.
HMN: How did things get so bad?
JF: A number of factors. For example, some MDR-TB patients from Papua New Guinea who had been getting treatment in Australia were sent back home—many of them to Daru—in order to give them care closer to their families.
This was well-intended, but available care was limited on Daru. Once the infection started spreading on the island, it became difficult to stop.
Because the islanders are poor, people share accommodations—often crowding 20 people into a single room. In addition, there were few diagnostic and treatment services available on the island.
Although services have improved over the years, they have not improved fast enough to keep up with the current outbreak of the disease.
Finally, international health and policy advisors to Papua New Guinea have not given the health program leaders advice that will help them to stop this outbreak.
HMN: You’ve called the outbreak a “time bomb.” Why do you use that term?
JF: Because one does not notice the full devastation of the event right away.
With TB, people can become infected with the bacterium and not become sick until months or years later.
Someone with TB can cough in a room and expel the bacterium, where it will remain infectious for hours. Hundreds of people could breathe in those infectious organisms and not know for some time that they have been infected.
Because infection is not readily apparent, TB is much more frightening than diseases we tend to hear a lot about, such as Ebola, where infection tends to lead rapidly to disease development.
But when I describe the situation as being like a time bomb, I also mean that if we act to do something now, we might be able to defuse the situation.
HMN: What would it take to stem this disease in Papua New Guinea?
JF: There needs to be a massive influx of resources—human and financial—into the country. Although the government has put together an excellent plan to stop the outbreak, it does not have the funding or the staff to put the plan into action. And it is likely that the situation on Daru Island is also happening elsewhere in the country.
Urgent action on a large scale is needed now to support the planning done by the government. These plans include active case finding, rapid diagnosis and treatment with optimal therapy and preventive measures for those who have been exposed to pathogens.
HMN: TB is a treatable disease, but it still kills more than a million people every year. What does the reaction to this outbreak say about efforts to get to zero deaths?
JF: According to the new WHO “End TB Strategy,” we are supposed to eliminate TB by 2030, which is only 14 years away. But we don’t know how to actually eliminate TB; we have tried to control only the impact the disease has on the world’s populations.
This control strategy has been highly ineffective: TB is once again the infectious disease that causes the highest mortality among adults around the world, even though it is curable.
But if we are serious about ending TB in just a decade and a half, we have to start actually eliminating it. Daru would be the ideal place to make this happen, since the number of cases is manageable and the geographic location where the cases are occurring is small.
However, so far there has been no real attempt to try to eliminate the disease on Daru. Since the global health organizations cannot even commit to eliminating MDR-TB on Daru, it is hard to believe that we will be successful in getting to zero anytime soon.
When a diamond miner named Sahr arrived at the Ebola treatment unit in Kenema, Sierra Leone, in December 2014, he saw red fences surrounding the area where people with suspected and confirmed cases of the disease were to be treated and he panicked.
The colorful barricades reminded him of the horror he experienced in 1996 as a child soldier in Sierra Leone’s civil war, when rebel fighters attached red cloths to their guns during live battles.
As terrifying as the war was, Sahr’s struggle with Ebola was even worse, he told a team of researchers who spoke with him during and following his treatment in the winter of 2014-2015. The researchers were hoping to illuminate the biological and social context of the 2013-2016 Ebola pandemic centered in West Africa.
“During the war, you could see your enemy; Ebola can’t be seen,” Sahr told them.
Sahr’s account, along with the case histories and life stories of three other Ebola survivors, is part of an ongoing research effort to make the disease visible in its full human and medical context.
The research, led by Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine at Harvard Medical School, and Eugene Richardson, an instructor in medicine at Brigham and Women’s Hosptial, a physician and research scientist at Partners In Health in Sierra Leone and a PhD candidate in the Department of Anthropology at Stanford University.
The researchers noted that after more than 25 documented outbreaks of Ebola in Africa during the last four decades, there is still little understanding about the political, ecological and economic forces that promote—or limit—its spread.
The study, published online in the December 2015 issue of Health and Human Rights Journal, is rich in detail that highlights the interconnecting threads woven throughout the 2013-2016 outbreak which sickened more than 28,000 people and ravaged the entire region of West Africa.
The study traces the connections between the closing of schools during quarantine and the rise in teen pregnancies, the deadly toll of the disease on caregivers, and the rise in deaths from unattended childbirth and malaria.
"To understand this Ebola pandemic, or any other transnational outbreak for that matter, we have to resist the urge for simplicity,” said Farmer, who is also co-founder of Partners In Health and editor-in-chief of Health and Human Rights Journal.
“That means going beyond the perfunctory explanations afforded by individual disciplines and, importantly, listening to the stories of those most affected. You can’t build a health care system without a faithful effort to appreciate the historical, economic and social context where the work needs to be done,” Farmer said.
Partners In Health helped to build, staff and supply Ebola treatment facilities in Sierra Leone and Liberia, two of the nations hardest hit by the epidemic.
In addition to emphasizing the importance of providing aggressive supportive care to those who were already sick, Farmer also highlighted the need to integrate research programs into clinical delivery platforms. That way, efforts to care for patients can also help improve understanding of the disease, test novel diagnostic tools and measure the effectiveness of new clinical interventions.
To further deepen understanding of the disease, Farmer, Richardson and other colleagues conducted extensive interviews to track the specific course of illness and treatment of four individuals who survived infection with Ebola virus disease.
They then analyzed the case histories and life stories in context, using analytical tools from a variety of disciplines ranging from anthropology to physiology, and studied them on a variety of scales from the global to the molecular.
Previous attempts to understand the dynamics of the epidemic have tended to focus on single aspects of the disease, the researchers said, obscuring the importance of the structural, political and economic forces that contributed to it and ignoring the human rights failures that also contributed to the severity of the outbreak, many of which have deep roots in West Africa’s colonial and post-colonial international relations.
“The whole region has suffered from centuries of transhemispheric relations of inequality, of which Ebola is just one of the many deadly manifestations,” Richardson said.
Other study collaborators included Songor Koedoyoma, chief of staff of the Kono District Ebola Response Center, Mohamed Bailor Barrie, a student in the master’s program in Global Health Delivery at HMS and co-founder of Wellbody Alliance (one of PIH’s chief partners in Sierra Leone), Dan Kelly, a co-founder of Wellbody Alliance, and Yusupha Dibba, medical director of Wellbody Alliance in Koidu, Sierra Leone.
This research was conducted with support from the Abundance Foundation.
He was known as a “frequent flyer,” a regular visitor to emergency departments and urgent care clinics who consistently failed to manage his diabetes. Living in Boston, he had access to some of the best medical care anywhere, but his illness remained out of control.
Monica Bharel, Harvard Medical School instructor in medicine at Massachusetts General Hospital and commissioner of the Massachusetts Department of Public Health, was recalling a patient she met early in her career.
At first, the patient’s repeated bouts of illness mystified her, but as she learned more about the man’s life, the mystery was solved. One key issue was the fact that he was homeless.
“People’s stories matter,” Bharel said. “We know so much about the pathophysiology of diseases, but we know so much less about where a man should store his insulin when he sleeps under a bridge.”
Bharel, who went on to serve as chief medical officer for the Boston Health Care for the Homeless Program was speaking about the challenges of caring for the most vulnerable patients at a seminar hosted by the Center for Primary Care at Harvard Medical School and the HMS Department of Global Health and Social Medicine. The crowded auditorium at the Joseph B. Martin conference center was filled with clinicians, researchers, advocates and medical students.
“Caring for poor people—whether they are in another country or living within the shadows of this campus—is a challenge requiring great creativity. That’s the real work of places like HMS.” —James O'Connell
She was joined by James O'Connell, HMS assistant professor of medicine and founder and president of the Boston Health Care for the Homeless Program, and Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine, head of the HMS Department of Global Health and Social Medicine, and founder of Partners In Health, an organization that delivers world class health care in places such as Haiti, Rwanda and Peru by collaborating with local communities and national governments.
The speakers shared stories from their work and discussed what they said were the few differences and many similarities between work in resource-limited settings internationally and work with vulnerable populations in Massachusetts.
Community Health Care
All three agreed that building personal relationships with individuals and communities is the foundation for providing excellent care.
“It’s about learning who you are serving and what they want,” O’Connell said, noting that homeless programs around the country all look different because different communities have different needs.
From Sierra Leone to Back Bay, where and how a patient lives has a huge impact on her health, the speakers said.
Bharrel noted a study that found the chances of having diabetes were more than three times higher for riders who take the MBTA to the economically challenged Dudley Square neighborhood in Boston than for the riders who take the MBTA to more affluent Arlington station. Yet the two mass transit stops are less than two miles apart.
Bharrel said non-clinical factors, including economic status, racism and lifestyle, have a much bigger impact on health in Massachusetts than clinical care.
“There are endemic health disparities that are all of our responsibility to address together,” Bharrel said. “Soaring health care costs won’t go down unless we do something about the social determinants of health.”
Farmer said that this was one difference between health care work in places like Boston and work in nations without existing health care systems, where spending on health and education are near zero.
Investing in Health
“The first thing we need to do there is let costs soar,” Farmer said, not only because money is needed to deliver better health, but because investments in health and education yield immense dividends in economic growth.
He also noted that even some countries that are struggling to build functioning health systems have managed to achieve levels of progress delivering certain kinds of care that richer nations have not been able to attain.
Rwanda has better HIV statistics than the United States—higher survival rates, lower transmission rates and greater adherence to medication plans—because they have robust systems of community health workers who can meet patients where they live and make sure their long-term medical needs are met, Farmer said.
“We can’t deliver good care for chronic illness without community health workers,” Farmer said. “But we also need hospitals. If I get hit by a car, I don’t want community based orthopedics; I want a hospital and a surgeon.”
The speakers expressed their shared feeling that the work of treating vulnerable patients was not only morally necessary but richly rewarding, providing complex medical and scientific challenges and opportunities to work with outstanding people, both within the communities served, on clinical teams, and in collaborations with researchers, educators, advocates and policy makers.
“Caring for poor people—whether they are in another country or living within the shadows of this campus—is a challenge requiring great creativity,” O’Connell said. “That’s the real work of places like HMS.”
Researchers from Harvard Medical School and Massachusetts General Hospital have completed the first stage of an important collaboration aimed at understanding the intricate variables of neuropsychiatric disease—something that currently eludes clinicians and scientists.
It contains induced pluripotent stem cells, or iPSCs, derived from skin cells taken from 100 people with neuropsychiatric diseases such as schizophrenia, bipolar disorder and major depression, and from 50 people without neuropsychiatric illness.
In addition, a detailed profile of each patient, obtained from hours of in-person assessment as well as from electronic medical records, is matched to each cell sample.
As a result, the scientific community can now for the first time access cells representing a broad swath of neuropsychiatric illness. This enables researchers to correlate molecular data with clinical information in areas such as variability of drug reactions between patients. The ultimate goal is to help treat, with greater precision, conditions that often elude effective management.
The cell collection and generation was led by investigators at Mass General, who in collaboration with Kohane and his team are working to characterize the cell lines at a molecular level. The cell repository, funded by the National Institutes of Health, is housed at Rutgers University.
“This biobank, in its current form, is only the beginning,” said Perlis, director of the MGH Psychiatry Center for Experimental Drugs and Diagnostics and HMS associate professor of psychiatry. “By next year we'll have cells from a total of four hundred patients, with additional clinical detail and additional cell types that we will share with investigators.”
A current major limitation to understanding brain diseases is the inability to access brain biopsies on living patients. As a result, researchers typically study blood cells from patients or examine post-mortem tissue. This is in stark contrast with diseases such as cancer, for which there are many existing repositories of highly characterized cells from patients.
The new biobank offers a way to push beyond this limitation.
A Big Step Forward
While the biobank is already a boon to the scientific community, researchers at MGH and the HMS Department of Biomedical Informatics will be adding additional layers of molecular data to all of the cell samples. This information will include whole genome sequencing and transcriptomic and epigenetic profiling of brain cells made from the stem cell lines.
Collaborators in the HMS Department of Neurobiology, led by Michael Greenberg, department chair and Nathan Marsh Pusey Professor of Neurobiology, will also work to examine characteristics of other types of neurons derived from these stem cells.
“This can potentially alter the entire way we look at and diagnose many neuropsychiatric conditions,” said Perlis.
“This can potentially alter the entire way we look at and diagnose many neuropsychiatric conditions,” said Perlis.
One example may be to understand how the cellular responses to medication correspond to the patient’s documented responses, comparing in vitro with in vivo. “This would be a big step forward in bringing precision medicine to psychiatry,” Perlis said.
“It’s important to recall that in the field of genomics, we didn't find interesting connections to disease until we had large enough samples to really investigate these complex conditions,” said Kohane, chair of the HMS Department of Biomedical Informatics.
“Our hypothesis is that here we will require far fewer patients," he said. "By measuring the molecular functioning of the cells of each patient rather than only their genetic risk, and combining that all that’s known of these people in terms of treatment response and cognitive function, we will discover a great deal of valuable information about these conditions.”
Added Perlis, "In the early days of genetics, there were frequent false positives because we were studying so few people. We're hoping to avoid the same problem in making cellular models, by ensuring that we have a sufficient number of cell lines to be confident in reporting differences between patient groups."
The generation of stem cell lines and characterization of patients and brain cell lines is funded jointly by the the National Institute of Mental Health, the National Human Genome Research Institute and a grant from the Centers of Excellence in Genomic Science program.
Hundreds of global experts on the science of health care delivery attended events on Oct. 25-27 at the Harvard Medical School Center for Global Health Delivery-Dubai, to discuss a plan for improving health worldwide.
HMS faculty joined leading clinicians, researchers, advocates and government representatives from Brazil, China, Dubai, India, Pakistan, Peru, Russia, South Africa and other countries discussed case studies from the vanguard of global health delivery.
“This Center is a remarkable place, where we have embarked on research and training that is moving us closer to that goal of ensuring that the fruits of modern medicine reach those who need it most,” said Salmaan Keshavjee, director of the Center and associate professor of global health and social medicine at HMS. “Our mission is scientific, but it is also profoundly moral.”
“You can take a drug all the way from the researcher’s laboratory bench to the hospital bedside, but if you can’t put it in people’s mouths, you haven’t met your goal,” Keshavjee said.
An evocative photographic exhibit featuring images by Shehzad Noorani, an award-winning documentary photographer, was on display during the events, showing the challenging social, economic and political contexts in which health care delivery must take place.
Events occurred over three days. The first event, the Center’s inaugural symposium, took place on Sunday, Oct. 25. Speakers examined care delivery gaps in the treatment of major diseases affecting the United Arab Emirates, the broader region and the world. These conditions included diabetes and obesity, surgical care, infectious disease and mental health. Speakers emphasized the importance of developing local capacity for research, systems building and care delivery. These topics are all at the core of the Center’s research and training mission.
His Excellency Humaid Al Qatami, chairman of the board and director general of the Dubai Health Authority, noted in a statement that the Center “will provide evidence-based data on which health policy and developmental programs can be based. This is vital to achieve effective outcomes and foster further development of the health sector.”
Many presenters and attendees shared that sense of the Center’s potential.
“Your activities in this region, at the intersection of Asia, Africa and the Middle East, are critically important,” said Jim Yong Kim, president of the World Bank Group in a video message. “This Center, I am sure, will play a defining role in addressing the gap in health care delivery.”
The second and third events were focused on presenting the scientific, clinical and policy case for a campaign to eradicate tuberculosis, and highlighting a new global effort underway to test that case.
On Monday morning, the Center hosted a launch event for a new series in The Lancet, which focused on charting a course to end the global epidemic of tuberculosis, a scourge that currently kills 1.5 million people every year.
On Monday afternoon and throughout the day Tuesday, the Center hosted the launch of Zero TB Cities, an ambitious program that aims to follow the course outlined in the Lancet papers to rapidly eliminate TB in municipalities around the globe.
Fighting the disease requires a comprehensive approach that includes actively identifying people with tuberculosis disease and infection, treating all forms of TB with targeted, effective therapies and addressing the many social factors that contribute to the spread of the epidemic and mortality from TB. Current policies generally advocate treating only the sickest patients, which allows the disease to continue to spread unchecked.
“There's been a breakdown somewhere,” said Pamela Das, senior executive editor at The Lancet, speaking at the launch of the Lancet series. “Here we sit today and we see what does work if we do it properly. We can't wait for global institutions … we've got to go out there and do it.”
The inaugural symposium on Sunday included a keynote address by Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine at Harvard and head of the Department of Global Health and Social Medicine at HMS. Jim Kim and Jeffrey S. Flier, dean of HMS, also addressed the meeting by video. The Monday and Tuesday events included leading tuberculosis researchers and clinicians from around the world.
“We at Harvard Medical School are privileged to collaborate with our colleagues in Dubai in this important effort to address gaps in global health care delivery in Dubai, the region and the world,” Flier said.
“We are pleased to welcome a world-class institution—the Harvard Medical School Center for Global Health Delivery-Dubai to the Mohammed Bin Rashid Academic Medical Center, the seat of medical education and research at Dubai Healthcare City,” said Her Excellency Dr. Raja Al Gurg, vice chairperson and executive director, Dubai Healthcare City Authority, in a statement.
The Center was established in 2014. All of the events were held at the Mohammed Bin Rashid Academic Medical Center in Dubai Healthcare City, where the Center recently opened its headquarters.
The inaugural symposium took place under the patronage of His Highness Sheikh Mohammed bin Rashid Al Maktoum, vice president and prime minister of the United Arab Emirates and ruler of Dubai.
Funding for the Center is being provided by a four-year grant from the Dubai Harvard Foundation for Medical Research. The events were supported by funding to HMS from Janssen Global.