Daily Archives: February 28, 2017

Last August, scientists injected a potential vaccine for Zika virus into a human being just 3 months after they had decided exactly what molecular recipe to use.

In the world of vaccine development, 3 months from design to injection is warp speed, says vaccine researcher Nelson Michael of the Walter Reed Army Institute of Research in Silver Spring, Md. Clinical trials can take years and epidemics can burn out before vaccines make it to doctors shelves. Even vaccine creation is typically sluggish.

But in this case, the vaccine is a bit of DNA, which means scientists can get moving fast. Unlike some traditional methods, DNA vaccines dont use dead or weakened viruses. Instead, they rely on a snippet of genetic material. This naked DNA carries, for example, the blueprints for Zika proteins. Its just a long sequence of DNA blocks.

With DNA vaccines, its easy to move very quickly, says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. All you need to do is get the right sequence, and Bingo! youre there.

Historically, though, DNA vaccines have been deviled with drawbacks. They work absolutely fantastically in mice, says infectious diseases physician Anna Durbin of Johns Hopkins Bloomberg School of Public Health. But they fail miserably when we use them in humans.

Researchers at the infectious diseases institute will soon begin the second phase of human clinical trials for a DNA vaccine candidate for Zika, vaccine clinical researcher Julie Ledgerwood said February 6 in Washington, D.C., at an American Society for Microbiology meeting on biothreats. The virus made headlines last year as it continued its tear through the Americas, and scientists confirmed its link to birth defects, including microcephaly (SN: 12/24/16, p. 19). Ledgerwood hopes to see efficacy data on the vaccine by the end of 2018.

Ultimately, we want a vaccine that can prevent congenital Zika infection, she said. We think the DNA vaccine platform is an opportunity to do things safely and very quickly.

Government researchers arent betting everything on DNA, though, Fauci points out. Weve got multiple shots on goal here, he says. A slew of other vaccine candidates, based on both traditional and new techniques, are also in the works. But the DNA vaccine has stepped up to the plate first, and the world will soon see if it can deliver.

If it works, Durbin says, weve hit a home run.

Making a DNA vaccine is simple, in principle. Scientists synthesize genes from a pathogen, insert them into a circular strand of DNA called a plasmid, make lots of copies and then inject the purified plasmid into a person. You can literally build a DNA vaccine in weeks, says Dan Barouch, an immunologist at Beth Israel Deaconess Medical Center and Harvard Medical School. The approach is flexible, too, he adds. Researchers can tinker with the DNA building blocks in the plasmid, adding bits from other viruses that might ultimately enhance the immune response.

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For a DNA vaccine against Zika, scientists insert genes for Zika proteins into a circular piece of DNA called a plasmid. Many copies of the plasmid are injected into muscle. Some of the DNA travels into cells nuclei, where it is used to make messenger RNA. After exiting the nucleus, mRNA helps build Zika proteins, which can form viruslike particles that trigger the immune system to make antibodies.

Barouchs team was the first to report a Zika DNA vaccine that offered protection in mice in a study published last June in Nature. Five weeks later, he and colleagues reported in Science that the vaccine, and two others created via different strategies, worked well in monkeys, too. And in September, a team led by government scientists, and including Barouch as a coauthor, came out with two additional DNA vaccine candidates, described in Science.

Its one of those additional candidates, called VRC 5283, that the infectious diseases institute plans to test in a Phase II trial. The trial will help researchers figure out the precise dose and number of injections to use. VRC 5283 includes the blueprints for making two Zika virus proteins, as well as DNA from Japanese encephalitis virus.

When the vaccine is injected into the body, a small amount of DNA makes its way into cells and on into the cell nucleus. There, molecular machinery reads the DNA and writes a message in RNA. When the message leaves the nucleus, it serves as a how-to guide for making Zika proteins. The proteins assemble into viruslike particles that trigger alarm bells in cells, which marshal their defenses. Cells then know the face of the enemy and are ready to fight if Zika invades.

At least, thats the idea. DNA vaccines are hardly a new concept, Barouch says. People have been calling them the vaccines of the future for decades. But they havent yet lived up to the hype.

Scientists have created DNA vaccines for dozens of pathogens, but so far, not one has been licensed for use in humans. One problem is that scientists need massive doses of DNA to provoke an immune response a few milligrams or so. That is a god-awful amount of plasmid DNA, Michael says. Its so much DNA that the liquid of each dose is viscous, he says. Its like syrup.

Naked DNA doesnt readily travel into the nucleus, so scientists dump a lot in the bloodstream to ensure that some winds up inside. The Phase II trial of VRC 5283 will test both four and eight milligrams of DNA, and people will receive three immunizations, each spaced weeks apart, Ledgerwood said. The best dosing regimen then will be used in the second part of the trial a test to see how VRC 5283 performs in thousands of participants in regions likely to see Zika outbreaks.

But even if the vaccine eventually ends up in clinics, ensuring that patients come back for multiple doses wont be easy, says University of Pennsylvania immunologist Drew Weissman. Giving people one shot is hard enough, he says. Giving them two more immunizations is an absolute nightmare.

Weissman and colleagues at the infectious diseases institute and elsewhere are working on a different kind of vaccine that could make multiple doses moot. Like the DNA vaccine for Zika, Weissmans uses genetic material. But instead of DNA, his vaccine relies on modified versions of messenger RNA that how-to guide for making proteins.

Unlike DNA vaccines, those made of messenger RNA dont have to stop in the nucleus first. That makes these vaccines more efficient, Fauci says. The modified Zika RNA vaccine was enough to protect monkeys from the virus five weeks after vaccination, Weissman and colleagues reported online February 2 in Nature. The dose was just 50 micrograms roughly a hundredth as much as a single dose of the DNA vaccine.

On February 17, a different team of researchers reported online in Cell even more RNA vaccines for Zika. The vaccines protected mice from the virus, and some even reduced the severity of a subsequent dengue infection.

Scientists still need to test RNA vaccines in humans to gauge how they stack up against other candidates, Michael says. But the bottom line is this: If a single shot works and lasts a long time, that would be a game changer.

One of the RNA vaccines reported in Cell began a clinical trial in December, but trials for Weissmans vaccine are still 12 to 18 months away. In the meantime, other vaccines are charging forward. The biotech company Inovio Pharmaceuticals, for example, has begun human trials with yet another DNA vaccine for Zika. (It comes with a little zap of electricity, which blasts tiny holes in cell membranes to help DNA slip in, researchers reported November 10 in NPJ Vaccines.)

And Michaels team at Walter Reed has partnered with Sanofi Pasteur on a more traditional approach. Researchers grow vats of virus, kill it, purify it and then use the killed virus in the vaccine. Its the same way Jonas Salk tackled polio in the 1950s. These inactivated virus vaccines are generally very safe, Nelson says, because the virus is as dead as a doornail. Nelson expects data from three Phase I clinical trials for the vaccine, called ZPIV, in early April.

But for a vaccine with both durability and efficacy, Fauci says, the gold standard is a live-attenuated vaccine. Such vaccines, like the one for measles, mumps and rubella, use weakened rather than killed viruses to rile up the immune system.

Its the broadest, best type of protection lifelong, we think, says Durbin, who is part of a team developing a live-attenuated vaccine for Zika. The downside is that scientists have to make sure that the weakened vaccine is harmless. Even then, Durbin says, we would never consider giving a live-attenuated vaccine to a pregnant woman.

When exactly scientists have a working Zika vaccine ready for use is totally dependent on the outbreak situation in South America and Puerto Rico, Fauci says. If new infections dont crop up over the coming spring and summer, scientists may have to wait years to collect the efficacy data needed for vaccine approval.

But the race to make a Zika vaccine probably wont come down to just one winner, he says. Having several kinds of vaccines in play would give public health officials flexibility: more weapons to fight the virus and an opportunity to tailor the response to different populations.

In fact, the fevered quest for a Zika vaccine isnt really a race at all, Barouch says. Were all working together.

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DNA may offer rapid road to Zika vaccine | Science News - Science News

February 28, 2017 Male billy goat from a feral herd in Mulranny, Co. Mayo, Ireland. Credit: John Joyce

Intensive selective breeding over the past 200 years and high extinction rates among feral populations has greatly reduced the genetic diversity present in domestic goat breeds. The effect these pressures have had on Irish and British goat populations has been explored in a landmark DNA study that compared modern-day domestic and feral goats with museum specimens from years gone by.

A collaborative team led by geneticists from Trinity College Dublin compared the mitochondrial DNA (mtDNA) of 15 historical taxidermy specimens from Britain and Ireland and nine modern samples taken from Irish dairy and feral populations.

The team has just published their results in the Royal Society journal Biology Letters. Their work provides the first example in which DNA from taxidermy specimens is used to answer questions about livestock genetics.

Lara Cassidy, a researcher from Trinity's School of Genetics and Microbiology, is the first author of the journal article. She said: "There is an amazing wealth of genetic information locked away in taxidermic collections of animals that were - and still are - important for agricultural reasons. As such these collections are invaluable in helping us study the population history of these domesticated animals."

"Studying these specimens and comparing them with modern-day animals also helps to pinpoint existing populations that have retained some of the past genetic diversity, much of which has been lost to industrialized breeding. Retaining this diversity as an option for future breeding is very important, but some of these populations are being pushed to extinction."

The geneticists' study highlights an endangered feral herd living in Mulranny, Co. Mayo, as one such unique population in need of protection. Mulranny goats show a genetic similarity to extinct 'Old Goat' populations that lived on the Isle of Skye in the 1800s. They can therefore be considered among the last remaining 'Old Irish' goats.

The 'Old Goat' populations of Britain and Ireland were once ubiquitous throughout the islands but today have been replaced in agriculture by improved Swiss breeds. The native 'Old Goats' are now only found in small feral herds, whose existence is under constant threat from habitat loss, culling and the ongoing impact of Swiss introgression.

The geneticists sampled a number of different 'Old Goat' herds among the 15 taxidermy specimens. The results showed these goats formed two genetic groupings, distinct from other European breeds. Importantly, all of the modern-day Irish dairy goats fell into a genetic groupings outside these two.

Dr Valeria Mattiangeli, one of the study's lead researchers, said: "This highlights the impact that transportation and mass importation of continental breeds has had on Ireland's goat populations, and underlines how selective breeding for agricultural purposes can impact the genetic diversity of animals."

Sen Carolan of the Old Irish Goat Society, who is a co-author of the journal article, said: "We hope this study will play a key role in saving what was and still is a diminutive creature that is both resilient and charismatic and that represents our cultural and pastoral history."

Explore further: Experiment shows goats capable of recognizing other goats by sight and sound

More information: Capturing goats: Documenting two hundred years of mitochondrial DNA diversity among goat populations from Britain and Ireland, Biology Letters, rsbl.royalsocietypublishing.org/lookup/doi/10.1098/rsbl.2016.0876

(Phys.org)A small team of researchers with Queen Mary University of London has found that goats are able to recognize their stable mates by both sight and sound. In their paper published in the journal Royal Society Open ...

Nagoya University-based researchers analyze ancient DNA of Neolithic domestic goats to reveal that the goats were introduced into the Southern Caucasus from the Fertile Crescent during the early sixth millennium BC, probably ...

A new strategy of conservation must be adopted if the black rhinoceros is to be saved from extinction, concludes a study involving scientists from Cardiff University.

Higher temperatures caused by global warming could help goat populations to thrive, say scientists.

Geneticists and anthropologists previously suspected that ancient Africans domesticated cattle native to the African continent nearly 10,000 years ago. Now, a team of University of Missouri researchers has completed the genetic ...

The ancestry of domesticated cattle proves more complex than previously thought, reports a paper published today in the open access journal Genome Biology. The first nuclear genome sequence from an ancient wild ox reveals ...

Intensive selective breeding over the past 200 years and high extinction rates among feral populations has greatly reduced the genetic diversity present in domestic goat breeds. The effect these pressures have had on Irish ...

Octopus, cuttlefish and squid are well known in the invertebrate world. With their ink-squirting decoy technique, ability to change colour, bizarre body plan and remarkable intelligence they highlight that lacking a back-bone ...

A University of Florida study shows that mollusk fossils provide a reliable measure of human-driven changes in marine ecosystems and shifts in ocean biodiversity across time and space.

Organic additives found in road salt alternativessuch as those used in the commercial products GeoMelt and Magic Saltact as a fertilizer to aquatic ecosystems, promoting the growth of algae and organisms that eat algae, ...

The Zika virus taking hold of the inner organelles of human liver and neural stem cells has been captured via light and electron microscopy. In Cell Reports on February 28, researchers in Germany show how the African and ...

In the world of fungi, Aspergillus is an industrial superstar. Aspergillus niger, for example, has been used for decades to produce citric acida compound frequently added to foods and pharmaceuticals through fermentation ...

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DNA from taxidermy specimens explains genetic structure of British and Irish goats - Phys.Org

James Raynor, who is serving 37 years in prison for shooting a man and participating in the gang-related murder of another, is now in the cross hairs of cold case investigators working on another Hartford homicide.

Detectives obtained a search warrant to get a sample of Raynor's DNA for their case.

Raynor, 33, was in court Tuesday because he objected to providing a DNA sample.

His lawyer, J. Patten Brown III, told Hartford Superior Court Judge Julia D. Dewey that his client's position was the state had obtained a DNA sample from him in 2014 and that he feared investigators will get his DNA and put it on the evidence they have.

"He thinks they want to smear his DNA on evidence to frame him," Brown said.

Dewey told Brown and Raynor that the search warrant is a lawful court order to Raynor to provide the DNA. She held him in contempt of court for refusing to provide it, and told him that detectives were authorized to use force to obtain the sample.

In Connecticut, investigators may legally use reasonable force to obtain DNA samples from inmates. The law was upheld by the state Supreme Court in 2016.

Detectives did obtain a sample before Raynor left the courthouse on Tuesday.

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Man Serving 37 Years For Shooting, Homicide Balks At Providing DNA For Another Homicide Case - Hartford Courant

DNAs ability to act like an electrical wire plays a part in how it replicates,new research shows.

In the early 1990s, Jacqueline Barton, professor of chemistry at Caltech, discovered an unexpected property of DNAthat it can act like an electrical wire to transfer electrons quickly across long distances. Later, she and colleagues showed that cells take advantage of this trait to help locate and repair potentially harmful mutations to DNA.

Now, Bartons lab has shown that this wire-like property of DNA is also involved in a different critical cellular function. When cells divide and replicate themselves in our bodiesfor example in the brain, heart, bone marrow, and fingernailsthe double-stranded helix of DNA is copied. DNA also copies itself in reproductive cells that are passed on to progeny.

The new study, based on work by graduate student Elizabeth OBrien in collaboration with Walter Chazins group at Vanderbilt University, offers evidencethat a key protein required for replicating DNA depends on electrons traveling through DNA.

Nature is the best chemist and knows exactly how to take advantage of DNA electron-transport chemistry, says Barton.

The electron transfer process in DNA occurs very quickly, says OBrien, lead author of the study in Science. It makes sense that the cell would utilize this quick-acting pathway to regulate DNA replication, which necessarily is a very rapid process.

The researchers found their first clue that DNA replication might involve the transport of electrons through the double helix by taking a closer look at the proteins involved. Two of the main players in DNA replication, critical at the start of the process, are the proteins DNA primase and DNA polymerase alpha. DNA primase typically binds to single-stranded, uncoiled DNA to begin the replication process. It creates a primer made of RNA to help DNA polymerase alpha start its job of copying the single strand of DNA to create a new segment of double-helical DNA.

DNA primase and DNA polymerase alpha molecules both contain iron-sulfur clusters. Barton and her colleagues previously discovered that these metal clusters are crucial for DNA electron transport in DNA repair. In DNA repair, specific proteins send electrons down the double helix to other DNA-bound repair proteins as a way to test the line, so to speak, and make sure there are no mutations in the DNA. If there are mutations, the line is essentially broken, alerting the cell that mutations are in need of repair. The iron-sulfur clusters in the DNA repair proteins are responsible for donating and accepting traveling electrons.

Barton and her group wanted to know if the iron-sulfur clusters were doing something similar in the DNA-replication proteins.

We knew the iron-sulfur clusters must be doing something in the DNA-replication proteins, otherwise why would they be there? Iron can damage the DNA, so nature would not have wanted the iron there were it not for a good reason, says Barton.

Through a series of tests in which mutations were introduced into the DNA primase protein, the researchers showed that this protein needs to be in an oxidized statewhich means it has lost electronsto bind tightly to DNA and participate in DNA electron transport. When the protein is reducedmeaning it has gained electronsit does not bind tightly to DNA.

The electronic state of the iron-sulfur cluster in DNA primase acts like an on/off switch to initiate DNA replication, says OBrien.

Whats more, the researchers demonstrated that electron transport through DNA plays a role in signaling DNA primase to leave the DNA strand. (Though DNA primase must bind to single-stranded DNA to kick off replication, the process cannot begin in earnest until the protein pops back off the strand).

The scientists propose that the DNA polymerase alpha protein, which sits on the double helix strand, sends electrons down the strand to DNA primase. DNA primase accepts the electrons, becomes reduced, and lets go of the DNA. This donation and acceptance of electrons is done with the help of the iron-sulfur clusters.

You have to get the DNA primase off the DNA quicklythat really starts the whole replication process, says Barton. Its a hand off of electrons from one cluster to the other through the DNA double helix.

Many proteins involved in DNA reactions also contain iron-sulfur clusters and may also play roles in DNA electron transport chemistry, Barton says. What began as a fundamental question 25 years ago about whether DNA could support migration of electrons continues to lead to new questions about the chemical workings of cells. Thats the wonder of basic research, she says. You start with one question and the answer leads you to new questions and new areas.

Funding for the work came from the National Institutes of Health.

Source: Caltech

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DNA acts like electrical wire to replicate itself - Futurity: Research News