Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
Dengue Fever. Malaria. Yellow Fever. West Nile Virus. These are some of the major mosquito-borne illnesses on Earth; that is, infectious diseases you can contract from a mosquito bite. And if you’ve been reading the news lately, you’ve likely seen Zika virus rapidly ascending the list. Zika is a Flavivirus just like most of the other mosquito-borne viruses, and despite its generally mild symptoms it has recently been implicated in serious birth defects. Several months ago, Brazil reported a spike in poor pregnancy outcomes in women who contracted Zika while they were pregnant. One such condition seen so far is microcephaly, in which a baby’s head is much smaller than it should be due to an improperly developing brain.
So what do we do to fight mosquito-borne illnesses? Scientists have been working on vaccines for years; recently, a new malaria vaccine called Mosquirix was approved by European regulators, and a couple of dengue vaccines are making their way through clinical trials. We all know about various mosquito repellents on the market, too, to ward these nuisance insects – try camping in the summer without fortifying your skin or clothing with some 25+ percent DEET. And in malaria-endemic nations, mosquito nets are highly recommended during the night. What about approaches that might be a little easier to impart on regions lacking robust enough infrastructure to provide their citizens with the proper precautions?
Recently, some researchers have been exploring a new approach to warding off mosquito-borne illnesses. Companies like UK-based Oxitec and labs around the United States such as UC Irvine and UC San Diego have turned to genetically engineered mosquitoes to eliminate the source of the problem. Oxitec has developed a “self-limiting gene”; that is, the company has developed a way to control mosquito populations by wiping them out. The genetically modified mosquitos are designed to be released into the wild, and when they reproduce they pass on the new gene to all their offspring. The resulting offspring then die before reaching reproductive maturity, and the mosquito population declines. By killing the mosquitoes in a given region, the diseases they carry die off as well.
So how are these mosquitoes made? As with most genetic manipulation, it all begins with the eggs: scientists use microscopic, specialized needles to inject DNA into one end of an egg. While most eggs won’t survive the penetration, the ones that do end up taking the DNA into the cells within them, incorporating the self-limiting gene into the developing insect’s genetic makeup. The insect’s genetic makeup includes its sex organs, meaning the new DNA can be passed on to future generations. Genetically modified eggs are incubated, hatched, and screened: in Oxitec’s case, the injected DNA contains both the lethal gene and a fluorescence gene in order to visualize successful DNA uptake. The success rate of this initial procedure is about one in several thousand, but all it takes is one viable genetically modified mosquito to then be bred countless times.
Another approach to genetic mosquito control involves modifying mosquitoes so that they kill pathogenic microbes living inside them and therefore cannot transmit deadly diseases to humans. At UC Irvine and UC San Diego, researchers have successfully done this to combat malaria. Scientists at UC Irvine discovered a set of genes in mice that confers a strong immune response to Plasmodium falciparum, the parasite responsible for malaria in humans. They inserted these genes into mosquito DNA, and the insects resisted parasitic infection. The issue was that these malaria-resistance genes were only passed on to offspring about 50% of the time; and in a region containing millions of mosquitoes, this isn’t good enough. Meanwhile, at UC San Diego, scientists developed a gene drive system using CRISPR/Cas9 and successfully engineered fruit flies to pass on an artificially inserted trait with a success rate closer to 97%. Couple this technology with UC Irvine’s genes, and you’ve got yourself a potential victory.
And victory it was. After months of trial and error to create a gene drive for mosquitoes that contained anti-malarial mouse genes (bet you don’t read that sentence every day), the tool was inserted into 680 mosquito larvae. About 37% of these larvae survived to adulthood and were mated with wild mosquitoes, and out of 25,712 offspring that were generated, 2 of them carried the mice genes. Those two mosquitoes were bred to produce 143 offspring, half of which carried the malaria-warding genes. The malaria resistant mosquitoes were once again bred with wild insects, and this time the malaria-resistance genes transferred to over 99% of the resulting offspring. This feat is just the beginning – more work needs to be done to produce a robust genetically-modified mosquito that is ready for release into the wild: fully reliable proliferation of the gene through generations is essential, and people living in regions where these insects could be released would need to okay the efforts.
Both genetic manipulations of mosquitoes are wonderfully innovative and show potential in the prevention of the diseases these insects can spread in human populations. Oxitec’s approach, which aims at wiping out mosquitoes altogether, sounds pretty good in theory – however, we don’t know the exact importance of mosquitoes in their ecosystems; what if the eradication of mosquitoes brings forth an even more dangerous pest? As a result, methods targeting insect immune responses to parasites might seem more attractive. This, too, could pose problems though – there are drug-resistant forms of malaria emerging in different parts of the world. What if mosquito-resistant malaria arises when challenged enough times with the immune-modified insects? Where else can the parasites learn to survive and circulate to complete their life cycles in humans or other hosts? Either way, it will be fascinating to see where both technologies, coupled with more traditional medical and environmental efforts, take us in the battle against mosquito-borne illnesses.
Read the UC Irvine and UC San Diego papers:
Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
6 billion and 4.5 billion: which figure represents the number of people in the world who own a toilet, and which one represents how many own a cell phone? I’ll give you a hint: more people in the world own a cell phone than a toilet.
Today, mobile phone usage encompasses just about every demographic group, and interestingly enough is highest amongst populations most in need of health interventions. As a result, it has a consummate potential to improve worldwide health, especially when coupled with the ever-increasing population also using the Internet. The ability to access and follow previously unreachable communities through mobile and Internet technology swings open many doors in a wide variety of medical fields to improve global healthcare.
Recent years have in fact seen new ideas for exploiting this access to information in meaningful ways. In healthcare, Internet and mobile technologies are starting to be used to organize both individual and aggregate data to facilitate medical intervention and yield predictive health information. Data does not only flow from consumers to large databanks of information, but can now be made available to individuals in forms that are tailored for small towns or valid across the world. Together, these information methodologies are yielding fresh insights into the factors that play a role in diseases and health in general. Organized, tailored information available on-the-go in the palm of one’s hand lends itself to rapid, active changes in behavior or environmental exposures to reduce health risks and optimize both preparedness and overall outcomes in a way we have not yet seen in traditional public health policy. A widespread use of digital monitoring systems adopted alongside traditional methods promises more comprehensible and prompt, community- and individual-oriented healthcare, and the ubiquity of people on the web as well as on mobile phones today is a strong testament to the importance of integrating such technologies in the not-so-distant future.
Of particular concern to public health are emerging infectious diseases, the leading causes of death worldwide and irritants to any community. Driven by socio-cultural, environmental, and ecological factors, epidemics of known, resistant, and previously unrecognized pathogens pose a serious threat to worldwide health. As a result, several monitoring methods have already been established in efforts to prevent, detect, and track rampant infectious agents.
Traditional monitoring of infectious disease is a predominantly passive process sustained and managed to differing degrees around the world. It works through submissions from physicians, laboratories, and other healthcare providers, all of which trickle into a centralized database. The potential inconsistency that arises amongst the varying resources all but guarantees information loss in translation and carries a significant opportunity cost in terms of time and effort. On average, the dissemination of public health data through traditional methods occurs two weeks after the information is initially collected. In the event of a public health emergency, such as the H1N1 pandemic in 2009, two weeks could lead to loss of life. The emerging field of digital monitoring through mobile and Internet technologies can drastically improve the response to infectious disease in a time- sensitive manner.
More specifically, the detection, tracking, reporting, and response systems can be improved by combining predictive analytics, anonymized hospital records, and interactive surveys to analyze current data simultaneously at home and around the world. Interestingly, all of these new approaches used to tackle an illness exploit exactly what they target: behavior. Just as one’s behavior changes in response to new information, the availability of the Internet and associated technologies has altered human behavior related to information seeking, collection, storage, and communication. In the US alone, health-related queries are estimated at approximately 8 million per day. Numerous studies have exploited this behavior on the premise that people who contract a disease will seek information about their condition from the web. Disease incidence can then be estimated by tracking changes in the frequencies of searches for key terms. For example, algorithms have reported accurate estimates of influenza incidence in a given region 1-2 weeks before traditional reports rolled in. Thus, Google Flu Trends was born. Clinical studies have reported positive correlation between Google Flu Trends predictions and emergency room crowding, showing that digital monitoring may become a near real-time tool to help local clinics and hospitals prepare and obtain the proper supplies and resources to deal with sudden surges in people exhibiting flu-like symptoms. Moreover, Google Flu Trends has shown to provide an indication of flu activity up to 4 weeks prior to the release of CDC reports, and with a 97.7% accuracy rate in many locations.
Internet search data has also accurately estimated the incidence of other infectious diseases, such as dengue, a tropical disease spread by mosquitoes. Search query data has provided information that was used to create statistically significantly accurate models of dengue transmission in multiple countries including Bolivia, Brazil, India, Indonesia, and Singapore. In contrast with traditional disease monitoring methods, it is worth noting that Internet resources are free, publicly available, and occur virtually in real-time.
If Internet monitoring of infectious diseases were to complement traditional systems rather than replace them, many predictable drawbacks of stand-alone Internet monitoring systems could also be avoided. Any changes in the status quo of Internet search behavior, such as media-driven interest, could in fact feed false positives in search trends. In addition, usually when someone has had the flu before, they know what to expect; after experiencing the flu or an influenza-like illness once, someone is less likely to Google their symptoms the next time they or a family member get sick. Over time, this could significantly lower the number of searches in a given area and impede the algorithmic predictions. Furthermore, the detection of significant patterns requires large data samples, so that Internet search trends are not very accurate or effective in small towns or for localized outbreaks. People could be searching for information about the flu for reasons other than their own health, which inflates the amount of “predictive” data. These queries could include research, aimless browsing, and sheer interest – I know I Googled “Flu” several times just writing this editorial.
Despite these drawbacks, the fact remains that digital monitoring targets people who are trying to recognize and interpret their illness in addition to those who are seeking treatment. This phenomenon provides public health officials with more data that could be used for preventive and predictive analysis, as traditional methods only target individuals who have already sought treatment and for whom prevention of the disease is no longer really an option. The monitoring of potential pathogens whose hosts experience symptoms but do not seek medical attention also is especially important in some instances. A prevalent symptom of intestinal viruses, for instance, is diarrhea, which many people may experience and choose to leave untreated. Information that does not reach the hospital can provide insight on undercover outbreaks and is otherwise lost without digital surveillance. The importance of prediction lies therefore in its potential to greatly increase prevention, which then not only promotes the control of pathogens, but also allows for a decrease in unnecessary or excessive dispensing of antibiotics. As a result, it may be possible to curb the evolution of resistant, more dangerous pathogens that are then harder to treat than if they had been avoided in the first place.
In order to target a more personalized epidemiological health plan that focuses on an individual’s specific community and individual health rather than state-, nation-, or worldwide disease trends, in the near future we may turn to the Internet by means of more and more mobile technologies in the form of apps and local surveys. These include apps on smart-phones with interactive maps and the ability to report local instances of illness. It may be possible to extend this approach also to SMS-based services for owners of more basic cell phones, which could employ text messaging to report instances of infectious disease and respond with brief simple-text surveys to obtain more information on the potential responsible pathogen and related symptoms in populations where smart phones are not rife.
Apps in the smart-phone world have already demonstrated the effectiveness of collecting and filtering media and user information outside of formal public health channels for improved situational awareness. For example, HealthMap’s app, Outbreaks Near Me, released in 2009, asks users from the general public to contribute reports from their own knowledge and experiences. The aim of the app is to provide local information via an interactive map to users in order to promote behavioral changes that may improve individual and community health. When enough people in a given geographical region have the service installed and use it correctly, the technology carries an incredible potential for one’s own community health status. Right now, the problem lies in a small user base.
Participatory epidemiology through mobile technology carries both great potential and significant problems. Most important among the latter are the concern for user privacy and the verification and filtering of submitted information. It will take a while to figure out effective ways of targeting misuse and guaranteeing consumer privacy. HealthMap for instance has reported its user submissions as coming from three categories: individuals referencing a news article (15%), eyewitness accounts of local events (41%), and personal accounts of illness of either the submitter or a close associate (13%). Everything else is filtered as spam. In any case, a crowd sourcing approach to infectious disease tracking, like Internet-based monitoring, should complement, not replace, traditional efforts.
Once the collection and analysis methods for participatory information have been refined to avoid fake, malicious reports, mobile epidemiological technologies can penetrate a large majority of communities around the world. As long as national and international market conditions remain suitable for the widespread sale of smart-phones and prevailing mobile data-collection technologies develop multi-platform capabilities, we face a future of great opportunities to gather detailed, structured real-time data for public health reporting, especially for underdeveloped regions that currently lack the resources to quickly diagnose, treat, and control disease. A disease can indeed be controlled before it becomes a pandemic, which is particularly vital in the profoundly interconnected world we live in where the spread of pathogens is accelerated by interpersonal communication and travel.
Moreover, when organizations know the symptoms or the specific disease plaguing a town or region in an underserved country, a more proper allocation of aid resources may also take place to replace the current practice known as Duffel Bag Medicine, which involves the sporadic and inexperienced distribution of the pills an organization obtained through donations. This practice is particularly dangerous when dispensing antibiotics or other medications that promote either the development of resistant pathogens or user addiction. Having prompt and prior knowledge allows relief groups to know what type of resources they should obtain, such as relevant vaccinations, symptom treatment, supplements, or, when appropriate, antibiotics. Even in resource-rich countries, individuals informed of an outbreak in their community may either be advised on proactive measures via the app itself to avoid contact with the pathogen, or they may be advised on proper courses of treatment. Often treatment, especially if the cause is a virus, just requires hydration and rest, so people can avoid unnecessary medications, which can account for up to 73% of antibiotic prescriptions, depending on symptoms.
User-oriented digital healthcare technology still has a long way to go. Digital natives’ demand for apps far outpaces the science needed to understand their benefits, risks, and overall impact on health outcomes. Moreover, issues of privacy, confidentiality, regulatory control, and human subject protection are important barriers to research in this area. In addition, Internet-based monitoring, while showing increased potential, still works best in high-income countries that provide ubiquitous Internet access. Efforts in increasing Internet usage in less wealthy countries are essential to allow Internet search monitoring to be applied globally. There is, however, promise to overcome these barriers to realize the full spectrum of digital, real-time health technologies to create safe, scalable, and effective programs. These programs are appealing from a logistical, economical, and epidemiological standpoint thanks to their intuitive and adaptable nature as well as their rapid turnover rates and inexpensive maintenance costs, unlike those of traditional monitoring systems. Because they rely so heavily on behavior, which is known to be quite stochastic, programs need to be flexible, built with models that incorporate several means of collecting information. When these systems are integrated with other sources such as traditional public health records and hospital data, and, for global health trends, with international policies, the tools to understand and address emerging problems will be literally in the palms of our hands.
Brigham and Women’s Hospital. “High rates of unnecessary prescribing of antibiotics continue.”
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Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
Vibrio cholerae is a comma-shaped, gram-negative bacterium and the etiologic agent of cholera. Cholera is a serious illness that causes severe dehydration and death if untreated, due to loss of fluids through horrible diarrhea. It causes disease in humans via the cholera toxin, which is released into host target cells by ingested bacteria and causes the opening of cellular ion channels that result in a surge of watery diarrhea out of the victim. Even though the infectious dose of cholera is relatively low (several thousand bacteria need to be ingested through water, or several hundred to a thousand through food), especially in regions with poor sanitation, untreated food/water, and poor sewerage the pathogen typically remains endemic until public health measures are taken to eliminate it. Cholera is therefore able to spread to individuals from the environment through their consumption of infected food and water. It also spreads between people through fecal-oral spread, which is exacerbated in areas with poor sanitation and/or in households, where people frequently come into contact with each other’s bodily fluids. Additional interactions between V. cholerae and the environment facilitate its ability to infect people, spread, and persist in human populations. The bacterium’s natural reservoir is chitinous organisms (such as planktons) living in water. Studies have shown that the bacteria actually biochemically interact with chitin, which promotes their evolution and proliferation, ultimately helping them survive in a dynamic environment. As a result, V. cholerae are able to live in an external environment as well as within human hosts. When individuals go to a contaminated river, for instance, and ingest water (cook with it, wash their food with it, drink it, you name it), they may consume the appropriate dose to wreak havoc on their gastrointestinal system. Furthermore, the proportion of asymptomatic to symptomatic cases is quite high with cholera: about 80 or 90 percent of infected individuals who have it do not actually get sick, whereas the other 10-20 percent become incredibly ill. Regardless of symptoms or lack thereof, infected individuals shed the bacterium for months or years after the initial entry of V. cholerae into their bodies, and can therefore unknowingly spread the disease to others. Cholera is essentially eradicated in developed nations with solid infrastructure including well-designed sewerage, which prevents the leaking of potentially infected fecal remnants around the environment, and treated water. However, in places like Haiti where a terrible cholera outbreak is currently underway, the environmental persistence of V. cholerae is a recipe for disaster in a country that lacks the public health infrastructure to treat its water and further prevent illness.