Researchers propose surveillance system for Zika virus and other infectious diseases (The Lancet)

Test tube image courtesy of the NIH

Image courtesy of the National Institutes of Health

By Catherine Zandonella, Office of the Dean for Research

A group of prominent researchers from seven institutions including Princeton University are calling for the establishment of a worldwide program to collect and test blood and other human bodily fluids to aid in the study and prevention of emerging infectious diseases such as the mosquito-borne Zika fever, which is caused by the Zika virus and has spread throughout Latin America and the Caribbean since early 2015.

In an article published in The Lancet April 5, the authors call for the creation of a World Serology Bank that would include storage repositories located around the world that use a common set of best practices to collect and evaluate blood and other bodily fluids from people infected by various pathogens. The resulting data would help scientists better understand the susceptibility of humans to emerging diseases such as Zika fever. The information could be shared widely among scientists who track disease.

The authors include Princeton’s C. Jessica Metcalf, an assistant professor of Ecology and Evolutionary Biology and Public Affairs in the Woodrow Wilson School for Public and International Affairs, and Bryan Grenfell, the Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and Public Affairs. In the interview below, Metcalf explains more about the World Serology Bank proposal.

Why is it important to create a World Serology Bank?

Serology is the study of bodily fluids including serum, the part of the blood that contains antibodies, with the aim of detecting the body’s immune response to pathogens. Serology provides us with the clearest window we have onto the landscape of susceptibility to pathogens across human populations, and the consequent risk of outbreaks. A World Serology Bank would shed light on the global risk of infectious disease outbreaks, and would be of tremendous public health benefit.

Why do you feel it is important to address this issue now?

With the emergence of pathogens like Zika virus, it becomes ever more important to understand what enhances or limits the global spread of these pathogens, and what the consequences of such spread may be across our pathogen communities. A World Serology Bank would provide a powerful mechanism toward such a global perspective.

What are the challenges involved in creating the Bank?

Challenges range from developing systems for collecting fluids, which can be done on a regular schedule or during specific disease events, to methods for sera storage and sera testing. Other challenges include defining who will administer the World Serology Bank, and what global data-sharing agreements will be put in place. Finally, we will need to develop new methods to translate what we learn from the evaluation of sera, such as patterns of susceptibility to specific pathogens, or protection from those pathogens. These methods will be driven by the underlying biology, and are likely to require an array of analytical innovations.

Read more

The article, “Use of serological surveys to generate key insights into the changing global landscape of infectious disease,” by C. Jessica E Metcalf, Jeremy Farrar, Felicity T. Cutts, Nicole E. Basta, Andrea L. Graham, Justin Lessler, Neil M. Ferguson, Donald S. Burke and Bryan T. Grenfell was published online in the journal The Lancet on April 5, 2016.


Study questions the prescription for drug resistance (Proceedings of the Royal Society B)

A drug-resistant strain of bacteria known as MRSA. Photo by James Gathany

A new study examines the question of aggressive versus moderate drug treatment on the emergence of drug-resistant pathogens. Shown is a strain of bacteria known as methicillin-resistant Staphylococcus aureus (MRSA). Photo by James Gathany

By Catherine Zandonella, Office of the Dean for Research

In response to the rise of drug-resistant pathogens, doctors are routinely cautioned against overprescribing antimicrobials. But when a patient has a confirmed bacterial infection, the advice is to treat aggressively to quash the infection before the bacteria can develop resistance.

A new study questions the accepted wisdom that aggressive treatment with high drug dosages and long durations is always the best way to stem the emergence and spread of resistant pathogens. The review of nearly 70 studies of antimicrobial resistance, which was authored by researchers at Princeton and other leading institutions and published last week in the journal Proceedings of the Royal Society B, reveals the lack of evidence behind the practice of aggressive treatment in many cases.

“We found that while there are many studies that test for resistance emergence between different drug regimes, surprisingly few have looked at the topic of how varying drug dosage might affect the emergence and spread of resistance,” said Ruthie Birger, a Princeton graduate student who works with C. Jessica Metcalf, an assistant professor of ecology and evolutionary biology and public affairs at Princeton’s Woodrow Wilson School, and Bryan Grenfell, the Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and Public Affairs in Princeton’s Woodrow Wilson School. Birger, Metcalf and Grenfell coauthored the paper with colleagues from 16 universities. “We are a long way from having the evidence for the best treatment decisions with respect to resistance for a range of diseases,” Birger said.

Microbes such as bacteria and parasites can evade today’s powerful drugs by undergoing genetic mutations that enable them to avoid being killed by the drug. For example, bacteria can develop enzymes that degrade certain antibiotics. The logic behind aggressive treatment goes something like this: kill off as many microbes as you can so that few will be around to evolve into resistant forms.

But some scientists have observed a different outcome in mice infected with both an already-resistant strain of malaria and a non-resistant strain. The high-dose drug treatment killed off the non-resistant malarial parasites, leaving the resistant strains to multiply and make the mice even sicker.

The idea that aggressive treatment may backfire against malarial parasites led the authors of the current study to comb the scientific literature to examine whether the same may be true for other types of microbes such as bacteria. The few studies that they found — mostly in laboratory cell cultures rather than animal models or patients — suggest that the picture is complicated, and depends on whether the resistance is new or existing, how many mutations are necessary for the pathogen to become resistant, and how long the drugs have been in use. “It’s remarkable how little we know about this topic,” said Metcalf. “The malaria study conducted by Silvie Huijben and colleagues at Pennsylvania State University is an inspiring step towards developing an evidence base for these important issues.”

In the current analysis, the study authors found that drug resistance is governed by two factors: the abundance of the pathogen and the strength of the selection pressure that drives the pathogen to evolve. Aggressive treatment deals with the first factor by killing off as much pathogen as possible, while moderate treatment may, for some pathogens, reduce the ability for the resistant pathogen to thrive (for example, by maintaining the competitive advantage of a co-infecting drug-sensitive strain of the pathogen) but still reduce total pathogen levels sufficiently that the patient can recover.

Finding the ideal dose and duration of treatment, one that cures the patient without aiding the spread of resistance, will likely be done on a disease by disease basis, the authors found.

One possibility is that moderate treatment might be best used against already-resistant microbes to prevent their spread. Moderate treatment may also be best for drugs that have been on the market for several years with plenty of time for resistant strains to develop.

Aggressive treatment might be best for pathogens that develop resistance slowly, over the course of several mutations. High doses early in the process could be effective at heading off the development of resistance.

Read the abstract.

Roger D. Kouyos, C. Jessica E. Metcalf, Ruthie Birger, Eili Y. Klein, Pia Abel zur Wiesch, Peter Ankomah, Nimalan Arinaminpathy, Tiffany L. Bogich, Sebastian Bonhoeffer, Charles Brower, Geoffrey Chi-Johnston, Ted Cohen, Troy Day, Bryan Greenhouse, Silvie Huijben, Joshua Metlay, Nicole Mideo, Laura C. Pollitt, Andrew F. Read, David L. Smith, Claire Standley, Nina Wale and Bryan Grenfell. Proc. R. Soc. B: Biological Sciences, 281, 20140566. Published Sept. 24, 2014

The work emerged from two workshops held at Princeton University and funded by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health; Science and Technology Directorate, Department of Homeland Security; contract HSHQDC-12-C-00058

Conservation versus innovation in the fight against antibiotic resistance (Science)

Pills (Image source: NIH)

(Image source: NIH)

“Antibiotic resistance is a problem of managing an open-access resource, such as fisheries or oil,” writes Ramanan Laxminarayan, a research scholar at Princeton University and the director of the Center for Disease Dynamics, Economics & Policy in Washington, D. C., in today’s issue of the journal Science. He goes on to say that individuals have little incentive to use antibiotics wisely, just as people have little incentive to conserve oil when it is plentiful.

As with many other natural resources, maintaining the effectiveness of antibiotics requires two approaches: conserving the existing resource and exploring new sources, Laxminarayan says. These two approaches are linked, however. “Just as incentives for finding new sources of oil reduce incentives to conserve oil,” Laxminarayan writes, “large public subsidies for new drug development discourage efforts to improve how existing antibiotics are used.” Yet new antibiotics tend to cost more than existing ones due to the expense of clinical trials and the fact that the easiest-to-find drugs may have already been discovered.

Laxminarayan’s analysis reveals that the benefits of conserving existing drugs are significant, and argues that the proposed increases in public subsidies for new antibiotics should be matched by greater spending on conservation of antibiotic effectiveness through public education, research and surveillance.

Ramanan Laxminarayan is a research scholar at the Princeton Environmental Institute. His perspective, “Antibiotic effectiveness: Balancing conservation against innovation,” appeared in the September 12, 2014 issue of Science.

Read the article.

Unlocking the potential of bacterial gene clusters to discover new antibiotics (Proc. Natl. Acad. Sci.)

High-throughput screening for the discovery of small molecules that activate silent bacterial gene clusters

High-throughput screening for the discovery of small molecules that activate silent bacterial gene clusters. Image courtesy of Mohammad Seyedsayamdost.

by Tien Nguyen, Department of Chemistry

Resistance to antibiotics has been steadily rising and poses a serious threat to the stronghold of existing treatments. Now, a method from Mohammad Seyedsayamdost, an assistant professor of chemistry at Princeton University, may open the door to the discovery of a host of potential drug candidates.

The vast majority of anti-infectives on the market today are bacterial natural products, made by biosynthetic gene clusters. Genome sequencing of bacteria has revealed that these active gene clusters are outnumbered approximately ten times by so-called silent gene clusters.

“Turning these clusters on would really expand our available chemical space to search for new antibiotic or otherwise therapeutically useful molecules,” Seyedsayamdost said.

In an article published last week in the journal Proceedings of the National Academy of Sciences, Seyedsayamdost reported a strategy to quickly screen whole libraries of compounds to find elicitors, small molecules that can turn on a specific gene cluster. He used a genetic reporter that fluoresces or generates a color when the gene cluster is activated to easily identify positive hits. Using this method, two silent gene clusters were successfully activated and a new metabolite was discovered.

Application of this work promises to uncover new bacterial natural products and provide insights into the regulatory networks that control silent gene clusters.

Read the abstract.

Seyedsayamdost, M. R. “High-throughput platform for the discovery of elicitors of silent bacterial gene clusters.” Proc. Natl. Acad. Sci. 2014, Early edition.

More or less equal? How men factor into the reproductive equation (Gender & Society)

A new study calls attention to the role of men’s behavior and health in reproductive outcomes, such as fetal health, birth defects and childhood diseases. (Image credit: CDC/Amanda Mills)

A new study calls attention to the role of men’s behavior and health in reproductive outcomes, such as fetal health, birth defects and childhood diseases. (Image credit: CDC/Amanda Mills)

By Bess Connolly Martell, Office of Public Affairs and Communications, Yale University

Researchers know a lot about how women’s bodily health affects their fertility, but less is known about how men’s health affects reproductive outcomes. Yale University researcher Rene Almeling and co-author Miranda Waggoner of Princeton University address this discrepancy in an article published Tuesday, Dec. 3, in the journal Gender & Society.

In the period before conception, family health history and current health behaviors matter for women and men alike, say the researchers, adding that more clinical research needs to be done on how men’s bodily health affects their sperm, and in turn, reproductive health outcomes.

“The lack of attention to men in research on reproduction leaves open many important questions, including how men’s reproductive contributions are understood,” say Almeling, an assistant professor of sociology at Yale, and Waggoner, a postdoctoral researcher in the Office of Population Research in the Woodrow Wilson School of Public and International Affairs at Princeton.

The vast majority of medical and social science research on reproduction focuses on women. It wasn’t until recently that scientists began studying the role that men’s behavior and men’s health play in reproductive outcomes, such as fetal health, birth defects and childhood diseases.

The stereotypical association of women with family and men with work has led to a focus on women’s bodies in reproduction, leaving the question of how men’s health contributes to reproduction unanswered.

“What kinds of advice, if any, do men receive about preparing their bodies for reproduction?” ask the researchers. “Men should be empowered with information about how their age, health history and unhealthy behaviors can affect pregnancy outcomes.”

The sperm bank is one of the few places where men’s reproductive health takes center stage, the researchers note. At sperm banks, men are counseled on healthy eating, avoiding stress and reducing alcohol consumption. Not adhering to this advice can and does lead to lower sperm counts, suggesting that this kind of guidance might be more broadly useful for men trying to conceive children with their partners.

There are also associated policy implications. The Affordable Care Act stipulates that women with private insurance are no longer required to pay for preconception health appointments, but excluding men from such coverage continues to obscure their role in reproduction, say Almeling and Waggoner. “Paying attention to how reproductive equations influence policy can suggest new and different avenues for improving public health,” say the sociologists. They add, “Recent public health initiatives devoted to preconception care offer at least the possibility that men’s reproductive contributions will be considered alongside women’s.”

Read the abstract.

Almeling, Rene and Miranda R. Waggoner. More and Less than Equal: How Men Factor in the Reproductive Equation. Gender & Society December 2013 27: 821-842, first published on April 25, 2013 doi:10.1177/0891243213484510.

Both authors received funding from the National Science Foundation (Almeling grant #0602871 and Waggoner grant #1029087), and Miranda Waggoner also received support from the National Institutes of Health (T32 HD007163).

Contaminated water linked to low-weight babies, prematurity (Canadian Journal of Economics)

By B. Rose Huber, Woodrow Wilson School of Public and International Affairs

Image: Shutter Stock

Image: Shutterstock.

Pregnant women living in areas with contaminated drinking water may be more likely to have babies that are premature or have low birth weights (less than 5.5 pounds), according to a study based at Princeton University’s Woodrow Wilson School of Public and International Affairs.

Published in the Canadian Journal of Economics, the study shows that the effects of contaminated water—such as cognitive and developmental impairments—are particularly significant for babies born to less-educated mothers. These mothers also are less likely to uproot from areas with contaminated water, which, the authors note, suggests a need for serious improvement in terms of communicating with people living in such environs.

“Fetuses are vulnerable to all types of pollution, including water contamination caused by chemicals and bacteria,” said Janet Currie, the Henry Putnam Professor of Economics and Public Affairs at the Wilson School and director of the Center for Health and Wellbeing. “This contamination can lead to a host of problems, including low-birth-weight babies who can have lifelong cognitive struggles. It’s a particular problem for less-educated women who also presumably have fewer options in terms of housing.”

While other studies have focused on the effects of air pollution on infant health, Currie’s is one of the first to evaluate the effects of water pollution on infants. Together with researchers from Columbia University and the University of California-San Diego, Currie examined ten years of New Jersey birth records and data on drinking-water quality collected from 1997 to 2007. All birth records contained information regarding the date of birth, the infant’s health at birth, and maternal characteristics such as race, education and marital status. To determine whether mothers relocated due to water contamination, the researchers studied sets of siblings and whether mothers moved between births.

Using data from the New Jersey Department of Environmental Protection (DEP), Currie and her team looked at violation records across 488 water districts in New Jersey and found that more than a quarter of districts had water contamination violations affecting more than 30,000 people. These violations included both chemical and bacterial contamination caused by such contaminants as dichloroethane — a solvent often used for plastics or as degreasers — as well as radon and coliform.

The researchers matched the birth records to the water systems that serve the infants’ residences. Because weather can dictate the amount of water a person consumes, they also incorporated daily temperatures into their data set.

“We found that infants exposed to contamination in utero tend to have mothers who are younger, less educated and less likely to be married than other mothers. They are also more likely to be African-American or Hispanic,” Currie said. “The results also suggest that mothers who are less educated are less likely than other mothers to move in response to contamination, while older mothers are more likely to drink bottled water or move.”

Currie notes that when a water district is affected, the DEP is required to send a notice to all residences. However, for renters, there may be routing difficulties.

“If someone puts something in your mailbox, do you even see it? Does your landlord pick it up?” said Currie. “Notices are being sent that people don’t receive. There’s an undercurrent here that the way information is sent isn’t adequate. We need to get this information to people directly.”

Currie suggests that health-care workers include literature about water contamination risks and hazards in clinics and exam rooms to reach more pregnant women.

“If it’s going to be harmful for some groups, we need to at least let those groups know about them, so they can avoid it,” said Currie.

In the future, Currie plans to continue studying environmental impacts on child health while also pursuing the relationship between home foreclosures and health.

Other collaborators for the study include: from Columbia University, Katherine Meckel, Matthew Neidell, and Wolfram Schlenker; and from the University of California, San Diego, Joshua Graff Zivin.

Read the abstract.

Currie, Janet, Joshua Graff Zivin, Katherine Meckel, Matthew Neidell, and Wolfram Schlenker. August 2013.  Something in the water: contaminated drinking water and infant health. Canadian Journal of Economics. Vol. 46, No. 3, pages 791-810.

Funding was provided by the John D. and Catherine T. MacArthur Foundation, the Environmental Protection Agency and the National Science Foundation.

Organizations shape pharmacists’ work as gatekeepers (Social Science and Medicine)

By Michael Hotchkiss, Office of Communications

Pharmacists regularly face a range of ethical dilemmas, from deciding whether to dispense emergency contraception to managing requests for narcotics, and must navigate a range of relationships with other health-care professionals.

Using 95 interviews with pharmacists working in retail and hospital settings, Princeton researcher Elizabeth Chiarello shows how organizations shape the way pharmacists exercise their roles as medical, legal, fiscal and moral gatekeepers. An article by Chiarello based on the research was published online by the journal Social Science and Medicine.

According to the paper by Chiarello, a sociologist working as a postdoctoral research associate at the Office of Population Research within the Woodrow Wilson School of International and Public Affairs, the findings suggest new directions for theorizing about ethical decision-making in medical contexts.

Read the abstract.

Chiarello, Elizabeth. 2013. How Organizational Context Affects Bioethical Decision-Making: Pharmacists’ Management of Gatekeeping Processes in Retail and Hospital Settings. Social Science and Medicine. doi: 10.1016/j.socscimed.2012.11.041

Funding for this research was provided by the Andrew W. Mellon Foundation, the American Council of Learned Societies, the U.S. Department and Health and Human Services Agency for Healthcare Research and Quality, the Princeton University Office of Population Research, the Princeton University Center for Health and Wellbeing, and a grant from the University of California, Irvine Center for Organizational Research.