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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.
Although tuberculosis has been curable and preventable since the 1950s, more than 4,000 people each day, or 1.5 million each year, still die from this airborne disease.
A new Series in The Lancet—led by Salmaan Keshavjee, Harvard Medical School associate professor of global health and social medicine—details a scientific, therapeutic and policy plan to rapidly stop deaths from TB and change the epidemic’s course, one community at a time.
The plan does not require new breakthroughs. Instead, it requires better use of tools that already exist.
“Ending the global tuberculosis epidemic requires the urgent deployment of a comprehensive package of effective, tried and tested interventions in low-income and middle-income settings,” Keshavjee said. “Failure to seize this opportunity now will constitute both a scientific and a moral failure.”
In preparing the series, Keshavjee, his co-editors and his colleagues at HMS’ Department of Global Health and Social Medicine brought together researchers, clinicians and advocates from governmental and nongovernmental organizations, hospitals and universities around the world for a series of working meetings and conferences.
“While TB incidence rates in high-income countries are in single-digit numbers, these rates are still in the hundreds in many countries of Asia, Africa and Latin America. The drivers of TB include poverty, poor housing, under-nutrition and HIV infection, underscoring the need to address this problem holistically,” said series co-editor, Soumya Swaminathan, director-general of the Indian Council of Medical Research.
"The drivers of TB include poverty, poor housing, under-nutrition and HIV infection." — Soumya Swaminathan
The series, which will be published online in The Lancet on Oct. 26 and as a standalone booklet, will be launched at a special event at the Harvard Medical School Center for Global Health Delivery-Dubai, where Keshavjee is director.
In addition, researchers, clinicians and policymakers will also meet to launch Zero TB Cities, an initiative that will apply the principles outlined in the Lancet series in municipalities around the world to create “islands of elimination” of the disease.
According to series co-editor David Dowdy, associate professor of medicine at Johns Hopkins University, “We cannot end TB globally without ending it locally. Cities are the places to start if we are to show the world that the status quo in TB can be changed, rapidly and dramatically.”
The series includes three commentaries that place the epidemic in historical, clinical and scientific context and four papers that detail a comprehensive strategy to quickly reach zero deaths from TB and to reach 2050 elimination targets more rapidly in high-burden settings.
The Series papers also provide the scientific and social policy rationale of comprehensive disease strategy. The keys to the elimination plan include targeting hotspots of transmission; active case finding to identify infected individuals before they can transmit disease to others; and prompt and proper treatment of all forms of tuberculosis.
This comprehensive approach is a stark contrast to current piecemeal practices that often target only the sickest patients and provide incomplete therapies for those who do receive treatment. The results have yielded steady but slow improvements in death rates, combined with a worrisome increase in drug-resistant strains of the disease.
“We have to hit this bug hard, and hit quickly. Cutting transmission in the community is key to the control of any infectious disease. Many cities in the world are seeing worrying increases in transmission of drug-resistant tuberculosis. All of us are vulnerable … and therefore, we must all act,” Swaminathan said.
“Business as usual can no longer be an option for the fight against tuberculosis,” writes Senior Executive Editor Pamela Das and Editor Richard Horton of The Lancet.
“We hope this series will be a springboard that can help shift the global tuberculosis epidemic from incremental annual improvements to an accelerating global movement for tuberculosis elimination,” he said.
The commentaries and papers in the series, with authors from more than a dozen nations, reflect this collaborative international effort.
The glacially slow decline in the death rate for tuberculosis—a decrease of less than 2 percent annually—is unacceptable, the authors argue, when the means to stop the epidemic have been available for more than half a century.
“We can’t wait another two centuries for a curable and preventable disease to disappear,” Keshavjee said.
This effort was funded by support to HMS from Janssen Global.
The Series will be launched on Monday, Oct. 26, 2015 at 10 a.m. (Dubai time), at a special event at the Harvard Medical School Center for Global Health Delivery-Dubai.
For more details, please visit: http://ghd-dubai.hms.harvard.edu/TB_lancet_manuscript_launch
To learn more about The Lancet Series: www.thelancet.com/series/how-to-eliminate-tuberculosis
A new test can accurately diagnose Ebola virus disease within minutes, providing clinicians with crucial information for treating patients and containing outbreaks.
Researchers from Harvard Medical School, Partners In Health and Boston Children’s Hospital have shown that a new commercially developed rapid diagnostic test performed at bedside was as sensitive as a conventional laboratory-based method used for clinical testing during the recent outbreak in Sierra Leone. The results are published in The Lancet.
While the West African Ebola epidemic has slowed since its peak last fall, the crisis simmers on; there were still 24 confirmed cases of Ebola reported in Guinea and Sierra Leone in the week ending June 14.
To fight Ebola, the first step is to determine which patients are sick with the disease and which with other illnesses with a similar presentation. To use the currently recommended molecular approach, laboratories must be built and samples of highly infectious blood must be drawn, often with unsafe needles and syringes, and then shipped over potentially great distances at substantial risk to the health care workers involved in the process. Then, clinicians and patients must wait for results—sometimes for several days.
These obstacles and delays prevent timely diagnosis and treatment, and also result in individuals without Ebola being admitted to holding units where they may become infected with the virus, the researchers said.
“Simplifying the process and speeding up diagnosis could have a major impact,” said Nira Pollock, senior author of the paper and HMS assistant professor of medicine and pathology and associate medical director of the Infectious Diseases Diagnostic Laboratory at Boston Children’s Hospital.
As the Ebola outbreak in West Africa began to surge in 2014, Pollock and Partners In Health researcher Jana Broadhurst worked with the research core of the HMS Department of Global Health and Social Medicine to reach out to teams around the world who were developing diagnostic tools that would enable clinicians to diagnose Ebola patients quickly.
One candidate, the ReEBOV Antigen Rapid Test, developed by Corgenix, seemed like a promising tool. Working with colleagues at Partners In Health and the Ministry of Health and Sanitation in Sierra Leone, the HMS team was able to plug into an environment that allowed it to train local technicians to perform the test and help collect data for the study. The team at the Public Health England lab at Port Loko, where clinical samples were routinely sent for standard molecular diagnostic testing, were also key collaborators. Corgenix donated test kits to the HMS team.
The field trial took place at two treatment centers operated by the Ministry of Health and Sanitation of Sierra Leone and supported by PIH, where 106 patients suspected of having Ebola were tested during February 2015 using the rapid diagnostic test (performed on a fingerstick blood sample at the point of care). The patients were also tested using the standard RT-PCR (performed on plasma in the laboratory). Both rapid diagnostic tests, on whole blood, and RT-PCR, on plasma, were also performed on 284 samples in the laboratory.
The rapid diagnostic test detected all confirmed cases of Ebola that were positive by the benchmark test in both point-of-care and laboratory testing with sensitivity of 100 percent (identifying all patients with Ebola found by the benchmark method), and a specificity of 92 percent (few false positives).
Surprisingly, the study also showed that the standard RT-PCR test, under the conditions deployed in the field, was itself an imperfect reference standard.
Both tests failed to detect a small number of Ebola cases that had been detected by an alternative lab test that was more sensitive than the benchmark test but was not available for wide usage. All of the missed cases showed very low levels of virus. The authors caution that given the limitations of the performance of the benchmark RT-PCR reference test in patients with low levels of the virus, more research is needed to assess how the new rapid diagnostic test will perform in patients still in the early stages of Ebola virus disease.
The ReEBOV test uses a drop of blood from a fingerstick performed with a safety lancet, which has a spring-loaded mechanism that prevents health care workers from receiving accidental needlesticks after the blood is sampled. The ReEBOV test works similarly to a home pregnancy test: the sample is applied to a treated strip, and if the sample is positive for Ebola, a colored line appears on the strip at a specific location.
The researchers noted that it was essential to study the test in the field to see whether it worked in the challenging conditions that clinicians face in rural clinics and in Ebola treatment units in such places as Sierra Leone. For example, wearing the required personal protective equipment made it potentially difficult to read the test strip, so instead of having one clinician check results, the research team developed a method in which two clinicians checked each test, with a third stepping up in cases where the first two disagreed.
“We’re talking about a truly extreme environment here,” said study co-author Megan Murray, HMS professor of global health and social medicine and director of research at Partners In Health.
Not only were there no electronic health records, but due to strict infection control measures, researchers were not permitted to take handwritten notes out of the treatment unit.
Because the researchers had existing relationships with Partners In Health clinicians who had already built collaborative relationships with local caregivers, they were able to build on those relationships to create an integrated clinical and research team.
“This is a powerful combination,” Murray said. “To get research that provides meaningful results, researchers need connections to the communities and health systems that they're trying to understand.“
Once the researchers saw that the test was effective, they shared their findings with the Partners In Health clinical network, with other partners in Sierra Leone and West Africa, and with the other governmental and non-governmental organizations working to end the Ebola epidemic.
“That’s another advantage of working closely with clinical care delivery teams: they can help us get the word out when we find something that works,” Murray said.
Ultimately, public health and regulatory officials in each of the affected countries will decide how the test is used in clinical and surveillance efforts, taking into account guidance from WHO and FDA.
Funding for the study was provided by a gift from the Abundance Foundation (Stephen Kahn). Corgenix provided test kits for the study but did not provide any monetary support; Corgenix personnel were not involved in data acquisition or analysis.
A map can tell you where you are, and it can also help lead to where you want to be.
The findings of the landmark Lancet Commission on Global Surgery report, which includes publications in seven academic journals and a series of teaching cases, are an assessment of the current state of need for surgery worldwide in resource-poor settings. The report also outlines steps that commissioners say will lead not just toward improved access to surgery for people around the world, but toward sustainable universal health care.
On May 6, the Commission held the Boston launch of the report at Harvard Medical School. The event was focused on the contributions that care providers, academic medical centers, industry and donor organizations in the developed world can make toward these goals. A series of similar events will take place around the world.
John Meara, the HMS Steven C. and Carmella R. Kletjian Professor of Global Health and Social Medicine in the Field of Global Surgery and lead author of the report, outlined the history of the commission process and pointed the way toward the future.
“We started with a clear vision,” said Meara, who is also HMS associate professor of surgery at Boston Children’s Hospital. “Universal access to safe, affordable, surgical care and anesthesia.”
The study more than doubled previous estimates of unmet need for surgical care, finding that 5 billion people are unable to access safe, timely affordable surgery and anesthesia. This leads to 18.6 million preventable early deaths each year, surpassing the number of people who die from HIV/AIDS, malaria and tuberculosis combined. To meet these needs, researchers calculated that an additional 143 million more surgical procedures were needed annually.
As if the costs in human life and health weren’t enough, the lack of surgical access also has dire economic costs: 33 million individuals face catastrophic expenditures that will plummet them into extreme poverty if they seek surgical care, and many low- and middle-income countries are fast approaching the point where losses in productivity from people hurt or killed by lack of access to proper surgical care will cost 2 percent of GDP.
“We call it a launch for a reason. It’s not the end of the journey. We have a long way to go, and we’re going to have to work together,” Meara said.
In spite of the human and economic costs, the Commission found that surgery is not only affordable, it is actually a high return investment, saving lives and preventing economic loss that far outweighs the costs of providing necessary care.
Reaching the necessary levels of access to surgery by 2030 would require an investment of $420 billion, the commission found. That investment would save an estimated $12 trillion in lost GDP over the same period, they found. Researchers at the launch noted that these estimate make surgery a “best buy” in global health.
“We have to think in a fundamentally different way about health care and surgery’s role in it in developing countries,” Jim Yong Kim, president of the World Bank and former head of the HMS Department of Global Health and Social Medicine, said in a taped video address. Kim and others also noted that, since surgery is crucial to health, it is an essential part of economic development.
“Without surgery, sustainable economic development is a fairy tale, a laughable fiction,” said Gavin Yamey, associate professor of epidemiology and biostatics at the University of California, San Francisco School of Medicine.
Throughout the day, speakers focused on the power of collaboration and accompaniment and emphasized that surgery is an indivisible and indispensible part of health care delivery. To accomplish these goals, surgeons will need to work with educators and students, clinicians and community health workers, hospital administrators and logistics experts. Speakers also emphasized the importance of integration, collaboration, broad-scale systems development, and building local capacity through training.
Many speakers highlighted the importance of creating pathways to unleash the passion, skills and commitment of young people throughout the world who want to make a career in global surgery.
The report features several “heat maps” that plot the availability of surgery and the supply of surgical professionals by country. In his afternoon keynote address, Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine at Harvard and head of the HMS Department of Global Health and Social Medicine, noted that the areas in the maps that indicate the greatest unmet surgical need correspond almost exactly to the countries that are undergoing what some call a “youth tsunami.”
Farmer suggested that instead of thinking of this coming wave of young people as a destructive, crashing force, we should see them as a source of enthusiasm, energy and innovation.
“We have to think of them not just as potential patients, but as future colleagues in global health and global surgery,” Farmer said.
A vaccination campaign that almost didn’t happen was widely effective in reducing transmission of cholera in the midst of an ongoing outbreak of the disease in rural Haiti.
According to a study led by Harvard Medical School researchers at Partners In Health, there were 63 percent fewer cholera cases among the thousands of adults and children who received the cholera vaccine Shanchol than among those who were unvaccinated. The results were published in the March issue of The Lancet Global Health.
“This study demonstrates that the vaccination campaign saved lives and reduced suffering,” said Louise Ivers, HMS associate professor of global health and social medicine and a senior health and policy adviser at Partners In Health. “We undertook the campaign as a public health emergency, but having data to demonstrate how effective it was helps to solidify the case for using vaccines in this kind of setting—and that helps transfer lessons from Haiti to other places where cholera occurs or may appear for the first time.”
The plan to provide the vaccine was surprisingly controversial. Skeptics cited several reasons: the vaccine had been proven effective in areas with smoldering, lingering cholera, not in a full-blown outbreak; the impoverished landscape and absence of a functioning health system in much of rural Haiti would present logistical challenges; and an approach common in resource-limited settings that delivers the minimum basic health care in order to save scarce funds.
Critics of the vaccination plan suggested that efforts would be better spent on basic hygiene education and hand-washing campaigns. The vaccine costs $1.85 per dose.
“When you see people dying, you want to do everything you can,” said Ivers, who is also HMS associate professor of medicine at Brigham and Women’s Hospital. This includes preventive measures such as hand washing, treatments like rehydration, and using the vaccine.
Working with the approval of the Haitian Ministry of Health, Partners In Health and its sister Haitian organization Zanmi Lasante carried out the vaccination program from April to June 2012, training field workers, fighting the rainy season mud and ensuring that 45,417 patients swallowed two doses of the drug two weeks apart.
“Our study contributes to mounting evidence that oral cholera vaccines have an important role to play as a component of comprehensive, integrated cholera control efforts in Haiti,” the study concludes.
The study also highlights the importance of integrating the development and testing of new vaccines and therapies, the creation of health care delivery systems and the collection of crucial research data in comprehensive, coordinated efforts.
The team also included physicians and researchers from Brigham and Women’s Hospital, Massachusetts General Hospital, Zamni Lasante and the Haitian Ministry of Health and Population. Molly Franke, HMS assistant professor of global health and social medicine, was senior author on the paper.
This research was funded by the National Institutes of Health, the Delivering Oral Vaccines Effectively project and the HMS Department of Global Health and Social Medicine.
Adapted from a story originally posted at PIH.
While the current Ebola outbreak in West Africa appears to be waning after claiming more than 9,000 lives, public health and scientific concerns about the crisis remain urgent. Harvard Medical School will host a symposium on March 5, 2015, to shed light on the issue.
“Rethinking the Response to Emerging Microbes: Vaccines and Therapeutics in the Ebola Era” will convene international experts in virology, infectious disease, vaccines and therapeutics. They will discuss strategies both to combat the current Ebola outbreak and to inform future preparedness for the unique challenges of this and other emerging infections.
- Overview of the Ebola virus, its pathogenesis and the state of the current outbreak
- What are our most promising current and future therapeutics and vaccines?
- What are the scientific and regulatory issues limiting development of Ebola vaccines and therapeutics?
- How can we be more prepared for future emerging infections?
Speakers will include Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and other leaders from government, the biomedical industry and academic research centers.
The symposium will be held from 8:30 a.m. to 5:15 p.m. March 5, 2015, in the Joseph B. Martin Conference Center Amphitheater in the New Research Building at Harvard Medical School.
This event is made possible by grants from PhRMA (the Pharmaceutical Research and Manufacturers of America) and the HMS Max Finland Lecture Fund.
Imagine administering a diagnostic test for Ebola while sweltering in an airtight hooded spacesuit—with thick rubber gloves on your fingers. Then consider waiting for results while someone else operates the technology that signals whether it’s a grave illness or a more ordinary infection that the person is suffering.
Thinking about devices in the hands of the people actually using them is exactly what a team of biomedical scientists and engineers from Harvard Medical School and MIT are doing as they design a diagnostic to detect Ebola virus and other dangerous microbes.
A cheap, reliable test made of paper that can rapidly determine infection is the goal of a team led by Lee Gehrke, HMS professor of microbiology and immunobiology and the Hermann von Helmholtz Professor of Health Sciences and Technology at MIT. They hope to make it as simple to use as a home pregnancy test. How cheap and how fast? Under $10 and under 20 minutes.
“That’s really the mantra of the work we are doing,” Gehrke said in an interview in his MIT office. “We are trying to devise devices that are easy to use in austere environments that have no power, no refrigeration, no specialized chemicals, no specialized instrumentation—and can give a quick triage notice of what disease a patient may have.”
Of all the crying needs seen in such abundance in West Africa during the Ebola epidemic, diagnostic testing is high on the list. Health workers need to know who is harboring infection and who is not—quickly—without relying exclusively on sophisticated equipment whose results require off-site interpretation or troubleshooting. Proper treatment and containment of infectious pathogens hang in the balance.
“Is the person handling the test going to have to have a PhD in microbiology, or will it be somebody who just finished cleaning up after a patient and has never seen a rapid test before? Will they be wearing thick gloves to protect themselves?” asked José Gómez-Márquez, director of MIT’s Little Devices Laboratory. “Making sure these things survive in an environment as hellish as what we see in West Africa can be a big challenge.”
For the past five years, long before Ebola began its sweep through Guinea, Liberia and Sierra Leone, Gómez-Márquez and Gehrke have been working with other scientists and engineers in the Harvard-MIT Program in Health Sciences and Technology to bring diagnostic tools to low- and middle-income countries.
Ebola virus infection may be the most terrifying outbreak right now, but other viruses perennially spread misery among people living in countries where health care systems are less than robust. Their common symptom is fever, so distinguishing among dengue fever, Marburg fever, yellow fever and chikungunya virus infections and their subtypes is important.
The researchers hope their answer is on paper, more specifically, 3 millimeter by 15 millimeter (1/8 inch by 9/16 inch) strips of paper that separate gold nanoparticle sensors carrying antibodies and single strands of DNA or RNA called aptamers. These sensors bind to certain microbial proteins in blood or serum that then flow through paper fluidic pathways to create patterns of lines that identify the pathogen.
Gehrke calls it a simple design based on the well-established technology known as lateral flow chromatography, or paper fluidics. The goal of this project is to show that a complex mixture of proteins or sera applied to the device can deliver a clear signal about which virus or pathogen is present in such a way that is not confused by cross-over from other viruses or serotypes.
While their work had advanced the furthest on a multiplexed dengue fever test, the team accelerated its pace on an Ebola test when the crisis emerged in West Africa. Last fall they sent their Ebola test to the Texas Biomedical Research Institute in San Antonio where former HMS colleagues Jean Patterson and Anthony Griffiths are involved in verifying its accuracy in animals experimentally infected with live virus in the institute’s Biosafety Level 4 Laboratory.
What they learn from dengue testing could help shape the Ebola test.
In dengue infection, discerning which serotypes are in a sample is important because immunity from one does not protect against infection with another. Changes in dengue virus samples can predict epidemics in regions where the cyclical, mosquito-borne disease is a threat.
Laboratory testing in Cambridge has shown that the team’s test can pick up the four dengue serotypes. Field testing will begin in the spring in Bucaramanga, Colombia, to make sure that differences in factors such as diet, for example, between populations in Cambridge and Colombia don’t interfere with the results. A sterile lab is different from a real-life clinic, where patients’ leftover blood samples will be used to test the test.
Colleagues in Colombia will also be observing how people use the paper-test device and how a mobile phone app can be enlisted to record and report their findings through simple MMS or SMS messages. The mobile phone removes the subjectivity from analyzing the test results, and the team is focused on developing a culturally and clinically appropriate phone interface to use with the device.
“The challenge with detecting viral proteins or viral antibodies is that their blood levels change during infection,” Gehrke explained. “The added value is that the changing levels provide information about the stage of the infection, which might be relevant to how the patient is treated.”
While the scientists cannot predict when either the Ebola or the dengue test would be ready for use in the real world, Gehrke and Gómez-Márquez said they will be making changes in an iterative way based on the Colombia testers’ results, speeding the process and broadening the definition of codesigners to include testers and their ideas.
To expand crowdsourcing even further, Gómez-Márquez wants to enlist patients as “citizen sensors.” Ultimately the scientists hope to combine data from these tests, which can be used not just in the clinic but also in the home, to create a real-time map of disease spread in parts of the world where mobile phones may be easier to find than health care. Public health researchers now rely on information that can be weeks old, but immediate, verifiable confirmation of infection could better guide medical response.
“We don’t think about this specifically as an Ebola test,” Gehrke said. “Rather, we are developing a platform that could be used for a number of different kinds of tests. Fortunately this Ebola outbreak is waning, but what’s coming next?”
When Ebola meets modern medicine, most patients survive.
But the Ebola epidemic in West Africa is raging far from the hospitals in Germany and the United States, where the few people infected with the virus have received prompt diagnosis and aggressive care.
Instead, patients in Liberia, Sierra Leone and Guinea are dying for lack of “staff, stuff, space and systems,” Paul Farmer told the Harvard Medical School community members who gathered to hear him talk about Ebola and global health equity.
Farmer is the Kolokotrones University Professor of Global Health and Social Medicine at Harvard and head of the HMS Department of Global Health and Social Medicine. He is also the co-founder and chief strategist of Partners In Health, whose mission is to bring the benefits of biomedical science to those most in need.
“Modern medicine and Ebola have never collided before,” he said. “What we are doing now is making them collide.”
Modern medicine means IV solutions and the nurses to deliver them, plus clinics to care for patients and systems to control spread of the infectious disease while winning the trust of the people they serve.
Farmer cast his glance around the Joseph B. Martin Center auditorium, appealing for volunteers to join the cause.
“The unswerving support of the leadership at the medical school and its affiliated hospitals has been and will be critical to turning the Ebola epidemic around,” he said.
On his trips to West Africa, he hears time and time again that the virus was spread by one person caring for another at home.
“Doctors and nurses are at high risk, but so is anyone providing care: children, relatives, neighbors, Good Samaritans,” he said. “The transmission chain of Ebola is caring.”
Hydration and electrolyte replacement are the minimum interventions required to help patients recover. During infection, Ebola patients, much like cholera patients, can lose up to 10 liters a day of fluids. There are not enough health care workers to make up the difference.
“In Liberia, a country of 4 million people, there were fewer than 50 physicians in the country working in health care delivery in the public sector before Ebola. You can imagine what it is now,” Farmer said. “I see 50 physicians on every floor of the Brigham on any given morning.”
Volunteers should be taken care of, too, he said, rather than met with threats of quarantine and stigma when they return.
Ebola’s impact on Liberia’s primary care system has been devastating and complete, he said. “If it was bad before, it’s nothing short of apocalyptic now.”
To help “our neighbors,” we need to think about building health systems. But before then, people need to trust the Ebola treatment units where they now fear they will die.
“We need to drop the mortality rate by providing quality health care,” he said.
Farmer buttressed his arguments by citing examples of work done by Partners In Health in Haiti and Rwanda.
In his introduction, Jeffrey S. Flier, HMS dean, said, “Instead of choosing between providing care and building local capacity, Paul finds a way to do both.”
In closing, Farmer reminded his audience of the medical response to people injured in the 2013 Boston Marathon bombings.
Because of staff, stuff, space and systems, he said, no one who made it alive to a Boston hospital died.
“Can we do it in West Africa?” he asked. “Of course we can.”
Over this summer and fall, enterovirus-D68 spread across the United States. This virus belongs to a virus family that is subclassified into familiar categories, including polio viruses, coxsackie A and B viruses, echoviruses and other enteroviruses.
These viruses cause a variety of illnesses, including gastrointestinal illness, rash and neurologic illnesses, such as aseptic meningitis. The respiratory tract is mildly affected.
EV-D68, however, was recognized as causing moderate to severe respiratory illness in children in the Midwest in August 2014. These affected children usually had a preexisting respiratory condition such as asthma.
Indeed, children with asthma seem to be particularly vulnerable with these children presenting symptoms such as cough, shortness of breath and difficulty breathing. Fever, which occurs in only about 30 percent of affected children, is not a major component of this illness. Thomas Bernard Kinane is an HMS associate professor of pediatrics at Massachusetts General Hospital and an international expert in pediatric respiratory conditions. Here he talks with Harvard Medicine News about EV-D68.
HMS: How concerned do people need to be about enterovirus?
KINANE: Most EV-D68 infections cause very mild symptoms, like a cough, runny nose or muscle aches. In patients with respiratory disease it can cause more serious symptoms, such as difficulty breathing or wheezing. These patients can be severely affected but almost all recover.
HMS: Who in particular might be more vulnerable or at most risk?
KINANE: Children with asthma seem to be particularly vulnerable, but asthma is not the only respiratory condition that is exacerbated by this virus. Patients with neuromuscular disease and interstitial lung disease seem to be similarly affected.
HMS: How does it differ from other more common viruses such as cold and flu?
KINANE: Enteroviruses are a different viral family from the cold (rhino) virus and the flu (influenza) virus. Enteroviruses do not usually affect the respiratory system as cold and flu viruses do. Indeed, this enterovirus is different from other enteroviruses as it seems to predominantly affect the respiratory systems.
HMS: In what sorts of ways is the biomedical research community making progress against these sorts of pathogens?
KINANE: This virus is relatively new and has only caused minor outbreaks of viral illness over the last 40 years. The medical community has focused on supportive care, which has allowed almost everyone to recover.
However, there is intense focus on another illness. Over the last two years, there was another unusual illness affecting a very small number of children. This illness causes acute muscle weakness, similar to polio. Two of these cases tested positive for EV-D68. It is difficult to know if this new condition is related to EV-D68 but is subject to intense research.
HMS: Are there more of these kinds of dangerous viruses out there in the community then there have been in the past, or are we just more aware?
KINANE: From time to time a new virus emerges; most of the viruses are variations of well-known viruses. The CDC has an excellent surveillance system. There is no reason to be concerned.