Zika May Damage the Brain by Hijacking Cells Related to Skull Formation

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 The ability to take control of cells that give rise to the skull may be key to Zika virus’ crippling effects on infants’ brain.
 

<a href="http://www.cell.com/cell-host-microbe/abstract/S1931-3128(16)30383-3">
 Researchers found
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 that Zika hijacks cells related to skull formation to produce excess molecules that damage neural progenitor cells, which give rise to different types of brain cells. The infection of these cells may explain why babies born to mothers affected by the virus have smaller-than-average heads—a condition known as microcephaly.
 

 “Some of the babies born to mothers affected by Zika not only have small brains, they also have facial abnormalities,” said Catherine Blish, one of the lead authors of the study. This detail spurred her and co-author Joanna Wysocka’s teams to focus on a group of cells, dubbed cranial neural crest cells, which develop into different head structures, including bones of the face.
 
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<figcaption>The infection of cells related to skull formation may explain why babies born to mothers affected by Zika have smaller-than-average heads.
 
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 Previous research had focused on the effects of Zika infection on cells that give rise to neurons. According to Ralph Marcucio, a developmental biologist at University of California San Francisco who was not involved in the research, this study helps shift the attention to other cell types. “[Cranial neural crest cells] would not be the first suspects of causing microcephaly,” he said.
 

 When the researchers added Zika virus to cranial neural crest cells in a laboratory dish, the virus not only infected those cells, but it was also able to hijack them to support its own growth. One day after infection, the number of viruses in the dish increased up to tenfold.
 

 Surprisingly, Zika did not kill the cells, Blish said. Infected cranial neural crest cells did, however, affect healthy neural progenitor cells—cells that give rise to different types of brain cells such as neurons. When the two cell populations were grown together, neural progenitor cells changed their shape or died, despite the fact that they were not infected with Zika—the two groups of cells were separated by a thin membrane that prevented viruses from passing through.
 

 To explain these results, the researchers had to look elsewhere. They knew that, during the first stages of pregnancy, cranial neural crest cells occupy a region next to the developing brain and communicate with it through chemical messengers known as cytokines. “Cytokines tell the developing brain when to develop and how,” Blish said.
 

 Zika-infected cranial neural crest cells produced 60 times more cytokines than non-infected cells. Since cytokines are small molecules that could easily cross the membrane used in the experiments, the researchers hypothesized that the excess of cytokines produced by infected cranial neural crest cells may be the culprit of the damage to neural progenitor cells. Indeed, adding large amounts of cytokines to neural progenitor cells grown alone made them alter their shape or die earlier than expected.
 

 Infected cranial neural crest cells may impair brain development by acting as a reservoir of new viruses and producing cytokines at unhealthy levels. According to Blish, the communication breakdown caused by the excess cytokines might cause microcephaly in some pregnant women. However, more experiments in living animals are needed to prove this connection.
 

 Andrea Da Poian, who studies virus-host interaction at the Federal University of Rio de Janeiro and was not involved in the research, pointed out that, although interesting, this is still only a hypothesis. According to Da Poian, because of the complexity of brain development, there is a long way to go before it will be possible to prove the effects of Zika infection on microcephaly.
 

 Marcucio echoed the need for more experiments in animals. “What is true in a laboratory dish might not be true in a living animal,” he said.
 

 Marcucio is intrigued by the idea that Zika could co-opt normal signals to disrupt the flow of information to the brain. “This work highlights the importance of a two-way communication between the brain and other cell types, especially in disease situations,” he said.
 
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 Photo credit:
 <a href="https://www.flickr.com/photos/leemcarthur/6243730836/">
 Lee &amp; Chantelle McArthur / Flickr (CC BY 2.0)
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Diet restriction can not just increase life span, but also improve the quality of life in old age.

Eating Less Could Extend Healthy Life

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 Bad news for companies selling brain-boosting, anti-aging products: the recipe for living a long life and keeping a sharp mind might be as simple as eating less.


 A recent
 <a href="http://www.nature.com/nature/journal/v537/n7620/full/nature19329.html">
 study
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 showed that feeding mice less food triples their lifespan and slows down the decay of several organs, particularly the brain. The research, published in the journal Nature, was carried out at the Erasmus University Medical Center and the National Institute for Public Health and the Environment (RIVM), The Netherlands.


 Many studies have shown that reducing food intake increases lifespan in a wide range of animals, from flies to monkeys, but there has been little information about the effects of diet restriction on health span—the period of time that an organism is healthy, not just alive.


 “Most previous studies have been preoccupied only with the impact of diet restriction on lifespan,” said George M. Martin, a pathologist at the University of Washington who was not involved in the research. According to Martin, the special merit of this study is that it looked at whether “a longer life would be one of good health.” In addition, it showed how consuming fewer calories allowed mice to live better for longer.


 The scientists who conducted the research think diet restriction reduces DNA damage, which is a leading cause of aging. “The beneficial effects may have to do with the way cells’ powerhouses, the mitochondria, generate energy,” said Martijn Dollé, one of the lead authors of the study. Diet restriction may force mitochondria to be more efficient and produce fewer byproducts that could damage DNA.

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 The researchers investigated the effects of diet restriction on mutant mice that age rapidly due to a defect in their DNA-repair machinery. These mice are used as models for accelerated aging diseases that affect humans, like progeria. Feeding the DNA-repair-deficient mice 30% less resulted in a dramatic extension of their lifespan, up to 250%. “When translating this to children with progeria, whose average life expectancy is around 12 years, it means that they could live up to 36 years,” Dollé said. However, he pointed out, there is no guarantee that diet restriction will result in identical lifespan benefits in humans.


 Also, although 30% food restriction resulted in extended lifespan, it doesn’t mean that feeding mice less than that would allow them to live even longer. “Too much food restriction will result in starvation, ultimately ending in shortened lifespan,” Dollé said.


 One of the most striking findings of the study was that diet restriction delayed the aging of key organs, such as kidneys, liver, testes, and the brain, which appeared to benefit the most. When DNA-repair-deficient mice ate less, they maintained 50% more neurons than their siblings that had unlimited access to food. Diet-restricted mice also preserved all of their motor skills: for example, they were able to run, whereas siblings that were allowed to eat as much as they wanted moved slowly and often
 <a href="http://www.nature.com/nature/journal/v537/n7620/fig_tab/nature19329_">
 fell
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 . According to Dollé, this finding may open new avenues for treating and preventing disorders such as Parkinson’s or Alzheimer’s.


 Once the researchers knew that diet restriction helped mice live healthier for longer, they wanted to see whether it was in fact reduced DNA damage that benefitted aging.

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 DNA damage is almost impossible to measure directly, so the researchers took an indirect approach. Because DNA damage is a random process, mutations accumulate more often in long genes than in short ones, making long genes less likely to be expressed. Therefore, the scientists looked at how many long genes were expressed in diet-restricted versus “all-you-can-eat” mice and found that long genes were better expressed in diet-restricted mice. This suggested that they had less DNA damage.


 The scientists then looked at cellular markers of DNA damage that could be seen under a microscope and observed that these were less common in diet-restricted mice than in their siblings that had unlimited food.


 How diet restriction drives DNA damage reduction is still under investigation. The authors speculate that diet restriction may work as an anti-aging “remedy” by increasing natural anti-oxidant defenses and boosting cells’ metabolism.


 George M. Martin and Junko Oshima, two medical doctors investigating age-related diseases, are optimistic that diet restriction could eventually help increase the lifespan of patients suffering from some premature aging syndromes. According to Martin, this study may also provide an incentive to develop drugs that “mimic the effects of diet restriction in humans.”


 Photo credit:
 <a href="https://www.flickr.com/photos/villoks/15381922698/">
 Ville Oksanen/Flickr (CC-BY)
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Cutting food intake increased lifespan and delayed brain aging in mice by reducing DNA damage.

Portable Drug-Maker Could Save Lives in Remote Regions

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 Manufacturing life-saving drugs might soon be as easy as preparing instant soup.
 

 “It’s like making ramen: just add water,” said Peter Nguyen, one of the authors of the
 <a href="http://www.cell.com/fulltext/S0092-8674(16)31246-6">
 paper
 </a>
 published in the journal Cell by a team of bioengineers at MIT and Harvard’s Wyss Institute.
 

 The newly-developed system—white powder in a 1.5-inch-tall tube—is “unassuming,” Nguyen said, but has been able to produce a wide range of therapeutics—from antimicrobials to vaccines.
 
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<img alt="" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/drug-kit.width-990_VrCod2k.jpg"/>
<figcaption>This simple kit can produce vaccines, antimicrobial peptides, and antibody conjugates, without power or refrigeration.
 
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 The system is based on freeze-dried pellets that contain the chemical building blocks needed to make molecules such as therapeutic compounds. Simply adding water to the pellets can start the production reaction.
 

 This compact, portable system might help make drugs more accessible in far-off or low-resource areas such as developing countries, war zones, and even space stations, Nguyen said.
 

 “Rapid access to vaccines in remote regions could change lives,” said Michael Jewett, a bioengineer at Northwestern University who was not involved in the study.
 

 To create freeze-dried reaction pellets, the bioengineers opened up cells and pulled out the innards that translate genetic instructions into molecules. Then they idled these tiny biological machines by exposing them to cold temperatures and low pressure, which removed all of the water.
 

 In the same way, the researchers freeze-dried DNA carrying the instructions for specific therapeutic molecules. The pellets whir to life when mixed with these DNA instructions and a drop of water and start producing therapeutics within minutes.
 

 Freeze-dried pellets were able to produce several antimicrobial compounds and more than 50 types of antibodies—molecules that can identify and disarm invaders such as viruses, bacteria, and cancer cells. The pellets were used to produce antibodies able to neutralize breast cancer cells and
 
 Clostridium difficile
 
 , a bacterium that can cause life-threatening diarrhea and inflammation of the intestine.
 

 The pellet-derived drugs were as effective as their commercial counterparts and could be safely ingested or applied to mice’s skin, depending on the compound.
 

 The investigators also employed the tiny biological machines to manufacture a diphtheria vaccine, which triggered an immune response in mice comparable to the one seen with traditional diphtheria shots.
 

 Other bioengineers look at the possibility of producing pharmaceuticals on demand with optimism. “This is an important first step for providing patient-specific treatments where treatments are not available now,” Jewett said.
 

 Today, pharmaceutical companies rely on a few centralized factories that manufacture products and dispatch them to points of care such as clinics and hospitals. However, the products have to be transported and stored at low temperatures to preserve their therapeutic activity. This makes global distribution a challenging process, especially in areas with low resources and limited access to electricity.
 

 The researchers hope that the pellet-based system will pave the way for moving the production of drugs and vaccines from manufacturing plants to hospitals, eliminating the challenges of transportation.
 

 Freeze-dried pellets and DNA can be stored at room temperature for one year, and possibly even longer, either in the same tube or separated. According to co-author Shimyn Slomovic, they could be used as a “virtual pharmacy.” When needed, a therapeutic molecule could be rapidly synthesized by mixing pellets with DNA and adding water without the need for refrigeration, expensive equipment, or specialized staff. “This technology has the potential to vastly lower the costs of therapeutics production and distribution,” Slomovic said.
 

 Some scientists believe there is still a long way to go. David Shoultz, head of drug development at the global health nonprofit PATH, said in an interview to STAT that it is unlikely that these technologies will allow “instant drug” or “instant vaccine” production in the next couple of years: “It’ll probably be more like 10 or 12 years. And we’re still going to need facilities, know-how, and people to implement them.”
 

 According to Slomovic, these concerns are understandable. “We’re creating a technology for an infrastructure that doesn’t exist yet,” he said. Centralized production and global distribution would be ineffective in extreme situations such as disease outbreaks, armed conflicts, or even missions to Mars. In these scenarios, freeze-dried pellets would represent a valid alternative. Just add water.
 
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Compared to other strains of yeast, beer yeasts' DNA show the most signs of domestication, or adaptation to living in a man-made environment.

Beer yeast is more 'sophisticated' than wine yeast

A pint of average ale is a more sophisticated drink than a glass of fancy wine, at least as far as the yeast is concerned.As farmers did with cattle and grains, brewers, bakers, and wine-makers “tamed” a wild microbe so that it suited their needs—producing fluffier loaves and tastier booze. Brewmasters in particular transformed beer yeast into the fermentation industry’s pet, according to two independent studies that have traced the genetic history of brewer’s yeast, the invisible ingredient that ferments ale beer, wine, and other products such as bread by transforming sugar into alcohol and bubbles.The researchers looked at the DNA of yeast strains used to make a variety of fermented products, including ale and wine. They found that the DNA of beer-fermenting strains is remarkably different from that of wild strains. In fact, beer yeasts are so specialized in fermenting malt and so accustomed to living in breweries that they are no longer able to survive in nature.Wine yeasts’ DNA, instead, is more similar to that of wild variants. “We compare [wine yeasts] to cats: they’re somehow domesticated—they clearly got better at fermenting wine—but they’re still okay living in the wild,” said Kevin Verstrepen, an associate professor at the University of Leuven and senior author of one of the studies. “Beer yeasts are more like dogs: they are completely tamed.”
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Verstrepen thinks these differences have to do with the way the two drinks are produced. “Wine is made once a year, while beer is produced all year round,” he said. Traditionally, after the harvest of the grapes, wine yeasts were grown in grape juice for about one month, but for the rest of the year they had to survive in nature—on grapes’ skin in vineyards.Beer yeasts, instead, were continuously kept in breweries where brewmasters provided abundant food in the form of sugar. “Historically, breweries were running ahead of wineries because brewers were recycling their yeasts throughout the year and constantly selecting the best batches,” Verstrepen said.Although the first evidence of beer production dates back 5,000 years ago, Verstrepen explained that brewers started to consciously select their best yeasts around the late 1500s, when beer production moved from private houses to pubs and monasteries.At the end of the beer-making process, yeast cells that have eaten all the sugar and produced all the alcohol sink to the bottom of the fermenter and form a sediment. “What happened—we know this from old brewing books—is that brewers learned to collect this sediment and put it into a new batch of beer fermentation,” Verstrepen said.By repeating this process with the yeasts that produced the best beers, brewers were allowing them to continually grow in, and therefore adapt to, the brewery environment. “This happened way before the discovery of microbes. It was really based on the brewers’ gut-feeling and craft,” Verstrepen said.Verstrepen and his team analyzed the DNA of over 150 strains of yeast used to produce ale beer, wine, bread, saké, and bioethanol—a fermented alternative to gasoline. In an <a href="http://www.cell.com/cell/abstract/S0092-8674(16)31071-6">article</a> published in the journal Cell , the researchers reported that all these industrial strains derive from a few wild ancestors. Industrial yeasts differ from their “parents” in that they show signs of domestication, or adaptation to living in a man-made environment such as a fermenter.Similar results have been obtained by geneticists led by José Paulo Sampaio at the Nova University of Lisbon, who analyzed the DNA of 90 industrial yeast strains. Their <a href="http://www.cell.com/current-biology/abstract/S0960-9822(16)30984-8">findings</a> are detailed in the journal Current Biology .Both teams found that the domestication signatures are most evident in beer yeasts’ DNA. For example, these yeasts have multiple copies of the genes that allow them to feed on maltose, one of the sugars they use to produce alcohol. “Yeasts sometimes come across maltose in nature, so they are able to eat it, but for beer yeasts, maltose is the main part of their diet,” Verstrepen said. “The extra copies of the genes involved in maltose uptake and metabolism allow [yeasts] to eat more quickly and do their job faster.” Yeasts that ferment other products such as wine do not have these extra copies.The scientists also found that beer yeasts do not produce a compound that wine yeasts do—one that smells like smoke or cloves. “This is an aroma compound that most wild yeasts would make, but in beer it is generally not desirable, so brewers must have selected natural variants that didn’t make this compound,” Sampaio said.“These studies lay the groundwork for some really interesting applied science,” said Scott Britton, research &amp; development scientist at Duvel Moortgat Brewery, who was not involved in the research. “They show how [yeast] strains have been manipulated by humans over time to help the brewing industry in terms of fermentation efficiency and flavor,” he said. According to Britton, knowing the genes that are important for yeasts to make tastier beer, faster, could help modern brewers improve their products.Peter Bouckaert, brewmaster at New Belgium Brewing Company, believes that brewers can now use this knowledge to breed the best strains and screen their offspring for desirable features, such as better aromas or quicker fermentation.For this reason, Bouckaert thinks that DNA analysis should be complemented by studies that look at which flavors and compounds are found in the final product. “[What] is useful to me is analyzing if what I want to be present in my beer is indeed present,” he said.
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Vicente Pelechano, a yeast geneticist at the Karolinska Institute who was not involved in either study, thinks more research is needed to understand the yeast traits that are meaningful to brewers. “The association between a gene and a specific trait is not straightforward in many cases,” he said.Most traits are determined by a series of factors, both genetic and environmental, Pelechano said. In humans, for example, traits like height and weight do not depend on a single gene but on a combination of multiple genes and environmental cues. Pelechano said the same might be true for traits such as aroma production in yeast.Nevertheless, Pelechano thinks these studies represent a useful resource for the brew community. “They provide a reference chart that will allow [brewers] to focus on the most desirable genes and decide which yeast strains they want to mix.”Verstrepen said several companies have approached him already. “[They’re] mostly beer brewers asking if we could make better yeasts for them,” he said. “[What we do] is just breeding, there is no genetic modification involved.”Verstrepen added that other labs worldwide are investing in producing superior wine yeasts. “Traditionally, wine yeasts have been lagging behind, but wine-makers are trying to close the gap.”Half of Verstrepen’s lab is now involved in applied research for influencing yeast traits that brewing companies care about. “I think for brewers these are gonna be fun times where they can experiment and create new beers with different flavors,” Verstrepen said.
Photo credit: <a href="https://www.flickr.com/photos/wagnertc/4800234604">Wagner T. Cassimiro "Aranha"/ Flickr (CC BY 2.0)</a>
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Beer yeasts are so specialized in fermenting malt and so accustomed to living in breweries that they are no longer able to survive in nature, researchers found.

Giorgia Guglielmi

Articles

Zika May Damage the Brain by Hijacking Cells Related to Skull Formation

Eating Less Could Extend Healthy Life

Portable Drug-Maker Could Save Lives in Remote Regions

Beer yeast is more 'sophisticated' than wine yeast

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