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October 20, 2017
Digest
Disease Resistance Spread Successfully from Modified to Wild Mosquitoes

Researchers engineer
GM mosquitoes to
compete and mate with
their wild counterparts.
Researchers engineer GM mosquitoes to compete and mate with their wild counterparts.

Using genetically modified (GM) mosquitoes to reduce or prevent the spread of infectious diseases is a new but rapidly expanding field of investigation. Among the challenges researchers face is ensuring that GM mosquitoes can compete and mate with their wild counterparts so the desired modification is preserved and spread in the wild population. Investigators at Johns Hopkins University have engineered GM mosquitoes to have an altered microbiota that suppresses human malaria-causing parasites. These GM mosquitoes preferred to mate with wild mosquitoes and passed along the desired protection to many generations of offspring.

The research was funded by NIAID. The work is reported in Science.

The researchers genetically modified Anopheles mosquitoes, which in nature spread the malaria- causing parasite Plasmodium. The team caged equal numbers of wild and GM mosquitoes and monitored their breeding over 10 generations. Ninety percent of the offspring in each generation passed along the GM trait. Even when combining 10 percent GM with 90 percent wild mosquitoes, the Plasmodium-resistance trait dominated after a few generations. Importantly, the GM mosquitoes maintained their resistance to the malaria parasite for 7 years.

The group also showed that the change in the microbiota resulted in a mating preference among the GM and wild mosquitoes. GM males showed a preference for wild females and wild males preferred GM females; these preferences contributed to the spread of the desired protective trait within the mosquito population.

The authors note that work was conducted in a laboratory setting and that more research is needed to determine if what they observed in the laboratory also will occur under natural conditions. Nevertheless, the study suggests that mosquitoes can be genetically modified to compete in nature with wild populations and spread resistance to the malaria-causing parasite. If implemented, this strategy could eventually result in decreased disease transmission to humans.

NIH Researchers Uncover Drain Pipes in Our Brains

By scanning the brains of healthy volunteers, researchers at NIH saw the first, long-sought evidence that our brains may drain some waste out through lymphatic vessels, the body’s sewer system. The results further suggest the vessels could act as a pipeline between the brain and the immune system.

“We literally watched people’s brains drain fluid into these vessels,” said Dr. Daniel Reich, senior investigator at NINDS and senior author of the study published online in eLife. “We hope that our results provide new insights to a variety of neurological disorders.”

Scientists saw evidence
that brains may drain waste
via lymphatic vessels.
Scientists saw evidence that brains may drain waste via lymphatic vessels.

Reich is a radiologist and neurologist who primarily uses magnetic resonance imaging (MRI) to investigate multiple sclerosis and other neurological disorders thought to involve the immune system. Led by postdoctoral fellows Dr. Martina Absinta and Dr. Seung-Kwon Ha, along with researchers from NCI, the team discovered lymphatic vessels in the dura, the leathery outer coating of the brain.

Lymphatic vessels are part of the body’s circulatory system. In most of the body they run alongside blood vessels. They transport lymph, a colorless fluid containing immune cells and waste, to the lymph nodes. Blood vessels deliver white blood cells to an organ and the lymphatic system removes the cells and recirculates them through the body. The process helps the immune system detect whether an organ is under attack from bacteria or viruses or has been injured.

In 1816, an Italian anatomist reported finding lymphatic vessels on the surface of the brain, but for two centuries, it was forgotten. Until recently, researchers in the modern era found no evidence of a lymphatic system in the brain, leaving some puzzled about how the brain drains waste and others to conclude that the brain is an exceptional organ. Then in 2015, two studies of mice found evidence of the brain’s lymphatic system in the dura. Coincidentally, that year, Reich saw a presentation by Dr. Jonathan Kipnis, a professor at the University of Virginia and an author of one of the mouse studies.

“I was completely surprised,” said Reich. “In medical school, we were taught that the brain has no lymphatic system. After Dr. Kipnis’s talk, I thought, maybe we could find it in human brains?”

To look for the vessels, Reich’s team used MRI to scan the brains of five healthy volunteers who had been injected with gadobutrol, a magnetic dye typically used to visualize brain blood vessels damaged by diseases such as multiple sclerosis or cancer. The dye molecules are small enough to leak out of blood vessels in the dura but too big to pass through the blood-brain barrier and enter other parts of the brain.

At first, when the researchers set the MRI to see blood vessels, the dura lit up brightly and they could not see any signs of the lymphatic system. But, when they tuned the scanner differently, the blood vessels disappeared and the researchers saw that dura also contained smaller but almost equally bright spots and lines that they suspected were lymph vessels. The results suggested that the dye leaked out of the blood vessels, flowed through the dura and into neighboring lymphatic vessels.

“These results could fundamentally change the way we think about how the brain and immune system inter-relate,” said NINDS director Dr. Walter Koroshetz.

Monoclonal Antibodies Against Zika Show Promise in Monkey Study

Zika virus particles (red)
shown in African green
monkey kidney cells
Zika virus particles (red) shown in African green monkey kidney cells

Using blood samples from an individual previously infected with Zika virus, scientists funded by NIAID have developed an antibody-based Zika virus therapeutic that protected monkeys from infection. Because monoclonal antibodies are generally safe, they believe that this antibody cocktail might be appropriate for uninfected pregnant women; because the antibodies will likely cross the placenta, the researchers hope that administration during pregnancy may protect both the pregnant woman and the fetus from Zika virus. The investigators are hoping to test this concept by pursuing studies in people.

The scientists isolated immune cells from the patient’s blood and used them to make 91 monoclonal antibodies—immune system fighters designed to bind to a specific part of an invading virus or bacterium to stop the infection. They identified three antibodies that bound to Zika virus surface proteins and each neutralized the virus. The researchers then administered a combination of these antibodies to rhesus macaques and exposed the animals to Zika virus one day later. During the 21-day study, all 4 monkeys who received the antibody cocktail showed no virus replication.

Researchers at the University of Miami and the Scripps Research Institute led the project with collaborators in Brazil and the U.S. The work was reported in Science Translational Medicine.

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