Posts Tagged ‘global health’
By: Emmette Hutchinson, PhD
Synthetic biology is an interdisciplinary field that utilizes an engineering approach to construct novel biological products, circuits and designer organisms. This field has the potential to revolutionize many aspects of society from chemical production to healthcare. Synthetic biology holds particular promise in the production of biological therapeutics or chemical compounds for the treatment of disease. Increased efficiency and stability of production can be especially beneficial when treating global diseases that are typically associated with poverty. Treatment for these conditions is typically funded by grants from large charitable foundations, sometimes leading to scarcity as funding recedes.
In 2015, 212 million cases of malaria were reported worldwide, predominantly among the poorest countries in the world. While major initiatives such as the President’s Malaria initiative and the Gates foundation focus on various aspects of combating the disease, such as the spread of the parasite and the eradication of the disease, respectively, cost-effective treatments for infections are still needed. The most efficacious treatments for malaria are artemisinin-based combination therapies (ACTs). The 2015 Nobel Prize in Medicine was awarded in part to Youyou Tu for her work demonstrating that artemisinin, an Artemisia annua (sweet wormwood) extract, was an effective anti-malarial treatment. Landmark research published in 2006 demonstrated synthetic production of artemisinic acid, a precursor to artemisin, in yeast. Prior to this study, the only source of artemisinin was tiny hairs found on the surface of the wormwood. The supply of artemisinin has previously been unstable, resulting in dramatic price fluctuations. These price spikes have resulted in both shortages and unattainable cost of treatment. The pharmaceutical giant Sanofi licensed the yeast strain with the hope of creating a more reliable source of artemisinin. In part, due to market forces pushing down the price of artemisinin (primarily a surge in world-wide Artemisia annua cultivation), Sanofi recently sold both its technology and production facilities to Huvepharma. Despite the potential of synthetic biology to disrupt the pharmaceutical industry, this is an example of how existing production methods can impede adoption of more efficient (and stable) synthetic approaches. An alternative to synthetic production of artemisinin in yeast, termed COSTREL (combinatorial supertransformation of transplastomic recipient lines), re-creates the enzymatic pathway necessary to produce artemisinin in tobacco. Although not as efficient as synthetic production of the chemical in yeast, this route offers a significant per-acre boost in artemisinin production over the native source and a potentially more open market to supply drug manufacturers.
Similar to malaria, snake bites predominantly affect impoverished regions of the world. This makes the use of life-saving anti-venoms particularly burdensome as they are both expensive and difficult to produce. The World Health Organization estimates that up to 2.5 million cases of envenoming occur each year, resulting in death, amputations and permanent disabilities. Antivenoms are typically produced using plasma from hyperimmune animals, an often expensive and time-consuming process. In some cases, the profit margins are considered too low to continue producing effective antivenoms such as FAV-Afrique, a polyvalent antivenom effective against 10 species of sub-Saharan snakes. Two recent approaches utilizing synthetic antibody fragments have shown promising effects for protection against specific snake venoms. In a screen for antibody fragments to snake venom, Prado and colleagues found two fragments that protected mice against muscle damage from Bothrops jararacussu and Bothrops brazili venom. Ramos and colleagues designed two synthetic DNA sequences encoding components of coral snake (Micrurus corallinus) venom. Serum obtained from animals immunized with these DNA sequences resulted in 60% survival of animals given a lethal dose of coral snake venom. This second approach eliminates the need for difficult-to-obtain venom when seeking to generate hyperimmune animals as anti-venom producers. It is possible that these or similar synthetic biology approaches could be utilized to produce FAV-Afrique or other polyvalent antivenoms in a faster, more cost-effective manner than hyperimmune animals.
While the possibility of artemisinic acid-producing yeast, high artemisinin-yielding tobacco, and more efficient sources of anti-venom are compelling, regulatory challenges and ethical dilemmas are abundant in the burgeoning field of synthetic biology. Both the US and the EU have recently held surveys and drafted opinions concerning the ethics and risks of synthetic biology. One potential issue with the use of synthetic biology approaches to industrial scale production of chemicals or recombinant proteins is the potential for uncontained spread of the recombinant organism or uncontrolled transfer of the modified genetic material. Another concern centers around the impact of synthetic biology on existing biological diversity. There are also concerns regarding the proliferation of synthetic biology capabilities and biosecurity. At the moment, the United States is in middle of an epidemic of opioid addiction. Synthesis of more complex chemicals in yeast also opens up issues with substance control. A research group has already demonstrated the ability to synthesize heroin in yeast, cheaply and effectively in much the same manner as one might brew beer, raising the possibility that new, designer substances of abuse could be produced in a similar manner. Approaches to the issue of biocontainment have varied, but as the control of synthetic transcriptional circuits becomes robust, more efficacious approaches to biocontainment can be developed. One recent approach to this problem implemented a two-part genetic version of a Dead Man’s Switch into E. coli, which will kill the synthetic organism when certain conditions are not met. As a standard operating procedure, this system would go a long way toward addressing containment of engineered organisms.
The engineering of novel biologicals, re-purposing of existing or development of new transcriptional circuits and entirely new organisms holds immense promise for all aspects of society. These technologies will likely impact the treatment of diseases typically associated with poverty initially, as the increased efficiency of production will lead to stability in price and decreased scarcity of therapeutics. Once concerns of containment and potential effects on existing ecosystems are sufficiently addressed, the broad application of these technologies becomes more reasonable. As the methodologies enabling the creation of designer organisms and novel biologicals improves, the market forces that impede adoption of more efficient synthetic sources of therapeutics may also have less of an impact.
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By: Arielle Glatman Zaretsky, PhD
Throughout history, humans have sought to understand the human body and remedy ailments. Since the realization that disease can be caused by infection and the establishment of Koch’s postulates, designed to demonstrate that a specific microbe causes a disease, humans have sought to identify and “cure” diseases. However, while we have been successful as a species at developing treatments for numerous microbes, viruses, and even parasites, pure cures that prevent future reinfection have remained elusive. Indeed, the only human disease that has been eradicated in the modern era (smallpox) was eliminated through the successful development and application of preventative vaccines, not the implementation of any treatment strategy. Furthermore, the two next most likely candidates for eradication, dracunculiasis (guinea worm disease) and poliomyelitis (polio), are approaching this status through the use of preventative measures, via water filtration and vaccination, respectively. In fact, despite the recent pushback from a scientifically unfounded anti-vaxxers movement, the use of a standardized vaccination regimen has led to clear reductions in disease incidence of numerous childhood ailments in the Americas, including measles, mumps, rubella, and many others. Thus, although the development of antibiotics and other medical interventions have dramatically improved human health, vaccines remain the gold standard of preventative treatment for the potential of disease elimination. By Centers for Disease Control and Prevention [Public domain], via Wikimedia Commons
Recently, there have been numerous outbreaks of emerging or reemerging infectious diseases. From SARS to Ebola to Zika virus, these epidemics have led to significant morbidity and mortality, and have incited global panic. In the modern era of air travel and a global economy, disease can spread quickly across continents, making containment difficult. Additionally, the low incidence of these diseases means that few efforts are exerted to the development of treatments and interventions for them, and when these are attempted, the low incidence further complicates the implementation of clinical trials. For example, though Ebola has been a public health concern since the first outbreak in 1976, no successful Ebola treatment or vaccine existed until the most recent outbreak of 2014-2016. This outbreak resulted in the deaths of more than 11,000 people, spread across more than 4 countries, and motivated the development of several treatments and 2 vaccine candidates, which have now reached human trials. However, these treatments currently remain unlicensed and are still undergoing testing, and were not available at the start or even the height of the outbreak when they were most needed. Instead, diseases that occur primarily in low income populations in developing countries are understudied, for lack of financial incentive. Thus, these pathogens can persist at low levels in populations, particularly in developing countries, creating a high likelihood of eventual outbreak and potential for future epidemics.
This stream of newly emerging diseases and the re-emergence of previously untreatable diseases brings the question of how to address these outbreaks and prevent global pandemics to the forefront for public health policy makers and agencies tasked with controlling infectious disease spread. Indeed, many regulatory bodies have integrated accelerated approval policies that can be implemented in an outbreak to hasten the bench to bedside process. Although the tools to identify new pathogens rapidly during an outbreak have advanced tremendously, the pathway from identification to treatment or prevention remains complicated. Regulatory and bureaucratic delays compound the slow and complicated research processes, and the ability to conduct clinical trials can be hindered by rare exposures to these pathogens. Thus, the World Health Organization (WHO) has compiled a blueprint for the prevention of future epidemics, meant to inspire partnerships in the development of tools, techniques, medications and approaches to reduce the frequency and severity of these disease outbreaks. Through the documentation and public declaration of disease priorities and approaches to promote research and development in these disease areas, WHO has set up a new phase of epidemic prevention through proactive research and strategy.
Recently, this inspired the establishment of the Coalition for Epidemic Preparedness Innovations (CEPI) by a mixed group of public and private funding organizations, including the Bill and Melinda Gates Foundation, inspired by the suggestion that an Ebola vaccine could have prevented the recent outbreak if not for the lack of funding slowing research and development, to begin to create a pipeline for developing solutions to control and contain outbreaks, thereby preventing epidemics. Instead of focusing on developing treatments to ongoing outbreaks, the mission at CEPI is to identify likely candidates for future outbreaks based on known epidemic threats and to lower the barriers for effective vaccine development through assisting with initial dose and safety trials, and providing support through both the research and clinical trials, and the regulatory and industry aspects. If successful, this approach could lead to a stockpile of ready-made vaccines, which could easily be deployed to sites of an outbreak and administered to aid workers to reduce their morality and improve containment. What makes this coalition both unique and exciting is the commitment to orphan vaccines, so called for their lack of financial appeal to the pharmaceutical industry that normally determines the research and development priorities, and the prioritization of vaccine development over treatment or other prophylactic approaches. The advantage of a vaccination strategy is that it prevents disease through one simple treatment, with numerous precedents for adaptation of the vaccine to a form that is permissive of the potential temperature fluctuations and shipping difficulties likely to arise in developing regions. Furthermore, it aids in containment, by preventing infection, and can be quickly administered to large at risk populations.
Thus, while the recent outbreaks have incited fear, there is reason for hope. Indeed, the realization of these vaccination approaches and improved fast tracking of planning and regulatory processes could have long reaching advantages for endemic countries, as well as global health and epidemic prevention.
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By: Teegan A. Dellibovi-Ragheb, PhD
The increasing frequency and scope of infectious disease outbreaks in recent years (such as SARS, MERS, Ebola and Zika) highlight the need for effective disease monitoring and response capabilities. The question is, can we implement programs to detect and prevent outbreaks before they occur, or will we always be reacting to existing outbreaks, trying to control the spread of disease and mitigate the harm to people and animals?
In some cases, the science suggests that we can predict the nature of the public health threat. For instance, scientists at the University of North Carolina at Chapel Hill identified a SARS-like virus, SHC014-CoV, that is currently circulating in Chinese horseshoe bat populations. This virus is highly pathogenic, does not respond to SARS-based therapies, and can infect human cells without the need for adaptive mutations. Furthermore, there are thought to be thousands of related coronaviruses in bat populations, some of which could emerge as human pathogens. These findings suggest that circulating SARS-like viruses have the potential to cause another global pandemic, and resources need to be dedicated to surveillance and the development of more effective therapeutics.
What is biosurveillance?
In 2012 President Obama released the first-ever National Strategy for Biosurveillance, whose purpose is to better integrate the many disparate governmental programs and non-governmental organizations that collect and monitor public health data. The Strategy defines biosurveillance as “the process of gathering, integrating, interpreting, and communicating essential information related to ‘all-hazards’ threats or disease activity affecting human, animal, or plant health to achieve early detection and warning, contribute to overall situational awareness of the health aspects of an incident, and to enable better decision making at all levels”. The “threats” described by the Strategy include emerging infectious diseases, pandemics, agricultural and food-borne illnesses, as well as the deliberate use of chemical, biological, radiological and nuclear (CBRN) weapons.
The overall goal of the Strategy is “to achieve a well-integrated national biosurveillance enterprise that saves lives by providing essential information for better decision making at all levels”. This goal is broken down into four core functions: (1) scan and discern the environment; (2) identify and integrate essential information; (3) inform and alert decision makers; and (4) forecast and advise potential impacts.
How are these programs implemented?
A number of programs were launched in response to President Obama’s Strategy. For instance, USAID’s Emerging Pandemic Threats (EPT) program created four complementary projects (Predict, Prevent, Identify, and Respond) which together aim to combat zoonotic outbreaks in 20 developing countries in Africa, Asia and Latin America that are hotspots of viral evolution and spread. Predict focuses on monitoring the wildlife-human interface to discover new and reemerging zoonotic diseases. The Prevent project aims to mitigate risk behavior associated with animal-to-human disease transmission. Identify works to strengthen laboratory diagnostic capabilities, and Respond focuses on preparing the public health workforce for an effective outbreak response.
There are many other agencies besides USAID and the State Department that participate in biosurveillance and biosecurity, including the Department of Health and Human Services (through the Biomedical Advanced Research and Development Authority). The Department of Defense and the Department of Homeland Security both have biosecurity programs as well (the Defense Threat Reduction Agency and the National Biodefense Analysis And Countermeasures Center, respectively). These focus more on protecting the health of armed forces and combatting deliberate acts of terror, however there is still a lot of overlap with emerging infectious diseases and global health. A comprehensive disaster preparedness strategy requires coordination between agencies that may not be used to working together, and who have very different structures and missions.
What are the challenges?
Global disease surveillance is a critical aspect of our biosecurity, due to accelerated population growth and migration, and worldwide movement of goods and food supplies. Political instability, cultural differences and lack of infrastructure in developing countries all present obstacles to effective global biosurveillance. These are complex issues, but are critically important to address, as rural populations in low- and middle-income countries can become hotspots of infectious disease outbreaks. This is in part due to the lack of sanitation and clean water, and the close contact with both domestic and wild animals.
Another challenge is determining the most effective metrics with which to monitor public health data. Often by the time a new pathogen has been positively identified and robust diagnostic measures implemented, a disease outbreak is well under way. In some cases, the actions of health workers can make the situation worse, such as in the tragic mishandling of the 2010 cholera outbreak in Haiti by the United Nations. One approach that has been shown to be effective for early detection is the use of syndromic surveillance systems, such as aggregating data from emergency room visits or the sale of over-the-counter medication. When combined with advanced computing techniques and adaptive machine learning methods this provides a powerful tool for the collection and integration of real-time data. This method can alert public health officials much earlier to the existence of a possible outbreak.
Scientific research on high-consequence pathogens is a key aspect of an effective biosecurity program. This is how we develop new diagnostic and therapeutic capabilities, as well as understand how pathogens spread and evolve. However, laboratories can also be the initial source of an infection, such as the laboratory-acquired tularemia outbreak, and research with the most dangerous pathogens (Select Agent Research) must be carefully monitored and regulated. It has been an ongoing challenge to balance the regulation of Select Agents with the critical need to enhance our scientific understanding of these pathogens. Of particular concern are gain-of-function studies, or Dual Use Research of Concern (DURC). From a scientific standpoint, these studies are vital to understanding pathogen evolution, which in turn helps us to predict the course of an outbreak and develop broad-spectrum therapeutics. However this also poses a security risk, since it means scientists are deliberately increasing the virulence of a given pathogen, such as the experimental adaptation of H5N1 avian influenza to mammalian transmission, which could pose a significant public health threat if deliberately misused.
How well are we doing?
The International Security Advisory Board, a committee established to provide independent analysis to the State Department on matters related to national and international security, published a report in May of 2016 on overseas disease outbreaks. They make a number of recommendations, including: (1) better integration of public health measures with foreign policy operations; (2) working with non-governmental organizations and international partners to increase preparedness planning and exercises; (3) increase financial support and reform structural issues at the World Health Organization to ensure effective communication during crises; (4) bolster lines of communication and data sharing across the federal government, in part through the establishment of interagency working groups; and (5) strengthening public health programs at the State Department and integrating public health experts into regional offices, foreign embassies and Washington for effective decision making at all levels.
The RAND Corporation, an independent think tank, conducted a review of the Department of Defense biosurveillance programs. They found that “more near-real-time analysis and better internal and external integration could enhance its performance and value”. They also found funding to be insufficient, and lacking a unified funding system. Improvements were needed in prioritizing the most critical programs, streamlining organization and governance, and increasing staff and facility resources.
RAND researchers also published an article assessing the nation’s health security research. They found that federal support is “heavily weighted toward preparing for bioterrorism and other biological threats, providing significantly less funding for challenges such as monster storms or attacks with conventional bombs”. In a study spanning seven non-defense agencies, including the National Institutes of Health (NIH) and the Centers for Disease Control (CDC), they found that fewer than 10% of federally funded projects address natural disasters. This could have broad consequences, especially considering that natural disasters such as earthquakes, hurricanes or tornadoes can create an environment for infectious diseases to take hold in a population. More work needs to be done to integrate biosurveillance and biosecurity programs across different agencies and allocate resources in a way that reflects the priorities laid out by the administration.
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By: Jessica Hostetler, PhD
The world made some good progress recently toward controlling or eliminating several diseases. Such gains are often long and hard fought. Vaccines are often a primary tool for eliminating diseases, which makes the rise in vaccine scepticism in many developed nations all the more troubling and fears of disease resurgences and outbreaks all too real.
The good news for disease control started in July with the commendation from the World Health Organization (WHO) to India for its work in eliminating yaws earlier in May of 2016. Yaws, often described as a “forgotten disease,” is a chronic skin disease caused by the bacterium Treponema pallidum, which is closely related to the organism that causes syphilis. It affects primarily children in poverty-stricken, crowded communities in about 13 countries with limited access to clean water, sanitation, and healthcare and can lead to severe disfigurement if not treated. Yaws is treated by a single dose of oral (Azithromycin) or injected (Benzathine penicillin) antibiotic. India tackled yaws through a campaign spanning years. “Highly targeted awareness and early treatment campaigns in vulnerable communities enabled treatment of yaws cases and interruption of disease transmission,” said Dr. Khetrapal Singh, the WHO Regional Director for South-East Asia in a WHO July press release. The success in India as the first country to eliminate yaws under the 2012 WHO neglected tropical diseases (NTD) roadmap gives renewed momentum toward global eradication in the remaining yaws-endemic countries by 2020.
More good news followed on September 5th with the announcement from WHO that Sri Lanka is now free of malaria. It is a large turnaround from the historical burden of the disease which was as high as 5 million cases per year in the 1930’s followed by a highly successful elimination program resulting in only 17 recorded cases in 1963. However, due to multiple factors, potentially including “human migrations, asymptomatic parasite-carriers, vector-reintroduction, behavioural changes in the vector and the emergence of drug and insecticide resistance,” cases soared again to half a million or more cases per year in the 1970s and 1980s. With a renewed focus on global malaria elimination in the 2000s, Sri Lanka has become a remarkable success story. As laid out in the WHO September press release, Sri Lanka’s strategy for elimination included targeting the parasites and the mosquitoes transmitting them through “mobile malaria clinics in high transmission areas” to give “prompt and effective treatment,” which reduced disease transmission and the parasite reservoir. Work such as this requires large teams of people for “effective surveillance, community engagement and health education.” But given Sri Lanka’s proximity to India, where malaria is still endemic, active surveillance for newly introduced cases will be essential to keep the disease at bay.
On September 27th, 2016, the Pan American Health Organization (PAHO) certified that the region of the Americas is free from endemic measles. This news isn’t strictly “new” as the last locally transmitted case of measles in the Americas occurred in Venezuela in 2002. Certification as being disease-free is a long process, however, and the Americas continued to experience over 5000 imported measles cases between 2003 and 2014, necessitating careful documentation to ensure local transmission had ended. Measles is a highly contagious virus and causes fever and a characteristic rash. It can lead to severe symptoms including “pneumonia, brain swelling and even death.” This is a historical success, but the WHO reports that measles still caused over 100,000 deaths globally, mostly children, in 2014. Continued vigilance and worldwide vaccination compliance are needed to maintain gains and reduce the disease where it still spreads endemically.
Such good news represents decades of hard work from international organizations, national governments and NGOs and many field workers on the ground. These efforts represent the best of humanity in working to alleviate suffering and eradicate disease. One of the primary tools in the fight against infectious diseases remains the development and mass administration of vaccines. In the US, vaccination skepticism has been growing for years on the heels of a now-retracted study in The Lancet in 1998 that proposed a link between the Measles-Mumps-Rubella (MMR) vaccine and the development of autism. While there is no evidence that vaccinations or vaccine ingredients cause autism in any way, the paper caused lasting damage to the public perception of vaccinations. A recent study examining American Academy of Pediatrics Periodic Surveys from 2006 and 2013 reports that while most parents no longer cite autism as a reason for avoiding vaccines for their children, many are now avoiding vaccinations because they are “unnecessary.” An increasing number of pediatricians (up from 6% in 2006 to 11% in 2013) report always dismissing patients for “continued vaccine refusal” citing both a lack of trust in the physician-patient relationship and concern for other patients as primary reasons. Non-compliance with vaccinations is largely viewed as the driver behind an outbreak of measles in and around the Disneyland resort in California in 2014-2015 as 67% of those with infections (who were vaccine eligible) “were intentionally unvaccinated because of personal beliefs.” Vaccination rates in some California communities had fallen below the level required for protection of the population; this spurred a controversial tightening of regulations requiring vaccinations for all public-school educated children with no exemption for religious or personal beliefs.
The international news is even more concerning with a recent global survey (with a commentary in Science) looking at attitudes toward vaccination showing that 41% of respondents from France and 31% of respondents from Japan disagreed with the statement that vaccines are safe. Russia had the highest scepticism about the importance of vaccines at 17%. The survey notes that “Countries with high levels of schooling and good access to health services are associated with lower rates of positive sentiment, pointing to an emerging inverse relationship between vaccine sentiments and socio-economic status.” The WHO reports that vaccines prevent 2-3 million deaths per year from diphtheria, tetanus, pertussis (whooping cough), and measles, but that as many as 1.5 million children under the age of 5 died from vaccine-preventable diseases in 2008. Vaccine-scepticism and outbreaks from vaccine non-compliance represent an alarming and avoidable threat as we aim to eliminate vaccine-preventable diseases from the world. As a perspective by Dr. Douglas S. Diekema in the New England Journal of Medicine notes, we must set a high goal in the US and globally to improve childhood vaccination rates through increased and free access to vaccines, but also swift rebuttals of unbalanced or incorrect reporting on vaccinations. The physician-patient relationship may offer the best opportunity to educate and “influence the vaccine-hesitant.”
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