Tag Archives: malaria

Dealing with mosquitos: a robot story and an engineered human tissue story

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I have two ‘mosquito and disease’ stories, the first concerning dengue fever and the second, malaria.

Dengue fever in Taiwan

A June 8, 2023 news item on phys.org features robotic vehicles, dengue fever, and mosquitoes,

Unmanned ground vehicles can be used to identify and eliminate the breeding sources of mosquitos that carry dengue fever in urban areas, according to a new study published in PLOS Neglected Tropical Diseases by Wei-Liang Liu of the Taiwan National Mosquito-Borne Diseases Control Research Center, and colleagues.

It turns out sewers are a problem according to this June 8, 2023 PLOS (Public Library of Science) news release on EurekAlert, provides more context and detail,

Dengue fever is an infectious disease caused by the dengue virus and spread by several mosquito species in the genus Aedes, which also spread chikungunya, yellow fever and zika. Through the process of urbanization, sewers have become easy breeding grounds for Aedes mosquitos and most current mosquito monitoring programs struggle to monitor and analyze the density of mosquitos in these hidden areas.

In the new control effort, researchers combined a crawling robot, wire-controlled cable car and real-time monitoring system into an unmanned ground vehicle system (UGV) that can take high-resolution, real-time images of areas within sewers. From May to August 2018, the system was deployed in five administrative districts in Kaohsiung city, Taiwan, with covered roadside sewer ditches suspected to be hotspots for mosquitos. Mosquito gravitraps were places above the sewers to monitor effects of the UGV intervention on adult mosquitos in the area.

In 20.7% of inspected sewers, the system found traces of Aedes mosquitos in stages from larvae to adult. In positive sewers, additional prevention control measures were carried out, using either insecticides or high-temperature water jets.  Immediately after these interventions, the gravitrap index (GI)—  a measure of the adult mosquito density nearby— dropped significantly from 0.62 to 0.19.

“The widespread use of UGVs can potentially eliminate some of the breeding sources of vector mosquitoes, thereby reducing the annual prevalence of dengue fever in Kaohsiung city,” the authors say.

Here’s a link to and a citation for the paper,

Use of unmanned ground vehicle systems in urbanized zones: A study of vector Mosquito surveillance in Kaohsiung by Yu-Xuan Chen, Chao-Ying Pan, Bo-Yu Chen, Shu-Wen Jeng, Chun-Hong Chen, Joh-Jong Huang, Chaur-Dong Chen, Wei-Liang Liu. PLOS Neglected Tropical Diseases DOI: https://doi.org/10.1371/journal.pntd.0011346 Published: June 8, 2023

This paper is open access.

Dengue on the rise

Like many diseases, dengue is one where you may not have symptoms (asymptomatic), or they’re relatively mild and can be handled at home, or you may need care in a hospital and, in some cases, it can be fatal.

The World Health Organization (WHO) notes that dengue fever cases have increased exponentially since 2000 (from the March 17, 2023 version of the WHO’s “Dengue and severe dengue” fact sheet),

Global burden

The incidence of dengue has grown dramatically around the world in recent decades, with cases reported to WHO increased from 505 430 cases in 2000 to 5.2 million in 2019. A vast majority of cases are asymptomatic or mild and self-managed, and hence the actual numbers of dengue cases are under-reported. Many cases are also misdiagnosed as other febrile illnesses (1).

One modelling estimate indicates 390 million dengue virus infections per year of which 96 million manifest clinically (2). Another study on the prevalence of dengue estimates that 3.9 billion people are at risk of infection with dengue viruses.

The disease is now endemic in more than 100 countries in the WHO Regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. The Americas, South-East Asia and Western Pacific regions are the most seriously affected, with Asia representing around 70% of the global disease burden.

Dengue is spreading to new areas including Europe, [emphasis mine] and explosive outbreaks are occurring. Local transmission was reported for the first time in France and Croatia in 2010 [emphasis mine] and imported cases were detected in 3 other European countries.

The largest number of dengue cases ever reported globally was in 2019. All regions were affected, and dengue transmission was recorded in Afghanistan for the first time. The American Region reported 3.1 million cases, with more than 25 000 classified as severe. A high number of cases were reported in Bangladesh (101 000), Malaysia (131 000) Philippines (420 000), Vietnam (320 000) in Asia.

Dengue continues to affect Brazil, Colombia, the Cook Islands, Fiji, India, Kenya, Paraguay, Peru, the Philippines, the Reunion Islands and Vietnam as of 2021. 

There’s information from an earlier version of the fact sheet, in my July 2, 2013 posting, highlighting different aspects of the disease, e.g., “About 2.5% of those affected die.”

A July 21, 2023 United Nations press release warns that the danger from mosquitoes spreading dengue fever could increase along with the temperature,

Global warming marked by higher average temperatures, precipitation and longer periods of drought, could prompt a record number of dengue infections worldwide, the World Health Organization (WHO) warned on Friday [July 21, 2023].

Despite the absence of mosquitoes infected with the dengue virus in Canada, the government has a Dengue fever information page. At this point, the concern is likely focused on travelers who’ve contracted the disease from elsewhere. However, I am guessing that researchers are keeping a close eye on Canadian mosquitoes as these situations can change.

Malaria in Florida (US)

The researchers from the University of Central Florida (UCF) couldn’t have known when they began their project to study mosquito bites and disease that Florida would register its first malaria cases in 20 years this summer, from a July 26, 2023 article by Stephanie Colombini for NPR ([US] National Public Radio), Note: Links have been removed,

…

First local transmission in U.S. in 20 years

Heath [Hannah Heath] is one of eight known people in recent months who have contracted malaria in the U.S., after being bitten by a local mosquito, rather than while traveling abroad. The cases comprise the nation’s first locally transmitted outbreak in 20 years. The last time this occurred was in 2003, when eight people tested positive for malaria in Palm Beach, Fla.

One of the eight cases is in Texas; the rest occurred in the northern part of Sarasota County.

The Florida Department of Health recorded the most recent case in its weekly arbovirus report for July 9-15 [2023].

For the past month, health officials have issued a mosquito-borne illness alert for residents in Sarasota and neighboring Manatee County. Mosquito management teams are working to suppress the population of the type of mosquito that carries malaria, Anopheles.

Sarasota Memorial Hospital has treated five of the county’s seven malaria patients, according to Dr. Manuel Gordillo, director of infection control.

“The cases that are coming in are classic malaria, you know they come in with fever, body aches, headaches, nausea, vomiting, diarrhea,” Gordillo said, explaining that his hospital usually treats just one or two patients a year who acquire malaria while traveling abroad in Central or South America, or Africa.

…

All the locally acquired cases were of Plasmodium vivax malaria, a strain that typically produces milder symptoms or can even be asymptomatic, according to the Centers for Disease Control and Prevention. But the strain can still cause death, and pregnant people and children are particularly vulnerable.

…

Malaria does not spread from human-to-human contact; a mosquito carrying the disease has to bite someone to transmit the parasites.

Workers with Sarasota County Mosquito Management Services have been especially busy since May 26 [2023], when the first local case was confirmed.

Like similar departments across Florida, the team is experienced in responding to small outbreaks of mosquito-borne illnesses such as West Nile virus or dengue. They have protocols for addressing travel-related cases of malaria as well, but have ramped up their efforts now that they have confirmation that transmission is occurring locally between mosquitoes and humans.

…

While organizations like the World Health Organization have cautioned climate change could lead to more global cases and deaths from malaria and other mosquito-borne diseases, experts say it’s too soon to tell if the local transmission seen these past two months has any connection to extreme heat or flooding.

“We don’t have any reason to think that climate change has contributed to these particular cases,” said Ben Beard, deputy director of the CDC’s US Centers for Disease Control and Prevention] division of vector-borne diseases and deputy incident manager for this year’s local malaria response.

“In a more general sense though, milder winters, earlier springs, warmer, longer summers – all of those things sort of translate into mosquitoes coming out earlier, getting their replication cycles sooner, going through those cycles faster and being out longer,” he said. And so we are concerned about the impact of climate change and environmental change in general on what we call vector-borne diseases.”.

Beard co-authored a 2019 report that highlights a significant increase in diseases spread by ticks and mosquitoes in recent decades. Lyme disease and West Nile virus were among the top five most prevalent.

“In the big picture it’s a very significant concern that we have,” he said.

…

Engineered tissue and bloodthirsty mosquitoes

A June 8, 2023 University of Central Florida (UCF) news release (also on EurekAlert) by Eric Eraso describes the research into engineered human tissue and features a ‘bloodthirsty’ video. First, the video,

Note: A link has been removed,

A UCF research team has engineered tissue with human cells that mosquitoes love to bite and feed upon — with the goal of helping fight deadly diseases transmitted by the biting insects.

A multidisciplinary team led by College of Medicine biomedical researcher Bradley Jay Willenberg with Mollie Jewett (UCF Burnett School of Biomedical Sciences) and Andrew Dickerson (University of Tennessee) lined 3D capillary gel biomaterials with human cells to create engineered tissue and then infused it with blood. Testing showed mosquitoes readily bite and blood feed on the constructs. Scientists hope to use this new platform to study how pathogens that mosquitoes carry impact and infect human cells and tissues. Presently, researchers rely largely upon animal models and cells cultured on flat dishes for such investigations.

Further, the new system holds great promise for blood feeding mosquito species that have proven difficult to rear and maintain as colonies in the laboratory, an important practical application. The Willenberg team’s work was published Friday in the journal Insects.

Mosquitos have often been called the world’s deadliest animal, as vector-borne illnesses, including those from mosquitos cause more than 700,000 deaths worldwide each year. Malaria, dengue, Zika virus and West Nile virus are all transmitted by mosquitos. Even for those who survive these illnesses, many are left suffering from organ failure, seizures and serious neurological impacts.

“Many people get sick with mosquito-borne illnesses every year, including in the United States. The toll of such diseases can be especially devastating for many countries around the world,” Willenberg says.

This worldwide impact of mosquito-borne disease is what drives Willenberg, whose lab employs a unique blend of biomedical engineering, biomaterials, tissue engineering, nanotechnology and vector biology to develop innovative mosquito surveillance, control and research tools. He said he hopes to adapt his new platform for application to other vectors such as ticks, which spread Lyme disease.

“We have demonstrated the initial proof-of-concept with this prototype” he says. “I think there are many potential ways to use this technology.”

Captured on video, Willenberg observed mosquitoes enthusiastically blood feeding from the engineered tissue, much as they would from a human host. This demonstration represents the achievement of a critical milestone for the technology: ensuring the tissue constructs were appetizing to the mosquitoes.

“As one of my mentors shared with me long ago, the goal of physicians and biomedical researchers is to help reduce human suffering,” he says. “So, if we can provide something that helps us learn about mosquitoes, intervene with diseases and, in some way, keep mosquitoes away from people, I think that is a positive.”

Willenberg came up with the engineered tissue idea when he learned the National Institutes of Health (NIH) was looking for new in vitro 3D models that could help study pathogens that mosquitoes and other biting arthropods carry.

“When I read about the NIH seeking these models, it got me thinking that maybe there is a way to get the mosquitoes to bite and blood feed [on the 3D models] directly,” he says. “Then I can bring in the mosquito to do the natural delivery and create a complete vector-host-pathogen interface model to study it all together.”

As this platform is still in its early stages, Willenberg wants to incorporate addition types of cells to move the system closer to human skin. He is also developing collaborations with experts that study pathogens and work with infected vectors, and is working with mosquito control organizations to see how they can use the technology.

“I have a particular vision for this platform, and am going after it. My experience too is that other good ideas and research directions will flourish when it gets into the hands of others,” he says. “At the end of the day, the collective ideas and efforts of the various research communities propel a system like ours to its full potential. So, if we can provide them tools to enable their work, while also moving ours forward at the same time, that is really exciting.”

Willenberg received his Ph.D. in biomedical engineering from the University of Florida and continued there for his postdoctoral training and then in scientist, adjunct scientist and lecturer positions. He joined the UCF College of Medicine in 2014, where he is currently an assistant professor of medicine.

Willenberg is also a co-founder, co-owner and manager of Saisijin Biotech, LLC and has a minor ownership stake in Sustained Release Technologies, Inc. Neither entity was involved in any way with the work presented in this story. Team members may also be listed as inventors on patent/patent applications that could result in royalty payments. This technology is available for licensing. To learn more, please visit ucf.flintbox.com/technologies/44c06966-2748-4c14-87d7-fc40cbb4f2c6.

Here’s a link to and a citation for the paper,

Engineered Human Tissue as A New Platform for Mosquito Bite-Site Biology Investigations by Corey E. Seavey, Mona Doshi, Andrew P. Panarello, Michael A. Felice, Andrew K. Dickerson, Mollie W. Jewett and Bradley J. Willenberg. Insects 2023, 14(6), 514; https://doi.org/10.3390/insects14060514 Published: 2 June 2023

This paper is open access.

That final paragraph in the news release is new to me. I’ve seen them list companies where the researchers have financial interests but this is the first time I’ve seen a news release that offers a statement attempting to cover all the bases including some future possibilities such as: “Team members may also be listed as inventors on patent/patent applications that could result in royalty payments.“

It seems pretty clear that there’s increasing concern about mosquito-borne diseases no matter where you live.

The latest and greatest in gene drives (for flies)

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This is a CRISPR (clustered regularly interspaced short palindromic repeats) story where the researchers are working on flies. If successful, this has much wider implications. From an April 10, 2019 news item on phys.org,

New CRISPR-based gene drives and broader active genetics technologies are revolutionizing the way scientists engineer the transfer of specific traits from one generation to another.

Scientists at the University of California San Diego have now developed a new version of a gene drive that opens the door to the spread of specific, favorable subtle genetic variants, also known as “alleles,” throughout a population.

The new “allelic drive,” described April 9 [2019] in Nature Communications, is equipped with a guide RNA (gRNA) that directs the CRISPR system to cut undesired variants of a gene and replace it with a preferred version of the gene. The new drive extends scientists’ ability to modify populations of organisms with precision editing. Using word processing as an analogy, CRISPR-based gene drives allow scientists to edit sentences of genetic information, while the new allelic drive offers letter-by-letter editing.

An April 9, 2019 University of California at San Diego (UCSD) news release (also on EurekAlert) by Mario Aguilera, which originated the news item, delves into this technique’s potential uses while further explaining the work


In one example of its potential applications, specific genes in agricultural pests that have become resistant to insecticides could be replaced by original natural genetic variants conferring sensitivity to insecticides using allelic drives that selectively swap the identities of a single protein residue (amino acid).

In addition to agricultural applications, disease-carrying insects could be a target for allelic drives.

“If we incorporate such a normalizing gRNA on a gene-drive element, for example, one designed to immunize mosquitoes against malaria, the resulting allelic gene drive will spread through a population. When this dual action drive encounters an insecticide-resistant allele, it will cut and repair it using the wild-type susceptible allele,” said Ethan Bier, the new paper’s senior author. “The result being that nearly all emerging progeny will be sensitive to insecticides as well as refractory to malaria transmission.”

“Forcing these species to return to their natural sensitive state using allelic drives would help break a downward cycle of ever-increasing and environmentally damaging pesticide over-use,” said Annabel Guichard, the paper’s first author.

The researchers describe two versions of the allelic drive, including “copy-cutting,” in which researchers use the CRISPR system to selectively cut the undesired version of a gene, and a more broadly applicable version referred to as “copy-grafting” that promotes transmission of a favored allele next to the site that is selectively protected from gRNA cleavage.

“An unexpected finding from this study is that mistakes created by such allelic drives do not get transmitted to the next generation,” said Guichard. “These mutations instead produce an unusual form of lethality referred to as ‘lethal mosaicism.’ This process helps make allelic drives more efficient by immediately eliminating unwanted mutations created by CRISPR-based drives.”

Although demonstrated in fruit flies, the new technology also has potential for broad application in insects, mammals and plants. According to the researchers, several variations of the allelic drive technology could be developed with combinations of favorable traits in crops that, for example, thrive in poor soil and arid environments to help feed the ever-growing world population.

Beyond environmental applications, allelic drives should enable next-generation engineering of animal models to study human disease as well as answer important questions in basic science. As a member of the Tata Institute for Genetics and Society (TIGS), Bier says allelic drives could be used to aid in environmental conservation efforts to protect vulnerable endemic species or stop the spread of invasive species.

Gene drives and active genetics systems are now being developed for use in mammals. The scientists say allelic drives could accelerate new laboratory strains of animal models of human disease that aid in the development of new cures.

Here’s a link to and a citation for the paper,

Efficient allelic-drive in Drosophila by Annabel Guichard, Tisha Haque, Marketta Bobik, Xiang-Ru S. Xu, Carissa Klanseck, Raja Babu Singh Kushwah, Mateus Berni, Bhagyashree Kaduskar, Valentino M. Gantz & Ethan Bier. Nature Communicationsvolume 10, Article number: 1640 (2019) DOI: https://doi.org/10.1038/s41467-019-09694-w Published 09 April 2019

This paper is open access.

For anyone new to gene drives, I have a February 8, 2018 posting that highlights a report from the UK on the latest in genetic engineering, which provides a definition for [synthetic] gene drives, and if you scroll down about 75% of the way, you’ll also find excerpts from an article for The Atlantic by Ed Yong on gene drives as proposed for a project in New Zealand.

Effective safety strategies for CRISPR (clustered regularly interspaced short palindromic repeats) gene drive experiments

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It’s very peculiar being able to understand each word individually in clustered regularly interspaced short palindromic repeats (CRISPR) but not being able to puzzle out much meaning other than the widely known ‘it’s a gene editor’.

Regardless, CRISPR is a powerful gene editing tool and that can lead to trouble. Even before CRISPR, we’ve had some genetic accidents. Perhaps the best known is the ‘killer bee’ or Africanized bee (from its Wikepedia entry),

The Africanized bee, also known as the Africanised honey bee, and known colloquially as “killer bee”, is a hybrid of the western honey bee species (Apis mellifera), produced originally by cross-breeding [emphasis mine] of the East African lowland honey bee (A. m. scutellata) with various European honey bees such as the Italian honey bee A. m. ligustica and the Iberian honey bee A. m. iberiensis.

The Africanized honey bee was first introduced to Brazil in 1956 in an effort to increase honey production, but 26 swarms escaped quarantine in 1957 [emphasis mine]. Since then, the hybrid has spread throughout South America and arrived in North America in 1985. Hives were found in South Texas of the United States in 1990.

Africanized bees are typically much more defensive than other varieties of honey bee, and react to disturbances faster than European honey bees. They can chase a person a quarter of a mile (400 m); they have killed some 1,000 humans, with victims receiving ten times more stings than from European honey bees. They have also killed horses and other animals.

…

Getting back to how powerful CRISPR is, a group of scientists has developed a set of strategies for safeguarding gene drive experiments (from a January 22, 2019 eLife press release also on EurekAlert),

Researchers have demonstrated for the first time how two molecular strategies can safeguard CRISPR gene drive experiments in the lab, according to a study published today in eLife.

Their findings, first reported on bioRxiv, suggest that scientists can effectively use synthetic target sites and split drives to conduct gene drive research, without the worry of causing an accidental spread throughout a natural population.

Gene drives, such as those trialled in malaria mosquitoes, are genetic packages designed to spread among populations. They do this via a process called ‘drive conversion’, where the Cas9 enzyme and a molecule called guide RNA (gRNA) cut at a certain site in the genome. The drive is then copied in when the DNA break is repaired.

“CRISPR-based gene drives have sparked both enthusiasm and deep concerns due to their potential for genetically altering entire species,” explains first author Jackson Champer, Postdoctoral Fellow in the Department of Biological Statistics and Computational Biology at Cornell University, New York. “This raises the question about our ability to prevent the unintended spread of such drives from the laboratory into the natural world.

“Current strategies for avoiding accidental spread involve physically confining drive-containing organisms. However, it is uncertain whether this sufficiently reduces the likelihood of any accidental escape into the wild, given the possibility of human error.”

Two molecular safeguarding strategies have recently been proposed that go beyond simply confining research organisms. The first is synthetic target site drive, which homes into engineered genomic sites that are absent in wild organisms. The second is split drive, where the drive construct lacks a type of enzyme called the endonuclease and relies instead on one engineered into a distant site.

“The nature of these strategies means that they should prevent an efficient spread outside of their respective laboratory lines,” Champer adds. “We wanted to see if they both had a similar performance to standard homing drives, and if they would therefore be suitable substitutes in early gene-drive research.”

To do this, the team designed and tested three synthetic target site drives in the fruit fly Drosophila melanogaster. Each drive targeted an enhanced green fluorescent protein (EGFP) gene introduced at one of three different sites in the genome. For split drives, they designed a drive construct that targeted the X-linked gene yellow and lacked Cas9.

Their analyses revealed that CRISPR gene drives with synthetic target sites such as EGFP show similar behaviour to standard drives, and can therefore be used for most testing in place of these drives. The split drives demonstrated similar performance, and also allow for natural sequences to be targeted in situations where the use of synthetic targets is difficult. These include population-suppression drives that require the targeting of naturally occurring genes

“Based on our findings, we suggest these safeguarding strategies should be adopted consistently in the development and testing of future gene drives,” says senior author Philipp Messer, Assistant Professor in the Department of Biological Statistics and Computational Biology at Cornell University. “This will be important for large-scale cage experiments aimed at improving our understanding of the expected population dynamics of candidate drives. Ultimately, this understanding will be crucial for discussing the feasibility and risks of releasing successful drives into the wild, for example to reduce malaria and other vector-borne diseases.”

Here’s a link to and a citation for the paper,

Molecular safeguarding of CRISPR gene drive experiments by Jackson Champer, Joan Chung, Yoo Lim Lee, Chen Liu, Emily Yang, Zhaoxin Wen, Andrew G Clark, Philipp W Messer. DOI: 10.7554/eLife.41439 Short Report Jan 22, 2019

This paper is open access. For anyone who doesn’t mind reading an earlier version of a paper you can find it at bioRxiv, at https://www.biorxiv.org/content/early/2018/09/08/411876.

elife, which i’ve mentioned here here before in a February 8, 2018 posting is a (from their About eLife webpage)

… non-profit organisation inspired by research funders and led by scientists. Our mission is to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science.

Nano-decoy for human influenza A virus

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While the implications for this research are exciting, keep in mind that so far they’ve been testing immune-compromised mice. An Oct. 24, 2016 news item on Nanowerk announces the research,

To infect its victims, influenza A heads for the lungs, where it latches onto sialic acid on the surface of cells. So researchers created the perfect decoy: A carefully constructed spherical nanoparticle coated in sialic acid lures the influenza A virus to its doom. When misted into the lungs, the nanoparticle traps influenza A, holding it until the virus self-destructs.

An Oct. 24, 2015 Rensselaer Polytechnic Institute press release by Mary L. Martialay, which originated the news item, describes the research (Note: Links have been removed),

In a study on immune-compromised mice, the treatment reduced influenza A mortality from 100 percent to 25 percent over 14 days. The novel approach, which is radically different from existing influenza A vaccines, and treatments based on neuraminidase inhibitors, could be extended to a host of viruses that use a similar approach to infecting humans, such as Zika, HIV, and malaria. …

“Instead of blocking the virus, we mimicked its target – it’s a completely novel approach,” said Robert Linhardt, a glycoprotein expert and Rensselaer Polytechnic Institute professor who led the research. “It is effective with influenza and we have reason to believe it will function with many other viruses. This could be a therapeutic in cases where vaccine is not an option, such as exposure to an unanticipated strain, or with immune-compromised patients.”

The project is a collaboration between researchers within the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer and several institutions in South Korea including Kyungpook National University. Lead author Seok-Joon Kwon, a CBIS research scientist, coordinated the project across borders, enabling the South Korean institutions to test a drug designed and characterized at Rensselaer. …

To access the interior of a cell and replicate itself, influenza A must first bind to the cell surface, and then cut itself free. It binds with the protein hemagglutinin, and severs that tie with the enzyme neuraminidase. Influenza A produces numerous variations each of hemagglutinin and neuraminidase, all of which are antigens within the pathogen that provoke an immune system response. Strains of influenza A are characterized according to the variation of hemagglutinin and neuraminidase they carry, thus the origin of the familiar H1N1 or H3N2 designations.

Medications to counter the virus do exist, but all are vulnerable to the continual antigenic evolution of the virus. A yearly vaccine is effective only if it matches the strain of virus that infects the body. And the virus has shown an ability to develop resistance to a class of therapeutics based on neuraminidase inhibitors, which bind to and block neuraminidase.

The new solution targets an aspect of infection that does not change: all hemagglutinin varieties of influenza A must bind to human sialic acid. To trap the virus, the team designed a dendrimer, a spherical nanoparticle with treelike branches emanating from its core. On the outermost branches, they attached molecules, or “ligands,” of sialic acid.

The research found that the size of the dendrimer and the spacing between the ligands is integral to the function of the nanoparticle. Hemagglutinin occurs in clusters of three, or “trimers,” on the surface of the virus, and researchers found that a spacing of 3 nanometers between ligands resulted in the strongest binding to the trimers. Once bound to the densely packed dendrimer, viral neuraminidase is unable to sever the link. The coat of the virus contains millions of trimers, but the research revealed that only a few links provokes the virus to discharge its genetic cargo and ultimately self-destruct.

A different approach, using a less structured nanoparticle, had been previously tested in unrelated research, but the nanoparticle selected proved both toxic, and could be inactivated by neuraminidase. The new approach is far more promising.

“The major accomplishment was in designing an architecture that is optimized to bind so tightly to the hemagglutinin, the neuraminidase can’t squeeze in and free the virus,” said Linhardt. “It’s trapped.”

Here’s a link to and a citation for the paper,

Nanostructured glycan architecture is important in the inhibition of influenza A virus infection by Seok-Joon Kwon, Dong Hee Na, Jong Hwan Kwak, Marc Douaisi, Fuming Zhang, Eun Ji Park, Jong-Hwan Park, Hana Youn, Chang-Seon Song, Ravi S. Kane, Jonathan S. Dordick, Kyung Bok Lee, & Robert J. Linhardt. Nature Nanotechnology (2016)  doi:10.1038/nnano.2016.181 Published online 24 October 2016

This paper is behind a paywall.

A ‘Candy Crush’ like video game for malaria

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Yesterday*, April 25, 2016 was* World Malaria Day and the launch date for a new video game according to an April 25, 2016 news item on ScienceDaily,

Shoot bubbles while helping research against malaria? It is possible with MalariaSpot Bubbles, an online game that launches on April 25, World Malaria Day. Players analyze digitalized images of parasites to differentiate between the five species that cause malaria. They do it while having fun shooting at mosquitoes and bubbles. It is an application to learning through play and to contribute to the research of new diagnosis methods. MalariaSpot Bubbles has been developed by researchers of the Biomedical Imaging Technologies Group at the Technical University of Madrid — International Excellence Campus Moncloa.

An April 25, 2016 Universidad Politécnica de Madrid (Technical University of Madrid) press release, which originated the news item, describes the game and the goal in more detail (Note 1: A link has been removed; Note 2: I believe this text was originally in Spanish and then translated by machine resulting in a few unusual grammatical structures),

MalariaSpot Bubbles is an educational tool to research how young students acquire skills through gaming. During World Malaria Day thousands of students will participate in “Olympic Malaria Videogames” playing MalariaSpot Bubbles, a video game that uses images of digitized blood samples. During this day school teams will compete to become the best virtual hunters of malaria parasites.

“Digital natives around the world spend millions of hours a day playing video games. MalariaSpot Bubbles is an experiment to explore this potential as a new solution to global health problems” says Daniel Cuadrado, MalariaSpot developer and researcher at the Technical University of Madrid.

Diagnosis for everyone by everyone

MalariaSpot Bubbles not only allow players to learn, but also to participate in the research of new tools for collaborative diagnosis online. Malaria is diagnosed by observing a blood smear with a microscope and looking for parasites. Part of the diagnostic protocol is to identify which of the five different species that cause malaria is present in the blood. “This is especially important to provide the proper treatment to the patients”, says María Linares, researcher at Hospital 12 de Octubre and MalariaSpot biomedical specialist. The aim of MalariaSpot Bubbles is to research if remote diagnosis could be performed collectively by non experts, expanding the concept initiated four years ago with the first version of the game MalariaSpot. This project has been recently featured in the prestigious medical journal The Lancet.

Here’s a video introduction to the game,

And, here’s a link to and a citation for the paper in Lancet,

Gamers join real-life fight against malaria and tuberculosis by Leonore Albers. Lancet Volume 16, No. 4, p418, April 2016 DOI: http://dx.doi.org/10.1016/S1473-3099(16)00136-5

This paper is behind a paywall.

Should you wish to play, the MalariaSpot Bubbles website is here.

*Oops! ‘Today’ changed to ‘Yesterday’ and ‘is’ changed to ‘was’ since today is April 26, 2016.

Weirdly fascinating account of malaria-carrying mosquitoes and insecticide-treated bed nets

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Researchers at the Liverpool School of Tropical Medicine (LSTM) have tracked mosquitoes to observe how they interact with insecticide-laden nets. From a Sept. 1, 2015 LSTM press release (also on EurekAlert),

LSTM vector biologists Dr Philip McCall and Ms Josie Parker worked with optical engineers Prof David Towers, Dr Natalia Angarita and Dr Catherine Towers from the University of Warwick’s School of Engineering to develop infrared video tracking technology that follows individual mosquitoes in flight as they try to reach a human sleeper inside a bed net. This system allowed the scientists to measure, define and characterise in fine detail, the behavioural events and sequences of the main African malaria vector, Anopheles gambiae, as it interacts with the net. Funded as part of the €12M AvecNet research consortium, the team’s initial results are published today in the journal Nature Scientific Reports.

Dr Philip McCall, senior author on the paper, said: “Essentially, the results demonstrated that an LLIN [Long-lasting insecticidal bed net] functions as a highly efficient, fast-acting, human-baited insecticidal trap. LLINs do not repel mosquitoes – they deliver insecticide very rapidly after the briefest contact: LLIN contact of less than 1 minute per mosquito during the first ten minutes can reduce mosquito activity such that after thirty minutes, virtually no mosquitoes are still flying. Surprisingly, mosquitoes were able to detect nets of any kind while still in flight, allowing them to decelerate before they ‘collided’ with the net surface.”

The use of this innovative approach to mosquito behaviour has provided unprecedented insight into the mode of action of our most important tool for preventing malaria transmission, under conditions that are as close to natural as possible. The findings potentially could influence many aspects of mosquito control, ranging from how we test mosquito populations for insecticide resistance to the design of a next generation of LLINs. An MRC Confidence in Concept grant has funded the team to use the tracking system to explore a number of novel LLIN designs, already patented as an outcome from the current research.

The tracking system also has been deployed in a rural Tanzania, results of which will be reported shortly. The team recently was awarded £0.9M support from the Medical Research Council (MRC) for the next stage of this project, where they will use a larger three-dimensional system to track mosquitoes throughout the entire domestic environment, in experimental houses in Tanzania.

Dr McCall continued: “preliminary results in field tests indicate that these laboratory findings are consistent with behaviour of wild mosquito populations which is very encouraging. We are at the early stages of this research, but we hope that our findings, and the use of this cutting edge technology, can contribute to the development of new and advanced vector control tools that will continue to save lives in endemic countries throughout the world.”

The fascinating part follows the link to and citation for the paper,

Infrared video tracking of Anopheles gambiae at insecticide-treated bed nets reveals rapid decisive impact after brief localised net contact by Josephine E.A. Parker, Natalia Angarita-Jaimes, Mayumi Abe, Catherine E. Towers, David Towers, & Philip J. McCall. Scientific Reports 5, Article number: 13392 (2015) doi:10.1038/srep13392 Published online: 01 September 2015

This open access paper provides an explanation for why this work was undertaken,

Delivering the ‘next generation’ of LLINs or similar tools will require a thorough understanding of how LLINs function, yet remarkably little is known of the mode of action or of precisely how mosquitoes behave at the LLIN interface. Recent studies using ‘sticky-nets’ reported that host-seeking female Anopheles spp. landed preferentially on the top surface of bed nets7,8 but that lethal capture method recorded only a single landing event and no other behaviours before or after. Although clustering at the net roof is likely to be a response to an attractant ‘plume’ rising from the human beneath [emphasis mine], this too remains speculative because knowledge of mosquito flight behaviour prior to blood-feeding and of the identity and location of the key attractants that mediate the host-seeking response is limited9,10,11,12. Importantly, how insecticide treatments influence that response is unclear. Some studies reported that insecticide residues repelled mosquitoes prior to contact13,14, which would reduce or eliminate the chance of mosquitoes receiving an effective dose and potentially divert them to unprotected hosts15. Others found no evidence for such repellency16,17,18,19 indicating that LLINs attract and impact on mosquitoes by direct contact.

A further complication is the existence of what is termed ‘contact-irritancy’ or ‘excito-repellency’ [emphasis miine], whereby brief exposure to an insecticide can result in mosquitoes exhibiting avoidance behaviour, potentially before a lethal dose has been delivered13,20. Remarkably, some basic details are missing: e.g. the minimum duration of LLIN contact necessary to deliver an effective dosage is not known. Despite these phenomena being recognised for decades20,21,22, when and how they occur and their relative importance in selecting for insecticide resistance have never been fully elucidated.

Consequently, behavioural resistance [emphasis mine] to insecticides remains poorly understood and rarely reported in mosquitoes, though the risk of vector populations switching blood-feeding times, locations or host preferences in order to avoid LLINs is recognized and closely monitored today23,24,25. However, additional but less apparent or detectable behavioural changes also might exist, potentially conferring partial or complete insecticide resistance (e.g. changes in sensitivity to repellents, attractants, or modified flight or resting behaviours). In the absence of definitions or quantifications of the basic behavioural events likely to be affected26,27, these changes cannot be investigated, let alone monitored.

I am fascinated by the ‘attractant plume’, ‘excito-repellency’, and the (new to me) notion that mosquitoes can exhibit behavioural resistance.

Killing mosquitos and other pests with genetics-based technology

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Having supplied more than one tasty meal for mosquitos (or, as some prefer, mosquitoes), I am not their friend but couldn’t help but wonder about unintended consequences (as per Max Weber) on reading about a new patent awarded to Kansas State University (from a Nov. 12, 2014 news item on Nanowerk),

Kansas State University researchers have developed a patented method of keeping mosquitoes and other insect pests at bay.

U.S. Patent 8,841,272, “Double-Stranded RNA-Based Nanoparticles for Insect Gene Silencing,” was recently awarded to the Kansas State University Research Foundation, a nonprofit corporation responsible for managing technology transfer activities at the university. The patent covers microscopic, genetics-based technology that can help safely kill mosquitos and other insect pests.

A Nov. 12, 2014 Kansas State University news release, which originated the news item, provides more detail about the research,

Kun Yan Zhu, professor of entomology; Xin Zhang, research associate in the Division of Biology; and Jianzhen Zhang, visiting scientist from Shanxi University in China, developed the technology: nanoparticles comprised of a nontoxic, biodegradable polymer matrix and insect derived double-stranded ribonucleic acid, or dsRNA. Double-stranded RNA is a synthesized molecule that can trigger a biological process known as RNA interference, or RNAi, to destroy the genetic code of an insect in a specific DNA sequence.

The technology is expected to have great potential for safe and effective control of insect pests, Zhu said.

“For example, we can buy cockroach bait that contains a toxic substance to kill cockroaches. However, the bait could potentially harm whatever else ingests it,” Zhu said. “If we can incorporate dsRNA specifically targeting a cockroach gene in the bait rather than a toxic substance, the bait would not harm other organisms, such as pets, because the dsRNA is designed to specifically disable the function of the cockroach gene.”

Researchers developed the technology while looking at how to disable gene functions in mosquito larvae. After testing a series of unsuccessful genetic techniques, the team turned to a nanoparticle-based approach.

Once ingested, the nanoparticles act as a Trojan horse, releasing the loosely bound dsRNA into the insect gut. The dsRNA then triggers a genetic chain reaction that destroys specific messenger RNA, or mRNA, in the developing insects. Messenger RNA carries important genetic information.

In the studies on mosquito larvae, researchers designed dsRNA to target the mRNA encoding the enzymes that help mosquitoes produce chitin, the main component in the hard exoskeleton of insects, crustaceans and arachnids.

Researchers found that the developing mosquitoes produced less chitin. As a result, the mosquitoes were more prone to insecticides as they no longer had a sufficient amount of chitin for a normal functioning protective shell. If the production of chitin can be further reduced, the insects can be killed without using any toxic insecticides.

While mosquitos were the primary insect for which the nanoparticle-based method was developed, the technology can be applied to other insect pests, Zhu said.

“Our dsRNA molecules were designed based on specific gene sequences of the mosquito,” Zhu said. “You can design species-specific dsRNA for the same or different genes for other insect pests. When you make baits containing gene-specific nanoparticles, you may be able to kill the insects through the RNAi pathway. We see this having really broad applications for insect pest management.”

The patent is currently available to license through the Kansas State University Institute for Commercialization, which licenses the university’s intellectual property. The Institute for Commercialization can be contacted at 785-532-3900 and ic@k-state.edu.

Eight U.S. patents have been awarded to the Kansas State University Research Foundation in 2014 for inventions by Kansas State University researchers.

Here’s an image of the ‘Trojan horse’ nanoparticles,

The nanoparticles, pictured as gold colored, are less than 100 nanometers in diameter. photo credit: bogdog Dan via photopincc

The nanoparticles, pictured as gold colored, are less than 100 nanometers in diameter. photo credit: bogdog Dan via photopincc

My guess is that the photographer has added some colour such as the gold and the pink to enhance the image as otherwise this would be a symphony of grey tones.

So, if this material will lead to weakened chitin such that pesticides and insecticides are more effective, does this mean that something else in the food chain will suffer because it no longer has mosquitos and other pests to munch on?

One last note, usually my ‘mosquito’ pieces concern malaria and the most recent of those was a Sept. 4, 2014 posting about a possible malaria vaccine being developed at the University of Connecticut.

Malaria vaccine with self-assembling nanoparticles

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This research was published in April 2013 so I’m not sure what has occasioned a Sept. 2014 push for publicity. Still, it’s interesting work which may lead to a more effective vaccine for malaria than some of the other solutions being tested.  From a Sept. 4, 2014 news item on Nanowerk,

A self-assembling nanoparticle designed by a University of Connecticut (UConn) professor is the key component of a potent new malaria vaccine that is showing promise in early tests.

For years, scientists trying to develop a malaria vaccine have been stymied by the malaria parasite’s ability to transform itself and “hide” in the liver and red blood cells of an infected person to avoid detection by the immune system.

But a novel protein nanoparticle developed by Peter Burkhard, a professor in the Department of Molecular & Cell Biology, in collaboration with David Lanar, an infectious disease specialist with the Walter Reed Army Institute of Research, has shown to be effective at getting the immune system to attack the most lethal species of malaria parasite, Plasmodium falciparum, after it enters the body and before it has a chance to hide and aggressively spread.

A  Sept. 3, 2014 University of Connecticut news release by Colin Poitras, which originated the news item, describes the particle and the research in greater detail,

The key to the vaccine’s success lies in the nanoparticle’s perfect icosahedral symmetry (think of the pattern on a soccer ball) and ability to carry on its surface up to 60 copies of the parasite’s protein. The proteins are arranged in a dense, carefully constructed cluster that the immune system perceives as a threat, prompting it to release large amounts of antibodies that can attack and kill the parasite.

In tests with mice, the vaccine was 90-100 percent effective in eradicating the Plasmodium falciparum parasite and maintaining long-term immunity over 15 months. That success rate is considerably higher than the reported success rate for RTS,S, the world’s most advanced malaria vaccine candidate currently undergoing phase 3 clinical trials, which is the last stage of testing before licensing.

“Both vaccines are similar, it’s just that the density of the RTS,S protein displays is much lower than ours,” says Burkhard. “The homogeneity of our vaccine is much higher, which produces a stronger immune system response. That is why we are confident that ours will be an improvement.

“Every single protein chain that forms our particle displays one of the pathogen’s protein molecules that are recognized by the immune system,” adds Burkhard, an expert in structural biology affiliated with UConn’s Institute of Materials Science. “With RTS,S, only about 14 percent of the vaccine’s protein is from the malaria parasite. We are able to achieve our high density because of the design of the nanoparticle, which we control.”

Here’s an image illustrating the nanoparticle,

This self-assembling protein nanoparticle relies on rigid protein structures called ‘coiled coils’ (blue and green in the image) to create a stable framework upon which scientists can attach malaria parasite antigens. Early tests show that injecting the nanoparticles into the body as a vaccine initiates a strong immune system response that destroys a malarial parasite when it enters the body and before it has time to spread. (Image courtesy of Peter Burkhard)

This self-assembling protein nanoparticle relies on rigid protein structures called ‘coiled coils’ (blue and green in the image) to create a stable framework upon which scientists can attach malaria parasite antigens. Early tests show that injecting the nanoparticles into the body as a vaccine initiates a strong immune system response that destroys a malarial parasite when it enters the body and before it has time to spread. (Image courtesy of Peter Burkhard)

The news release goes on to explain why malaria is considered a major, global health problem and how the researchers approached the problem with developing a malaria vaccine for humans,

The search for a malaria vaccine is one of the most important research projects in global public health. The disease is commonly transported through the bites of nighttime mosquitoes. Those infected suffer from severe fevers, chills, and a flu-like illness. In severe cases, malaria causes seizures, severe anemia, respiratory distress, and kidney failure. Each year, more than 200 million cases of malaria are reported worldwide. The World Health Organization estimated that 627,000 people died from malaria in 2012, many of them children living in sub-Saharan Africa.

It took the researchers more than 10 years to finalize the precise assembly of the nanoparticle as the critical carrier of the vaccine and find the right parts of the malaria protein to trigger an effective immune response. The research was further complicated by the fact that the malaria parasite that impacts mice used in lab tests is structurally different from the one infecting humans.

The scientists used a creative approach to get around the problem.

“Testing the vaccine’s efficacy was difficult because the parasite that causes malaria in humans only grows in humans,” Lanar says. “But we developed a little trick. We took a mouse malaria parasite and put in its DNA a piece of DNA from the human malaria parasite that we wanted our vaccine to attack. That allowed us to conduct inexpensive mouse studies to test the vaccine before going to expensive human trials.”

The pair’s research has been supported by a $2 million grant from the National Institutes of Health and $2 million from the U.S. Military Infectious Disease Research Program. A request for an additional $7 million in funding from the U.S. Army to conduct the next phase of vaccine development, including manufacturing and human trials, is pending.

“We are on schedule to manufacture the vaccine for human use early next year,” says Lanar. “It will take about six months to finish quality control and toxicology studies on the final product and get permission from the FDA to do human trials.”

Lanar says the team hopes to begin early testing in humans in 2016 and, if the results are promising, field trials in malaria endemic areas will follow in 2017. The required field trial testing could last five years or more before the vaccine is available for licensure and public use, Lanar says.

Martin Edlund, CEO of Malaria No More, a New York-based nonprofit focused on fighting deaths from malaria, says, “This research presents a promising new approach to developing a malaria vaccine. Innovative work such as what’s being done at the University of Connecticut puts us closer than we’ve ever been to ending one of the world’s oldest, costliest, and deadliest diseases.”

A Switzerland-based company, Alpha-O-Peptides, founded by Burkhard, holds the patent on the self-assembling nanoparticle used in the malaria vaccine. Burkhard is also exploring other potential uses for the nanoparticle, including a vaccine that will fight animal flu and one that will help people with nicotine addiction. Professor Mazhar Khan from UConn’s Department of Pathobiology is collaborating with Burkhard on the animal flu vaccine.

Here’s a link to and a citation for the paper,

Mechanisms of protective immune responses induced by the Plasmodium falciparum circumsporozoite protein-based, self-assembling protein nanoparticle vaccine by Margaret E McCoy, Hannah E Golden, Tais APF Doll, Yongkun Yang, Stephen A Kaba, Peter Burkhard, and David E Lanar. Malaria Journal 2013, 12:136 doi:10.1186/1475-2875-12-136

This is an open access article.

Science, politics, and logic

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I started the week with a posting where I highlighted a presentation about algae, biofuels, policy making, and politics (my Apr. 8, 2013 posting: Algae factories could produce nanocellulose for biofuels and more) and I’m going to end this week with another politics/policy posting, this time focusing on artemisinin and malaria.

Malaria is a serious, serious problem in many parts of the world as Brendan Borrell notes in his Apr. 4, 2013 article, The WHO vs. the Tea Doctor, about an herbal tea that contains artemisinin, for Slate.com,

Of all the illnesses that have afflicted humanity over millennia, few have left their mark quite like malaria, which infects 200 million people each year and kills at least 655,000, most of whom are children. [emphasis mine] Falciparum malaria—the most common type in sub-Saharan Africa—starts as a debilitating fever, which can progress in severe cases to convulsions, brain damage, and death. In this part of the world, it’s almost impossible to stay completely free of the parasites for long. Adults often display a low level of immunity, which makes each subsequent infection painful and unpleasant but usually not fatal.

As I’m about to contrast the information in Borrell’s article with the information in an Apr. 11, 2013 news release from the University of California Berkeley on EurekAlert, about the development of a synthetic artemisinin, I’m going to highlight their ‘agreement’ as the seriousness of the malaria problem,

… a lifesaver for the hundreds of millions of people in developing countries who each year contract malaria and more than 650,000, most of them children, who die of the disease. [emphasis mine]

Borrell sets the discussion for his take on the artemisinin situation with a little history (Note: Links have been removed),

The story of artemisinin demonstrates that even the best malaria drugs are worthless if they are not getting to the people who need them. In the late 1990s, African malaria parasites had become resistant to standard treatments such as chloroquine, and malaria deaths in Uganda doubled in a decade. By the early 2000s, there was a proven alternative: artemisinin combination therapies [ACTs]. Nevertheless, the Global Fund for AIDS, Tuberculosis, and Malaria repeatedly rejected countries’ requests for money for ACTs, funding failing treatments over ACTs at a rate of 10-to-1. In 2004, a group of fed-up scientists writing in the Lancet called these decisions “medical malpractice.” Today, although ACTs are heavily subsidized by the international aid community, local clinics frequently run out of stock, and Africans often end up with substandard, ineffective, and sometimes counterfeit medications.

Borrell goes on to recount the story of a  Chinese plant, sweet wormwood ((Artemisia annua), which is the source for both a class of anti-malarial drugs and a tea (Note: A link has been removed),

It [sweet wormwood] can also be grown in wetter parts of Africa, and a year’s supply costs no more than a few dollars. Although the tea itself has traditionally been used in treatment, not prevention, in China, a randomized controlled trial on this farm showed that workers who drank it regularly reduced their risk of suffering from multiple episodes of malaria by one-third. For a group of people who were once waylaid by this mosquito-borne disease four or more times per year, the tea is a godsend.

According to the article, WHO (World Health Organization) and most malaria researchers are opposed to the tea’s use. Reasons given include the claim that herbal concoctions are more dangerous and less effective than pharmaceuticals and that use of the tea could lead to the malaria parasite developing resistance to the drugs.

There are two issues I have with the first claim about herbal concoctions. Having perused the Compendium of Pharmaceuticals (CPS), I can tell you the last I looked it was huge and listed thousands and thousands of drugs and their side effects (did you know that death is considered a side effect?). Fabrication in a laboratory does not equal safety any more that chopping something off a plant and brewing it as a tea equals safety. Personally, I don’t understand why they aren’t testing the tea, which is derived from sweet wormwood and successfully passed one randomized clinical trial, to see if the result can be repeated and also to test it against the drugs in human clinical trials.

As for the second claim that use of the tea could lead to the malaria parasite developing resistance to the drugs, isn’t that what happened to anti-malarial drugs in the late 1990s? Using chloroquine led to resistance against chloroquine. Following this claim to its logical end, we should never use any drug or herbal concoction as either might lead to resistance.

As for the tea’s successful clinical trial, the researcher experienced difficulty getting his study published (from the article; Note: A link has been removed),

While the workers are effusive about the tea, malaria experts have taken less kindly to it. When Ogwang [Patrick Ogwang of the Ugandan Ministry of Health] tried to publish the results in Malaria Journal, a reviewer largely praised the quality of the science but nixed publication out of concern that use of the tea could render ACTs ineffective. It’s a remarkably patronizing recommendation: that a scientific journal should keep the latest evidence out of the hands of Africans, lest they begin treating themselves. Marcel Hommel, editor in chief of the journal, defends the decision, saying, “It is the responsibility of an editor to avoid publishing papers that promote interventions which could potentially put patients at risk.” Ogwang eventually published his results in a less prestigious journal.

Borrell expresses reservations about herbal medicines/concoctions and he supports having the drugs for special cases but he also notes a study which suggests that a tea made from the plant might be more effective for adults and for less severe cases. From the article (Note: Links have been removed),

In the case of malaria, Anamed and others also argue that it makes sense to preserve stocks of conventional drugs for children and severe cases. One reason ACTs have been so expensive is the cost of isolating artemisinin, but there have long been indications that using a cruder, cheaper whole-plant extract could potentially be more effective and cheaper. In a study conducted in rats last year, University of Massachusetts researchers compared a single dose of pure artemisinin to dried whole leaves, and found that the whole plant was better at killing malaria parasites. And while millions have been spent bioengineering bacteria to crank out pure artemisinin on a budget, you still have to get it to the people who need it.

The resistance that the experts fear has been proved true, according to Borrell’s article, in areas where artemisinin drugs have been distributed and used with abandon.

Coincidentally or not, the University of California Berekeley announced a the development of semi-synthetic artemisinin in the Apr. 11, 2013 news release mentioned earlier,

Twelve years after a breakthrough discovery in his University of California, Berkeley, laboratory, professor of chemical engineering Jay Keasling is seeing his dream come true.

On April 11 [2013], the pharmaceutical company Sanofi will launch the large-scale production of a partially synthetic version of artemisinin, a chemical critical to making today’s front-line antimalaria drug, based on Keasling’s discovery.

The drug is the first triumph of the nascent field of synthetic biology and will be, Keasling hopes, a lifesaver ….

Keasling and colleagues at Amyris, a company he cofounded in 2003 to bring the lab-bench discovery to the marketplace, will publish in the April 25 issue of Nature the sequence of genes they introduced into yeast that allowed Sanofi to make the chemical precursor of artemisinin. The paper will be available online April 10.

“It is incredible,” said Keasling, who also serves as associate director for biosciences at Lawrence Berkeley National Laboratory and as CEO of the Joint Bioenergy Institute in Emeryville, Calif. “The time scale hasn’t been that long, it just seems like a long time. There were many places along the way where it could have failed.”

The yeast strain developed by Amyris based on Keasling’s initial research and now used by Sanofi produces a chemical precursor of artemisinin, a compound that until now has been extracted from the sweet wormwood plant, Artemsia annua. Artemisinin from either sweet wormwood or the engineered yeast is then turned into the active antimalarial drug , and typically mixed with another antimalarial drug in what is called arteminsinin combination therapy, or ACT.

Global demand for artemisinin has increased since 2005, when the World Health Organization identified ACTs as the most effective malaria treatment available. Sanofi said that it is committed to producing semisynthetic artemisinin using a no-profit, no-loss production model, which will help to maintain a low price for developing countries. Though the price of ACTs will vary from product to product, the new source for its key ingredient, in addition to the plant-derived supply, should lead to a stable cost and steady supply, Keasling said.

Unfortunately, no details about Sanofi’s no-profit, no-loss production model are offered. Perhaps a reader could ease my ignorance? I am interpreting this model to mean that while Sanofi won’t make money from the project, it does expect to recoup its costs (no-loss). (I most recently mentioned Sanofi, a French multinational, in an Apr. 9, 2013 posting about the winners of its 2013 competition for Canadian students.)

The backers of the research do provide some reasoning for this synthetic biology artemisinin project (from the news release),

“The production of semisynthetic artemisinin will help secure part of the world’s supply and maintain the cost of this raw material at acceptable levels for public health authorities around the world and ultimately benefit patients,” said Dr. Robert Sebbag, vice-president of Access to Medicines at Sanofi. “This is a pivotal milestone in the fight against malaria.” [emphasis mine]

I wonder what constitutes an ‘acceptable’ level of costs to public health authorities and, for that matter, to Sanofi. After all, I was under the impression after reading Borrell’s article that all one needed to do was to cultivate the plant and harvest it for materials to make tea.  There was no mention of difficulties cultivating the plant in countries outside of China where it originated nor was there any mention that it was expensive to cultivate.

There are some fairly big names, in addition to Sanofi, involved in this synthetic biology project,

The success is due in large part to two grants totaling $53.3 million from the Bill & Melinda Gates Foundation to OneWorld Health, the drug development program for PATH, an international nonprofit organization aiming to transform global health through innovation. [emphasis mine] OneWorld Health shepherded the drug’s development out of Keasling’s UC Berkeley lab to Amyris for scale-up and then to pharmaceutical firm Sanofi, based in France, for production.

I am pointing out some interesting relationships with the intention of providing a view of a complex situation with many well-intentioned players, where lines of opposition have been drawn and the people most at risk seemingly forgotten. If the tea hasn’t caused resistance in over 1,500 years of use in China while the drugs have already done so on the Thai-Cambodian border as per Borrell’s article, why isn’t it being accepted and used? While some might point at corporate profit requirements (and I’m not discounting that motive regardless of what Sanofi’s company executives say), there are also issues of institutionalized opposition to any developments made outside of the medical establishment, and the fetishization of the laboratory environment where drugs are made pure in a pure environment while herbs come from the ‘dirty’ earth.

Home pregnancy tests inspire simple diagnostics containing gold nanoparticles

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PhD student Kyryl Zagorovsky and Professor Warren Chan of the University of Toronto’s Institute of Biomaterials and Biomedical Engineering (IBBME) have created a rapid diagnostic biosensor according to a Feb. 28, 2013 news item on phys.org,

A diagnostic “cocktail” containing a single drop of blood, a dribble of water, and a dose of DNA powder with gold particles could mean rapid diagnosis and treatment of the world’s leading diseases in the near future. …

The recent winner of the NSERC E.W.R. Steacie Memorial Fellowship, Professor Chan and his lab study nanoparticles: in particular, the use of gold particles in sizes so small that they are measured in the nanoscale. Chan and his group are working on custom-designing nanoparticles to target and illuminate cancer cells and tumours, with the potential of one day being able to deliver drugs to cancer cells.

But it’s a study recently published in Angewandte Chemie that’s raising some interesting questions about the future of this relatively new frontier of science.

Zagorovsky’s rapid diagnostic biosensor will allow technicians to test for multiple diseases at one time with one small sample, and with high accuracy and sensitivity. The biosensor relies upon gold particles in much the same vein as your average pregnancy test. With a pregnancy test, gold particles turn the test window red because the particles are linked with an antigen that detects a certain hormone in the urine of a pregnant woman.

(Until now, I’d never thought about how a pregnancy test actually works and always assumed it was similar to a litmus paper test of acid.) The University of Toronto’s Feb. 28, 2013 news release, which originated the news item, describes the technology in more detail,

Currently, scientists can target a particular disease by linking gold particles with DNA strands. When a sample containing the disease gene (e.g., Malaria) is present, it clumps the gold particles, turning the sample blue.

Rather than clumping the particles together, Zagorovsky immerses the gold particles in a DNA-based enzyme solution (DNA-zyme) that, when the disease gene is introduced, ‘snip’ the DNA from the gold particles, turning the sample red.

“It’s like a pair of scissors,” said Zagorovsky. “The target gene activates the scissors that cut the DNA links holding gold particles together.”

The advantage is that far less of the gene needs to be present for the solution to show noticeable colour changes, amplifying detection. A single DNA-zyme can clip up to 600 ‘links’ between the target genes.

Just a single drop from a biological sample such as saliva or blood can potentially be tested in parallel, so that multiple diseases can be tested in one sitting.

But the team has also demonstrated that [it] can transform the testing solution into a powder, making it light and far easier to ship than solutions, which degrade over time. Powder can be stored for years at a time, and offers hope that the technology can be developed into efficient, cheap, over-the-counter tests for diseases such as HIV and malaria for developing countries, where access to portable diagnostics is a necessity. [emphases mine]

I think the fact that the testing solution can be made into powder is exciting news. Medical technologies can be wonderful but if they require special handling and training (e.g., a standard vaccine is in a solution which needs to be refrigerated [that’s expensive in some parts of the world] and someone who is specially trained has to administer the injection) then they’re confined to the few who have access and can afford it.

Here’s a citation and a link to the researchers’ paper,

A Plasmonic DNAzyme Strategy for Point-of-Care Genetic Detection of Infectious Pathogens by Kyryl Zagorovsky, and Dr. Warren C. W. Chan. Angewandte Chemie International Edition DOI: 10.1002/anie.201208715 Article first published online: 10 FEB 2013

Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This article is behind a paywall.

ETA Mar. 1, 2013 10:42 am PST: I made a quick change to the title. Hopefully this one makes more sense than the first one did.