Posts Tagged ‘Malaria’
By: Steven Brooks, PhD
Science diplomacy is an important conduit through which nations can cooperate with each other to help address issues of common concern. Establishing international collaborations based on scientific research and resource sharing can be a valuable tool to promote advances in global health and to help foster research communities in developing nations. In 2001, Nelson Mandela proposed a model for building and advancing a network of institutions investing in Science, Engineering, and Technology (SET) across sub-Saharan Africa (SSA) to enhance economic diversification, promote job growth, and improve living conditions for peoples across the region. Since then, significant strides have been made by many international organizations, including the World Health Organization, World Bank, and United Nations, to invest in SET institutions and researchers across SSA. Much work is still needed, however, to address the significant global health disparities affecting SSA. According to the United Nations Development Programme, life expectancy in SSA is on average only 46 years. Among the largest contributory factors to this gap is HIV/AIDS, but non-communicable diseases and genetic conditions such as Sickle Cell Disease (SCD) contribute as well. SCD in particular offers a stark geographic contrast in disease outcome: in the United States, childhood mortality (up to age 18) from SCD is below 10%, while in SSA the early childhood mortality rate is 50-90% by age 5. This drastic difference in childhood mortality from SCD raises an important question- why is the difference in mortality rates so large, and what can be done to eliminate it?
SCD represents a significant public health success in the United States. From the early 1970s, average life expectancy of people with SCD has substantially increased from 14 years of age to over 40 years, and childhood mortality rates have continued to decline. These vast improvements in SCD mortality in the US are attributable to improvements in screening and early diagnosis, as well as surveillance for early childhood infections and prophylactic treatments. Availability of therapies like hydroxyurea and access to blood transfusions have also contributed to reducing childhood mortality, while several currently ongoing clinical trials in the US are testing the use of bone marrow transplantation as a curative procedure for patients with severe complications of SCD. While the best practices for diagnosing and treating SCD are well-established in developed nations, lack of global implementation has meant that these advances in treatment have had very limited effect on reducing mortality and improving quality of life in developing nations. More than 85% of all new SCD cases occur in SSA, with over 240,000 infants with SCD born in SSA annually (compared to less than 2,000 in the US). Many nations in SSA do not have the resources or personnel to implement protocols for screening and diagnosis, and many children are born outside of hospitals. As a result, most children born with SCD in SSA will go undiagnosed, and therefore untreated, leading to devastatingly high rates of early childhood mortality for children with SCD.
The disparity in health outcomes between children born with SCD in developed nations and developing nations in SSA should be addressed through science diplomacy. An opportunity exists for diplomatic cooperation between scientists and health officials from the US and their counterparts in SSA to build infrastructure and train researchers and healthcare professionals to diagnose, treat, and innovate new solutions for SCD. The crucial first steps towards improving outcomes in SCD – parental and newborn screening, early childhood nutrition standards, parental and community education, and anti-bacterial and anti-viral vaccinations and prophylaxis – are achievable through diplomatic efforts and collaboration with governmental health agencies across SSA. Proof of this concept has been demonstrated in Bamako, Mali, with the success of the CRLD (The Center for Sickle Cell Disease Research and Control), a SCD-specific treatment and research center that reflects an effort of the government of Mali, with funding and medical resources provided by the Foundation Pierre Fabre. The CRLD utilizes modern diagnostic techniques to screen for SCD. It also provides immunizations, hospitalizations, and access to preventive medicine, and provides education and outreach to patients and to the larger community. Historically, the infant mortality rate from SCD in Mali was estimated to be 50% by age 5. Since the opening of the CRLD in 2005, only 81 of the over 6,000 patients enrolled at CRLD have died, a mortality rate for this cohort that is comparable to rates in the US and UK. The CRLD also has modern laboratories that conduct research, with over 20 academic papers published from the CRLD so far. The ongoing success of the CRLD is proof that investment in, and collaboration with, governments and medical professionals in Africa can lead to equitable health outcomes in SCD. Similar investments by the US government and the National Institutes of Health (NIH), possibly through intramural research programs, and in cooperation with health-focused private foundations, could lead to similar success stories in communities across SSA.
The NIH supports and facilitates collaborations in global health research through the NIH Fogarty International Center (FIC), which currently sponsors projects in 20 countries across SSA. NIH has also invested intramural resources into collaborations in SSA to combat Malaria. The National Institute of Allergy and Infectious Diseases (NIAID) trains and sponsors investigators to independently conduct research in Mali (NIAID’s Mali ICER (International Centers of Excellence in Research)). Despite its significant history of investment in SSA, the NIH offers almost no international support for research related to SCD. The NIH FIC only currently funds one project related to SCD, preventing pediatric stroke in Nigerian Children. The Division of Intramural Research at the NIH is currently home to robust basic science and clinical-translational research on SCD. Intramural researchers can and should collaborate with clinicians and scientists from SSA who will lead the effort to combat SCD in their home nations. More broadly, the NIH could spearhead an initiative to bring together stakeholders from the US government, health ministries from nations in SSA, and private foundations that support efforts to reduce or eradicate global disease, to begin establishing a network of laboratory and clinical facilities for testing and treatment, as well as to train clinicians and researchers from SSA in diagnostic and research techniques specific to SCD, and to design and disseminate educational resources for increasing communal knowledge regarding SCD across SSA.
In addition to significantly improving SCD mortality and health outcomes in SSA, these efforts of science diplomacy will have substantial benefits in the US as well. The US is home to a sizeable, and growing population of people living with SCD. As life expectancy continues to increase, new challenges will arise for effectively treating serious complications associated with SCD, such as renal disease, stroke, cardiovascular disease, heart failure, cardiomyopathy, and pulmonary hypertension. By collaborating with researchers and healthcare leaders studying large populations of people with SCD in SSA, the NIH will foster innovation and generate new insights about SCD that are uniquely informed by the data and perspectives of African scientists and populations. The NIH and the US government can establish a mutually beneficial program of treatment, education, and research that will enable developing nations to treat their patients with the same methods available in the US. Investing in 21st century methods of diagnosis and treatment, as well as contributing funding, training, and infrastructure to clinicians and researchers in SSA, can strengthen diplomatic relationships between governmental leaders and scientists alike and lead to lasting collaborations that strengthens research and innovation into new treatments for SCD.
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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: 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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