In late 2010, cholera spread through the streams and rivers of Haiti, killing hundreds of people within weeks. Using maps of river networks and population centers, Princeton researchers and their collaborators created a mathematical model to predict where the disease would strike next and help aid workers get supplies ready for the next outbreak.
“There are two things that set Princeton global health research apart from the rest,” said Adel Mahmoud, an expert in international health and a lecturer with the rank of professor of molecular biology and public policy in the Woodrow Wilson School of Public and International Affairs. “One is the interdisciplinary nature, and the other is the depth of the scientific research — this is fundamental and mechanistic research.”
This depth can be found in every type of international health research at Princeton. Some researchers work in laboratories, uncovering basic mechanisms of pathogen behavior. Some crunch numbers from huge datasets. Others are out in the field, documenting the medical and social impact of global health interventions through case studies and patients’ life stories. All are engaged in finding ways to critically assess what does and does not work in helping people live healthy lives.
The researchers come from a variety of disciplines including anthropology, chemistry, economics, engineering, molecular biology, history, political science, ecology and evolution. “Princeton is well-suited to study different dimensions of global health because we have a structure that lends itself to interdisciplinary study,” said Bryan Grenfell, the Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and Public Affairs at the Woodrow Wilson School.
“Together we are producing a more realistic and improved science of global health, and training researchers to tackle the novel ecologies of disease and health in the context of globalization, technology access and enduring inequalities,” said João Biehl, co-director of Princeton’s Program in Global Health and Health Policy and the Susan Dod Brown Professor of Anthropology.
Interrupting cell talk
Bonnie Bassler, the Squibb Professor in Molecular Biology and a Howard Hughes Medical Institute (HHMI) investigator, leads a team studying how single bacterial cells talk to each other, work that could lead to the development of new antibiotics.
“All our existing antibiotics kill bacteria,” Bassler said. “We come at the problem from a different direction: What if we could modify bacteria so that they cannot talk to each other, and therefore cannot perform the group behaviors required to successfully infect the host?”
Bassler’s research indicates that bacterial cells communicate with each other through the exchange of small molecules called autoinducers that enable the single-celled bacteria to act as a collective. “They allow bacteria to act like multicellular organisms,” Bassler said. For example, this cellto- cell communication helps bacteria know when to initiate infection. By exchanging autoinducers, bacteria take a headcount of their numbers. This process of “quorum sensing” can control bacterial activities such as the production of virulence factors needed for infecting hosts or making biofilms on surfaces.
Bassler’s team has discovered a number of novel compounds that trick the bacteria that cause cholera into shutting down virulence, thus stopping the bacterial infection. The research was published in a June 2012 issue of the journal PLOS Pathogens. The work, which was supported by HHMI, the National Institutes of Health and the National Science Foundation, could lead to new approaches to stopping cholera, a disease that afflicts roughly 200,000 people worldwide each year, according to the World Health Organization.
Predicting the next outbreak
While Bassler works on potential treatments for cholera, civil and environmental engineering professor Ignacio Rodríguez-Iturbe is developing models capable of predicting where the deadly disease will go next.
Primarily waterborne, cholera bacteria are excreted in feces and can survive in water for long periods of time. Weak sanitary conditions due to devastation from the 2010 Haiti earthquake, combined with rainfall washing bacteria into rivers and streams, make it likely that cholera will persist in Haiti for the next several years, said Rodríguez-Iturbe, the James S. McDonnell Distinguished University Professor of Civil and Environmental Engineering. Predicting where the disease is headed next could save lives by giving health officials time to distribute electrolyte-replacement fluids and antibiotics while educating the population about preventing disease transmission.
Rodríguez-Iturbe and his colleagues modeled the movement of the bacteria through river networks using data on the locations of reported cases as well as maps of Haiti’s river basins and rainfall climatology, plus scenarios of possible weather patterns and rainfall. They included factors to account for the movement of people between towns and the susceptibility of individuals based on previous cholera exposure. For the work, which was funded by the European Research Council and the Swiss National Science Foundation, Rodríguez-Iturbe worked with long-time collaborator Andrea Rinaldo, an ecohydrology professor at École Polytechnique Fédérale de Lausanne in France.
Earlier this year, Rodríguez-Iturbe and Rinaldo reviewed the success of the model in predicting the course of the outbreak. Writing in an April 2012 issue of the journal Proceedings of the National Academy of Sciences, the researchers concluded that mathematical models of large-scale outbreaks are an essential component of future cholera epidemic control. They are now refining their predictions of where cholera will surface in Haiti through 2014 and improving their models of human mobility with the help of cellphone usage data.
“The model does an outstanding job of predicting a second peak of the outbreak,” said Rodríguez-Iturbe. “It also allows us to try interventions and to predict how well they will work.” He and Rinaldo are planning a cooperative research project with Médicins Sans Frontières to explore using the model to predict disease cases in Haiti.
Nightlights reveal disease patterns
Tracking disease outbreaks can be difficult in regions where transportation is limited, but one Princeton researcher found a way to do it from above. Nita Bharti, a postdoctoral researcher in ecology and evolutionary biology working in the lab of Professor Bryan Grenfell, led a project to use satellite images of nighttime lights to gauge the risk of a measles outbreak.
Bharti and her co-authors used nighttime images of the three largest cities in the West African nation of Niger to correlate seasonal movement of human populations with the onset of measles epidemics during the country’s dry season, roughly from September to May. Night-light data images taken between 2000 and 2004 by a U.S. Department of Defense satellite indicated where people were clustering by capturing the expansion and increasing brightness of lighted areas. In work supported by the Bill and Melinda Gates Foundation, the researchers compared those images to records from Niger’s Ministry of Health of measles cases from the same years.
The team found that measles cases were most prevalent when a city’s lighted area was largest and brightest. Monitoring changes in nighttime lights can clearly indicate where and when a population is expanding and where an epidemic would most likely occur, and could help healthcare workers plan ways to combat outbreaks rather than just respond to them, Bharti said.The researchers reported the results in a December 2011 issue of the journal Science.
“Once you establish the patterns of epidemics, you can adjust your intervention strategy,” she said.
Policies that shape health
Intervention strategies can save lives, but they can sometimes backfire. For example, overprescribing antibiotics has had lasting repercussions on the development of antibiotic resistance in some of the most deadly bacteria such as E. coli and methicillin-resistant Staphylococcus aureus (MRSA), according to research led by Ramanan Laxminarayan, a research scholar in the Princeton Environmental Institute and director of the Center for Disease Dynamics, Economics and Policy in Washington, D.C.
In a study published in the journal Clinical Infectious Diseases in July 2012, Laxminarayan and his co-authors looked at data on how antibiotic usage from 1999 to 2007 preceded development of antibiotic resistance in E. coli and MRSA. They found that the number of prescriptions for certain antibiotics correlated to the development of resistant bacteria roughly one month later. Support for the research came from Princeton’s Health Grand Challenges Program and the Robert Wood Johnson Foundation.
Although the study relied on prescribing patterns in the United States, Laxminarayan noted that antibiotic resistance has become a global problem and that studies like this one can help health officials set policies. “This research is an example of how economics and disease modeling can inform the design of policy in a way that has a direct impact on people’s lives,” said Laxminarayan.
The power of numbers
Much of the global health research at Princeton takes place within the Center for Health and Wellbeing, an interdisciplinary unit in the Woodrow Wilson School, which seeks to foster research and teaching on multiple aspects of health and well-being in both developed and developing countries.
The center’s director, Janet Currie, is a health economist who uses large datasets to uncover relationships that might otherwise be missed. Entries on birth certificates, disease registries and other records are typical sources for Currie, Princeton’s Henry Putnam Professor of Economics and Public Affairs. “My typical data set is millions of observations,” she said.
Using these observations, Currie and economist Maya Rossin-Slater of Columbia University reported earlier this year that pregnant mothers who experience the stress of a hurricane or major tropical storm are at an elevated risk of giving birth to a child with health problems requiring immediate medical care, or suffering complications from labor and delivery.
The study used more than 1.2 million birth records and found that mothers living within 30 kilometers of a hurricane’s path during their third trimester were 60 percent more likely to have a newborn with abnormal conditions such as requiring a respirator. The work, which was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, was described in a working paper circulated in May 2012 by the National Bureau of Economic Research.
The power of the story
Princeton anthropologist João Biehl works at the level of the community and the individual in the poverty-stricken urban centers of Brazil to put a human face on the plight of people who have been abandoned by the health care system. Biehl listens to people and documents their experiences, and observes patients and communities over time to find out how health care interventions work or do not work for individuals, families and the population at large.
“Many things cannot be captured by numbers,” said the Brazilian-born Biehl. “They have to be captured by other things — by life stories, by case studies.”
Health care interventions vary greatly both between and within nations, depending on factors such as socioeconomic status and political institutions and commitments. For example, Brazil’s constitution grants all citizens the right to health. This constitutional right has enabled Brazilians to obtain free HIV/AIDS treatments. It also has given rise to a flood of lawsuits against the government by individuals seeking a variety of medicines for a range of diseases, including rare genetic disorders, and a backlash of accusations that doctors and pharmaceutical companies are encouraging the practice for their own benefit.
To find out if these charges were true, Biehl and his colleagues reviewed more than 1,000 access-to-treatment lawsuits filed in the southern Brazilian state of Rio Grande do Sul. Working with Human Rights Watch epidemiologist Joseph Amon, director of the organization’s health and human rights division, and with funding from the Ford Foundation and Princeton’s Health Grand Challenges Initiative, Biehl and his research team interviewed physicians, public counsels, judges, policymakers, patients and their families.
They discovered that, rather than the claims coming from well-to-do individuals seeking expensive brandname drugs, more than half of the cases were brought by very poor people using help from public defenders. About two-thirds of the requested drugs were already on government formularies and should have been available. The researchers published the results in the June 2012 issue of the journal Health and Human Rights.
“We showed that economically disadvantaged individuals are leveraging public legal assistance and a receptive judicial system to hold the state accountable to its mandates and to have their medical needs met,” Biehl said.
Senior thesis research in global health
Rotavirus vaccination for children under 5 in Ghana would be a highly cost-effective public health intervention, according to a Princeton study published in the journal Vaccine in February 2012. First author Collette Abbott, a 2010 Princeton graduate, conducted the work as part of her senior thesis with Adel Mahmoud of Princeton and George Armah, an epidemiologist at the University of Ghana.
Abbott, Collette, Benjamin Tiede, George Armah and Adel Mahmoud. 2012. “Evaluation of Cost-Effectiveness of Live Oral Pentavalent Reassortant Rotavirus Vaccine Introduction in Ghana.” Vaccine. Vol. 30: 2582-87.
Biehl, João, Joseph J. Amon, Mariana P. Socal and Adriana Petryna. “Between the Court and the Clinic: Lawsuits for Medicines and the Right to Health in Brazil.” Health and Human Rights, Vol. 14, no. 1: 1-17.
Bharti, Nina, Andrew J. Tatem, Matthew J. Ferrari, Rebecca F. Grais, Ali Djibo and Bryan T. Grenfell. 2011. “Explaining Seasonal Fluctuations of Measles in Niger Using Nighttime Lights Imagery,” Science. Vol. 334, no. 6061: 1424-27.
Currie, Janet and Maya Rossin-Slater. 2012. “Weathering the Storm: Hurricanes and Birth Outcomes.” NBER Working Paper No. 18070. May 2012. JEL No. I12.
Ng, Wai-Leung, Lark Perez, Jianping Cong, Martin F. Semmelhack and Bonnie L. Bassler. 2012. “Broad Spectrum Pro-Quorum-Sensing Molecules as Inhibitors of Virulence in Vibrios.” PLoS Pathog., Vol. 8, no. 6: e1002767.
Rinaldo, Andrea, Enrico Bertuzzo, Lorenzo Mari, Lorenzo Righetto, Melanie Blokesch, Marino Gatto, Renato Casagrandi, Megan Murray, Silvan M. Vesenbeckh and Ignacio Rodríguez-Iturbe. 2012. “Reassessment of the 2010–2011 Haiti Cholera Outbreak and Rainfall-Driven Multiseason Projections.” PNAS, Vol. 109, no. 17: 6602-07.
Sun, Lova, Eili Y. Klein and Ramanan Laxminarayan. 2012. “Seasonality and Temporal Correlation between Community Antibiotic Use and Resistance in the United States.” Clin. Infect. Dis. Vol. 55, no. 5: 687-94.