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Combating Mosquitoes with an Engineered Fungus

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Caption: Anopheles coluzzii mosquito with transgenic fungus (green) emerging from its body after death. Credit: Brian Lovett, University of Maryland, College Park

Almost everywhere humans live on this planet, mosquitoes carry microbes that cause potentially deadly diseases, from West Nile virus to malaria. While chemical insecticides offer a line of defense, mosquito populations often grow resistant to them. So, it’s intriguing to learn that we may now have another ally in this important fight: a genetically engineered fungus!

Reporting in the journal Science, an international research team supported by NIH describes how this new approach might be used to combat malaria [1]. A fungus called Metarhizium pingshaense is a natural enemy of the mosquito, but, by itself, it kills mosquitoes too slowly to control transmission of malaria. To make this fungus an even more efficient mosquito killer, researchers engineered it to carry a gene encoding a toxin, derived from a spider, that is deadly to insects. Tests of the souped-up fungus in a unique contained facility designed to simulate a West African village found it safely and rapidly killed insecticide-resistant mosquitoes, reducing their numbers by more than 99 percent within 45 days.

Mosquitoes are the deadliest animals in the world. More than 3.2 billion people—about half of all humans—are at risk for malaria, and more than 400,000 die each year from the disease. Other mosquito-borne illnesses, including Zika and dengue viruses, sicken millions more each year. By combining existing insect control strategies with the latest technical innovation, it should be possible to lower those numbers.

In the latest study, Raymond St. Leger and Brian Lovett, University of Maryland, College Park, teamed with Abdoulaye Diabate and colleagues from Institut de Recherche en Sciences de la Santé/Cente Muraz, Burkina Faso, West Africa. The researchers employed a strategy that’s been in use around the world for more than 100 years to control agricultural pests.

The approach involves the fungal species Metarhizium, which kills a variety of insects. Earlier studies had shown that spores from a specific Metarhizium strain could make a big enough dent in a mosquito population to raise the possibility of using the fungus to reduce infective bites among humans [2]. But killing off the mosquitoes required very large quantities of fungal spores and usually took a couple of weeks.

Here’s where things turned innovative. To boost the fungus’s potency, St. Leger and colleagues used genetic engineering to add a toxin derived from the Australian Blue Mountains funnel-web spider. The toxin came with a major advantage: the U.S. Environmental Protection Agency (EPA) already has approved its use as a safe-and-effective insecticidal protein.

Besides giving the engineered fungus that ability to produce a spider toxin, the researchers added another clever element. They didn’t want the fungus to produce the toxin all the time—only after it comes in contact with a mosquito’s hemolymph, the insect equivalent of blood. So, they needed to insert a control switch, and the researchers knew just where to find the needed part.

Once inside a mosquito, the fungus naturally produces a structural protein called collagen that shields it from the insect’s immune system. A genetic switch that turns “on” when it detects an insect’s hemolymph controls that collagen production. To ensure that the spider toxin was produced at just the right time, the researchers hotwired their Metarhizium to begin producing it under the control of this same genetic switch.

The next step was to test this modified organism in a more natural, but controlled, environment. The researchers spent more than a year in Burkina Faso building a specialized facility called a MosquitoSphere. It’s similar to a very large greenhouse, but with mosquito netting instead of glass.

The MosquitoSphere has six separate compartments, four of which contain West African huts, along with native plants and breeding sites for mosquitoes. The researchers hung a black cotton sheet, previously soaked in sesame oil, on the wall of a hut in each of three chambers.

In one hut, the sesame oil contained genetically engineered fungal spores. In the second hut, the oil contained natural fungal spores. In the third hut, there were no spores at all. Then, they released 1,000 adult male and 500 adult female mosquitoes into each chamber and watched what happened over the next 45 days.

In the hut without spores, the mosquitoes established a stable population of almost 1,400. In the chamber with the natural spores, 450 mosquitoes survived. But, in the chamber with the engineered fungus, the researchers counted just 13 survivors—too few to sustain a viable population.

The researchers say they suspect the fungus would be relatively easy to contain in nature. It’s sticky and not easily airborne. The spores are also extremely sensitive to sunlight, making it difficult for them to travel far. Importantly, the fungus didn’t harm other beneficial insects, including honeybees.

Caution is warranted before considering the release of a genetically engineered organism into the wild. In the meantime, the genetically engineered fungus also will serve as a platform for continued technology development.

The system can be readily adapted to target mosquitoes or other insects , perhaps using different natural toxins if insects might grow resistant to Metarhizium just as they have to traditional insecticides. Interestingly, the researchers note that the engineered fungi appear to make mosquitoes sensitive to chemical insecticides again, suggesting that the two types of insect-killers might be used successfully in combination.

References:

[1] Transgenic Metarhizium rapidly kills mosquitoes in a malaria-endemic region of Burkina Faso. Lovett B, Bilgo E, Millogo SA, Ouattarra AK, Sare I, Gnambani EJ, Dabire RK, Diabate A, St Leger RJ. Science. 2019 May 31;364(6443):894-897.

[2] An entomopathogenic fungus for control of adult African malaria mosquitoes. Scholte EJ, Ng’habi K, Kihonda J, Takken W, Paaijmans K, Abdulla S, Killeen GF, Knols BG. Science. 2005 Jun 10;308(5728):1641-2.

Links:

Transgenic Fungus Rapidly Killed Malaria Mosquitoes in West African Study (University of Maryland News Release)

Malaria (National Institute of Allergy and Infectious Diseases/NIH)

Funnel-Web Spiders (Australian Museum, Sydney)

Video: 2016 Grand Challenges Spotlight Talk: Abdoulaye Diabaté (YouTube)

Raymond St. Leger (University of Maryland, College Park)

NIH Support: National Institute of Allergy and Infectious Diseases


Seven More Awesome Technologies Made Possible by Your Tax Dollars

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We live in a world energized by technological advances, from that new app on your smartphone to drones and self-driving cars. As you can see from this video, NIH-supported researchers are also major contributors, developing a wide range of amazing biomedical technologies that offer tremendous potential to improve our health.

Produced by the NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB), this video starts by showcasing some cool fluorescent markers that are custom-designed to light up specific cells in the body. This technology is already helping surgeons see and remove tumor cells with greater precision in people with head and neck cancer [1]. Further down the road, it might also be used to light up nerves, which can be very difficult to see—and spare—during operations for cancer and other conditions.

Other great things to come include:

  • A wearable tattoo that detects alcohol levels in perspiration and wirelessly transmits the information to a smartphone.
  • Flexible coils that produce high quality images during magnetic resonance imaging (MRI) [2-3]. In the future, these individualized, screen-printed coils may improve the comfort and decrease the scan times of people undergoing MRI, especially infants and small children.
  • A time-release capsule filled with a star-shaped polymer containing the anti-malarial drug ivermectin. The capsule slowly dissolves in the stomach over two weeks, with the goal of reducing the need for daily doses of ivermectin to prevent malaria infections in at-risk people [4].
  • A new radiotracer to detect prostate cancer that has spread to other parts of the body. Early clinical trial results show the radiotracer, made up of carrier molecules bonded tightly to a radioactive atom, appears to be safe and effective [5].
  • A new supercooling technique that promises to extend the time that organs donated for transplantation can remain viable outside the body [6-7]. For example, current technology can preserve donated livers outside the body for just 24 hours. In animal studies, this new technique quadruples that storage time to up to four days.
  • A wearable skin patch with dissolvable microneedles capable of effectively delivering an influenza vaccine. This painless technology, which has produced promising early results in humans, may offer a simple, affordable alternative to needle-and-syringe immunization [8].

If you like what you see here, be sure to check out this previous NIH video that shows six more awesome biomedical technologies that your tax dollars are helping to create. So, let me extend a big thanks to you from those of us at NIH—and from all Americans who care about the future of their health—for your strong, continued support!

References:

[1] Image-guided surgery in cancer: A strategy to reduce incidence of positive surgical margins. Wiley Interdiscip Rev Syst Biol Med. 2018 Feb 23.

[2] Screen-printed flexible MRI receive coils. Corea JR, Flynn AM, Lechêne B, Scott G, Reed GD, Shin PJ, Lustig M, Arias AC. Nat Commun. 2016 Mar 10;7:10839.

[3] Printed Receive Coils with High Acoustic Transparency for Magnetic Resonance Guided Focused Ultrasound. Corea J, Ye P, Seo D, Butts-Pauly K, Arias AC, Lustig M. Sci Rep. 2018 Feb 21;8(1):3392.

[4] Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals. Bellinger AM, Jafari M1, Grant TM, Zhang S, Slater HC, Wenger EA, Mo S, Lee YL, Mazdiyasni H, Kogan L, Barman R, Cleveland C, Booth L, Bensel T, Minahan D, Hurowitz HM, Tai T, Daily J, Nikolic B, Wood L, Eckhoff PA, Langer R, Traverso G. Sci Transl Med. 2016 Nov 16;8(365):365ra157.

[5] Clinical Translation of a Dual Integrin avb3– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, 68Ga-BBN-RGD. Zhang J, Niu G, Lang L, Li F, Fan X, Yan X, Yao S, Yan W, Huo L, Chen L, Li Z, Zhu Z, Chen X. J Nucl Med. 2017 Feb;58(2):228-234.

[6] Supercooling enables long-term transplantation survival following 4 days of liver preservation. Berendsen TA, Bruinsma BG, Puts CF, Saeidi N, Usta OB, Uygun BE, Izamis ML, Toner M, Yarmush ML, Uygun K. Nat Med. 2014 Jul;20(7):790-793.

[7] The promise of organ and tissue preservation to transform medicine. Giwa S, Lewis JK, Alvarez L, Langer R, Roth AE, et a. Nat Biotechnol. 2017 Jun 7;35(6):530-542.

[8] The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. Rouphael NG, Paine M, Mosley R, Henry S, McAllister DV, Kalluri H, Pewin W, Frew PM, Yu T, Thornburg NJ, Kabbani S, Lai L, Vassilieva EV, Skountzou I, Compans RW, Mulligan MJ, Prausnitz MR; TIV-MNP 2015 Study Group.

Links:

National Institute of Biomedical Imaging and Bioengineering (NIH)

Center for Wearable Sensors (University of California, San Diego)

Hyperpolarized MRI Technology Resource Center (University of California, San Francisco)

Center for Engineering in Medicine (Massachusetts General Hospital, Boston)

Center for Drug Design, Development and Delivery (Georgia Tech University, Atlanta)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases


Tagging Essential Malaria Genes to Advance Drug Development

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Red blood cell infected with malaria-causing parasites

Caption: Colorized scanning electron micrograph of a blood cell infected with malaria parasites (blue with dots) surrounded by uninfected cells (red).
Credit: National Institute of Allergy and Infectious Diseases, NIH

As a volunteer physician in a small hospital in Nigeria 30 years ago, I was bitten by lots of mosquitoes and soon came down with headache, chills, fever, and muscle aches. It was malaria. Fortunately, the drug available to me then was effective, but I was pretty sick for a few days. Since that time, malarial drug resistance has become steadily more widespread. In fact, the treatment that cured me would be of little use today. Combination drug therapies including artemisinin have been introduced to take the place of the older drugs [1], but experts are concerned the mosquito-borne parasites that cause malaria are showing signs of drug resistance again.

So, researchers have been searching the genome of Plasmodium falciparum, the most-lethal species of the malaria parasite, for potentially better targets for drug or vaccine development. You wouldn’t think such work would be too tough because the genome of P. falciparum was sequenced more than 15 years ago [2]. Yet it’s proven to be a major challenge because the genetic blueprint of this protozoan parasite has an unusual bias towards two nucleotides (adenine and thymine), which makes it difficult to use standard research tools to study the functions of its genes.

Now, using a creative new spin on an old technique, an NIH-funded research team has solved this difficult problem and, for the first time, completely characterized the genes in the P. falciparum genome [3]. Their work identified 2,680 genes essential to P. falciparum’s growth and survival in red blood cells, where it does the most damage in humans. This gene list will serve as an important guide in the years ahead as researchers seek to identify the equivalent of a malarial Achilles heel, and use that to develop new and better ways to fight this deadly tropical disease.


Creative Minds: Building a CRISPR Gene Drive Against Malaria

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Valentino Gantz

Valentino Gantz/Credit: Erik Jepsen

Researchers have used Drosophila melanogaster, the common fruit fly that sometimes hovers around kitchens, to make seminal discoveries involving genetics, the nervous system, and behavior, just to name a few. Could a new life-saving approach to prevent malaria be next? Valentino Gantz, a researcher at the University of California, San Diego, is on a path to answer that question.

Gantz has received a 2016 NIH Director’s Early Independence Award to use Drosophila to hone a new bioengineered tool that acts as a so-called “gene drive,” which spreads a new genetically encoded trait through a population much faster than would otherwise be possible. The lessons learned while working with flies will ultimately be applied to developing a more foolproof system for use in mosquitoes with the hope of stopping the transmission of malaria and potentially other serious mosquito-borne diseases.


Snapshots of Life: Neurons in a New Light

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Mouse Midbrain

Credit: Michael Shribak, Marine Biological Laboratory, Woods Hole, MA

Birds do it, bees do it, and even educated fleas do it. No, not fall in love, as the late Ella Fitzgerald so famously sang. Birds and insects can see polarized light—that is, light waves transmitted in a single directional plane—in ways that provides them with a far more colorful and detailed view of the world than is possible with the human eye.

Still, thanks to innovations in microscope technology, scientists have been able to tap into the power of polarized light vision to explore the inner workings of many complex biological systems, including the brain. In this image, researchers used a recently developed polarized light microscope to trace the spatial orientation of neurons in a thin section of the mouse midbrain. Neurons that stretch horizontally appear green, while those oriented at a 45-degree angle are pinkish-red and those at 225 degrees are purplish-blue. What’s amazing is that these colors don’t involve staining or tagging the cells with fluorescent markers: the colors are generated strictly from the light interacting with the physical orientation of each neuron.


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