Daily Archives: July 29, 2017

SpaceX’s First Mars Rocket Will Launch This November – Fortune

Posted: July 29, 2017 at 6:47 pm

SpaceX CEO Elon Musk announced via Twitter on Thursday that the company will aim for a November launch for the Falcon Heavy, the huge rocket capable of taking crewed missions to Mars.

As Musk recently emphasized , though, that launch will be just the beginning of flight testing, and theres a good chance that the vehicle does not make it into orbit on the first try.

Its also worth noting, as The Verge has, that the Falcon Heavy has already had tentative launch targets that didnt come to fruition. In 2011, for instance, Musk said the Falcon Heavy would launch in 2013 or 2014.

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Joining a tradition of Muskian optimism, the Heavy turned out to be a much bigger engineering challenge than anticipated. It has 27 engines, three times as many as SpaceXs Falcon 9, and all of those engines have to be carefully synchronized for a successful launch. But the firmer target date, and recent milestones including a test-fire of a booster on the ground, suggest things are on track this time around.

The Heavy needs all those engines to deliver its 54-ton payloads, potentially including human crew and infrastructure for crewed bases, as far as Mars. Earlier this year, SpaceX pushed back its target date for the first Mars missions from 2018 to 2020.

(Musks colonization road map also includes an even bigger rocket, with 550 metric tons of orbital lift, but its still in early development .)

Most importantly for SpaceXs plans, the Falcon Heavy, like the Falcon 9, will have reusable components that land intact on Earth after launch. Re-use is projected to drastically reduce launch costs, but even after success with the Falcon 9, that trick could be several years coming for Falcon Heavy.

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When genetic engineering is the environmentally friendly choice – Ensia

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July 27, 2017 Which is more disruptive to a plant: genetic engineering or conventional breeding?

It often surprises people to learn that GE commonly causes less disruption to plants than conventional techniques of breeding. But equally profound is the realization that the latest GE techniques, coupled with a rapidly expanding ability to analyze massive amounts of genetic material, allow us to make super-modest changes in crop plant genes that will enable farmers to produce more food with fewer adverse environmental impacts. Such super-modest changes are possible with CRISPR-based genome editing, a powerful set of new genetic tools that is leading a revolution in biology.

My interest in GE crops stems from my desire to provide more effective and sustainable plant disease control for farmers worldwide. Diseases often destroy 10 to 15 percent of potential crop production, resulting in global losses of billions of dollars annually. The risk of disease-related losses provides an incentive to farmers to use disease-control products such as pesticides. One of my strongest areas of expertise is in the use of pesticides for disease control. Pesticides certainly can be useful in farming systems worldwide, but they have significant downsides from a sustainability perspective. Used improperly, they can contaminate foods. They can pose a risk to farm workers. And they must be manufactured, shipped and applied all processes with a measurable environmental footprint. Therefore, I am always seeking to reduce pesticide use by offering farmers more sustainable approaches to disease management.

What follows are examples of how minimal GE changes can be applied to make farming more environmentally friendly by protecting crops from disease. They represent just a small sampling of the broad landscape of opportunities for enhancing food security and agricultural sustainability that innovations in molecular biology offer today.

Genetically altering crops the way these examples demonstrate creates no cause for concern for plants or people. Mutations occur naturally every time a plant makes a seed; in fact, they are the very foundation of evolution. All of the food we eat has all kinds of mutations, and eating plants with mutations does not cause mutations in us.

Knocking Out Susceptibility

A striking example of how a tiny genetic change can make a big difference to plant health is the strategy of knocking out a plant gene that microorganisms can benefit from. Invading microorganisms sometimes hijack certain plant molecules to help themselves infect the plant. A gene that produces such a plant molecule is known as a susceptibility gene.

We can use CRISPR-based genome editing to create a targeted mutation in a susceptibility gene. A change of as little as a single nucleotide in the plants genetic material the smallest genetic change possible can confer disease resistance in a way that is absolutely indistinguishable from natural mutations that can happen spontaneously. Yet if the target gene and mutation site are carefully selected, a one-nucleotide mutation may be enough to achieve an important outcome.

There is a substantial body of research showing proof-of-concept that a knockout of a susceptibility gene can increase resistance in plants to a very wide variety of disease-causing microorganisms. An example that caught my attention pertained to powdery mildew of wheat, because fungicides (pesticides that control fungi) are commonly used against this disease. While this particular genetic knockout is not yet commercialized, I personally would rather eat wheat products from varieties that control disease through genetics than from crops treated with fungicides.

The Power of Viral Snippets

Plant viruses are often difficult to control in susceptible crop varieties. Conventional breeding can help make plants resistant to viruses, but sometimes it is not successful.

Early approaches to engineering virus resistance in plants involved inserting a gene from the virus into the plants genetic material. For example, plant-infecting viruses are surrounded by a protective layer of protein, called the coat protein. The gene for the coat protein of a virus called papaya ring spot virus was inserted into papaya. Through a process called RNAi, this empowers the plant to inactivate the virus when it invades. GE papaya has been a spectacular success, in large part saving the Hawaiian papaya industry.

Aerial view of a field trial showing virus-resistant papaya growing well while the surrounding susceptible papaya is severely damaged by the virus. Reproduced with permission from Gonsalves, D., et al. 2004. Transgenic virus-resistant papaya: From hope to reality in controlling papaya ringspot virus in Hawaii. APSnet Features. Online. DOI: 10.1094/APSnetFeature-2004-0704

Through time, researchers discovered that even just a very small fragment from one viral gene can stimulate RNAi-based resistance if precisely placed within a specific location in the plants DNA. Even better, they found we can stack resistance genes engineered with extremely modest changes in order to create a plant highly resistant to multiple viruses. This is important because, in the field, crops are often exposed to infection by several viruses.

Does eating this tiny bit of a viral gene sequence concern me? Absolutely not, for many reasons, including:

Tweaking Sentry Molecules

Microorganisms can often overcome plants biochemical defenses by producing molecules called effectors that interfere with those defenses. Plants respond by evolving proteins to recognize and disable these effector molecules. These recognition proteins are called R proteins (R standing for resistance). Their job is to recognize the invading effector molecule and trigger additional defenses. A third interesting approach, then, to help plants resist an invading microorganism is to engineer an R protein so that it recognizes effector molecules other than the one it evolved to detect. We can then use CRISPR to supply a plant with the very small amount of DNA needed to empower it to make this protein.

This approach, like susceptibility knockouts, is quite feasible, based on published research. Commercial implementation will require some willing private- or public-sector entity to do the development work and to face the very substantial and costly challenges of the regulatory process.

Engineered for Sustainability

The three examples here show that extremely modest engineered changes in plant genetics can result in very important benefits. All three examples involve engineered changes that trigger the natural defenses of the plant. No novel defense mechanisms were introduced in these research projects, a fact that may appeal to some consumers. The wise use of the advanced GE methods illustrated here, as well as others described elsewhere, has the potential to increase the sustainability of our food production systems, particularly given the well-established safety of GE crops and their products for consumption.

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In US first, scientists edit genes of human embryos – ABC News

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For the first time in the United States, scientists have edited the genes of human embryos, a controversial step toward someday helping babies avoid inherited diseases.

The experiment was just an exercise in science the embryos were not allowed to develop for more than a few days and were never intended to be implanted into a womb, according to MIT Technology Review, which first reported the news.

Officials at Oregon Health & Science University confirmed Thursday that the work took place there and said results would be published in a journal soon. It is thought to be the first such work in the U.S.; previous experiments like this have been reported from China. How many embryos were created and edited in the experiments has not been revealed.

The Oregon scientists reportedly used a technique called CRISPR, which allows specific sections of DNA to be altered or replaced. It's like using a molecular scissors to cut and paste DNA, and is much more precise than some types of gene therapy that cannot ensure that desired changes will take place exactly where and as intended. With gene editing, these so-called "germline" changes are permanent and would be passed down to any offspring.

The approach holds great potential to avoid many genetic diseases, but has raised fears of "designer babies" if done for less lofty reasons, such as producing desirable traits.

Last year, Britain said some of its scientists could edit embryo genes to better understand human development.

And earlier this year in the U.S., the National Academy of Sciences and National Academy of Medicine said in a report that altering the genes of embryos might be OK if done under strict criteria and aimed at preventing serious disease.

"This is the kind of research that the report discussed," University of Wisconsin-Madison bioethicist R. Alta Charo said of the news of Oregon's work. She co-led the National Academies panel but was not commenting on its behalf Thursday.

"This was purely laboratory-based work that is incredibly valuable for helping us understand how one might make these germline changes in a way that is precise and safe. But it's only a first step," she said.

"We still have regulatory barriers in the United States to ever trying this to achieve a pregnancy. The public has plenty of time" to weigh in on whether that should occur, she said. "Any such experiment aimed at a pregnancy would need FDA approval, and the agency is currently not allowed to even consider such a request" because of limits set by Congress.

One prominent genetics expert, Dr. Eric Topol, director of the Scripps Translational Science Institute in La Jolla, California, said gene editing of embryos is "an unstoppable, inevitable science, and this is more proof it can be done."

Experiments are in the works now in the U.S. using gene-edited cells to try to treat people with various diseases, but "in order to really have a cure, you want to get this at the embryo stage," he said. "If it isn't done in this country, it will be done elsewhere."

There are other ways that some parents who know they carry a problem gene can avoid passing it to their children, he added. They can create embryos through in vitro fertilization, screen them in the lab and implant only ones free of the defect.

Dr. Robert C. Green, a medical geneticist at Harvard Medical School, said the prospect of editing embryos to avoid disease "is inevitable and exciting," and that "with proper controls in place, it's going to lead to huge advances in human health."

The need for it is clear, he added: "Our research has suggested that there are far more disease-associated mutations in the general public than was previously suspected."

Hank Greely, director of Stanford University's Center for Law and the Biosciences, called CRISPR "the most exciting thing I've seen in biology in the 25 years I've been watching it," with tremendous possibilities to aid human health.

"Everybody should calm down" because this is just one of many steps advancing the science, and there are regulatory safeguards already in place. "We've got time to do it carefully," he said.

Michael Watson, executive director of the American College of Medical Genetics and Genomics, said the college thinks that any work aimed at pregnancy is premature, but the lab work is a necessary first step.

"That's the only way we're going to learn" if it's safe or feasible, he said.

Marilynn Marchione can be followed at http://twitter.com/MMarchioneAP

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Report: Scientists edit human embryos for first time in US – kfor.com

Posted: at 6:46 pm

America reportedly has moved ahead in a controversial race to tinker with human DNA but the scientific feat is shrouded in unanswered questions.

The MIT Technology Review published on Wednesday a news report about the first-known experiment to create genetically modified human embryos in the United States using a gene-editing tool called CRISPR.

Shoukhrat Mitalipov, director of the Oregon Health & Science Universitys Center for Embryonic Cell and Gene Therapy, reportedly led the new research. Mitalipov and the university would not confirm details of the research to CNN.

Results of the peer-reviewed study are expected to be published soon in a scientific journal. No further information will be provided before then, according to an emailed statement from the universitys press office. Another researcher cited in the MIT report, the Salk Institutes Jun Wu, did not reply to CNNs request for comment.

Mitalipov also declined to comment in the MIT Technology Review report, referencing the research results have not been published yet in a peer-reviewed scientific journal, which is considered the gold standard for scientific research. The author of the MIT report would not confirm to CNN whether he had seen the paper.

Previously, Mitalipov and his colleagues reported the first success in cloning human stem cells in 2013, successfully reprogramming human skin cells back to their embryonic state. In 2007, a research team led by Mitalipov announced they created the first cloned monkey embryo and extracted stem cells from it.

The MIT Technology Review reported the researchers in Portland, Oregon edited the DNA of a large number of one-cell embryos, specifically targeting genes associated with inherited diseases in those embryos. The MIT Technology Review could not determine which disease genes had been chosen for editing in the new research.

Im not surprised that they were looking at genetic diseases to try and see if they could target them, because thats exactly where I think the future inevitably leads, said Arthur Caplan, a professor and founding head of the division of bioethics at New York University Langone Medical Center, who was not involved in the research.

CRISPR research and controversy

Previously, scientists in China were the first in the world to reveal attempts to modify genes in human embryos using CRISPR. Three separate papers were published in scientific journals describing various studies in China on gene editing in human embryos.

When it comes to the new research, my reaction was this is an interesting incremental step and, boy, I bet its going to get blown up as being more important than it is, said Hank Greely, professor of law and genetics at Stanford University, who was not involved in the research. Its not the first time anybody has CRISPR-ed human embryos. Its not the first time anybodys CRISPR-ed viable human embryos. Its certainly not the first time people have CRISPR-ed viable mammalian embryos. Its the first time its been done in the US, but the embryos dont care where they are.

Yet, the research has already generated attention and controversy.

This is pushing the research faster than I thought we would see, said Dana Carroll, professor of biochemistry at the University of Utah, if the MIT Technology Review report rings true. Carroll has used CRISPR in his own studies but was not involved in the new research.

He pointed out the new research reportedly involved earlier, more delicate embryos, and CRISPR reportedly was still demonstrated as efficient.

From the perspective of research that would ultimately make germline editing safer and more effective, the earlier embryos will provide more relevant information, he said.

CRISPR an acronym for clustered, regularly interspaced, short palindromic repeats allows scientists to cut and edit small pieces of DNA at precise areas along a DNA strand, essentially modifying DNA.

Once scientists discovered they could develop a system that modifies pieces of DNA, they tested the gene-editing technology in microbes, then non-human mammals, then non-human primates and then, by 2015, human embryos.

The controversy surrounding gene-editing in human embryos partly stems from concern the changes CRISPR makes in DNA can be passed down to the offspring of those embryos later in life, from generation to generation. Down the line, that could possibly impact the genetic makeup of humans in erratic ways.

There is also considerable concern about off-target effects, such as making mutations at sites in the genome other than the intended target, Carroll said.

In other words, an edit made in one area of DNA possibly could cause problems in another, as a ripple or domino effect, which could be concerning.

Some CRISPR critics also have argued gene-editing may give way to eugenics and to allowing embryos to be edited with certain features in order to develop so-called designer babies.

Though, not all experts are too concerned.

Treating diseases

Some people are worried about wheres this all going to head? Are we going to wind up with super babies and eugenics? And, to me, I dont find that an interesting objection. Its too soon for that objection, Caplan said. Clearly, if were going to let this research proceed, its going to be to treat diseases and prevent diseases.

The enthusiasm surrounding gene-editing in human embryos partly stems from the promise CRISPR has shown in editing away and treating devastating intractable diseases. Earlier this year, the National Academies of Sciences, Engineering and Medicine published a report on human genome editing, addressing potential applications of gene editing, including the possible prevention or treatment of disease.

I hope the applications will be for the treatment of serious diseases and in cases where a sensible alternative is not available, as the National Academies report proposes, Carroll said.

Greely said: The National Academy of Sciences came out with a big report on Valentines Day this year about genome editing in humans, and I thought they very usefully divided it into three categories: basic research, treating living people and making changes that will pass down from generation to generation.

As for the reported new research, this is category one. This is basic research, he said. Category three is the ethically crucial one; this isnt that. Were still a long way from that.

Whats next

Other strides have been made recently in CRISPR research. Scientists at the Memorial Sloan Kettering Cancer Center in New York used the technology to genetically engineer immune cells to target and kill tumor cells in mice.

The mouse study was published in the journal Nature in February. More research is needed to determine whether similar results would appear in humans.

Last year, scientists in the Netherlands published a study in the journal PLOS Pathogens demonstrating CRISPR could be used to edit the DNA of three types of herpes viruses in a petri dish. More research is needed to see whether this tool could be used to fight herpes in actual humans.

Other examples of diseases where CRISPR could show promise as a treatment or preventive approach in the future include cystic fibrosis, sickle cell, hemophilia and mitochondrial diseases, such as the rare degenerative condition that the terminally-ill British infant Charlie Gard has, Caplan said.

There are what are called point mutations where you can go in and fix one genetic error. The simpler the genetic error, the easier it might be to try to repair it using a CRISPR gene-insertion technique, Caplan said about genetic diseases. I think rather than trying to treat cystic fibrosis, or treat sickle cell, or treat hemophilia, it does make ethical sense to figure out ways to prevent it. Now, obviously if its too risky we wont do it. If its too dangerous or maybe it wont work, we still dont know. Were in the early, early days (of research), but I dont think its fear of eugenics that should stop us.

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A race is underway to repair our hearing with medicine … – TechCrunch

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On any bustling city street, in the middle of the afternoon, its probably the case that half or more people are wearing earbuds, while the rest are abiding the noise pollution all around them. No one thinks twice about it, either.

The reality is that from a very young age, our hearing is now under assault.Little wonder that one in eight people in the United States aged 12 years or older has hearing loss in both ears, based on standard hearing examinations. By age 65, one in three people has hearing loss.

The problem will only grow as more people flock to city centers. According to recent United Nations data, roughly 54 percent of the worlds population lives in urban areas right now, and that number is expected to hit 66 percent by 2050, meaning cities could take in another 2.5 billion people, accounting for population growth.

With any luck, in our lifetimes, potentially soon, even, some of this hearing loss will be fixable not with hearing aids or cochlear implants, which arent available to everyone and dont work for a high percentage of people anyway. Scientists think instead that the combination of human genetics and single cell expression profiling has brought us to the point where medicine can help fix hearing. In fact, there are right now a small number of outfits quietly racing to develop the first approved drug for hearing loss, and if, like us, you live with a playlist unspooling in your ears part of each day, you should be rooting for them to succeed.

Some are further along than others, as a recent Xconomy piece observed. San Diego-basedOtonomyhas a drug for swimmers ear that could be approved this year. Meanwhile,Auris Medical, a Swiss biotech whose tinnitus candidate last year failed to beat a so-called dummy therapy in a Phase 3 trial, is currently working on other hearing loss conditions.

Both Otonomy and Auris Medical are publicly traded, but they have peers (and rivals) in the still-private world. Two young startups to watch they have strong founders and top venture backing on their side areFrequency Therapeutics and Decibel Therapeutics, both based in Boston.

Decibel Therapeutics was incubated by the powerhouse investment firm and incubator Third Rock Ventures. Along with SROne (a venture fund that counts GlaxoSmithKline as its sole investor), Third Rock provided the company with $52 million to get started in 2015, and it more recently raised an undisclosed amount of funding from GV.

Anthony Philippakis, a venture partner at GV who led the deal, says one aspect of Decibel that excited him is its portfolio approach, with some of its focus on single cell genomics, some on human genetics, some on direct-to-patient clinical trials and some on generating phenotypic data about the hearing system. (Philippakis seems to have embraced a portfolio approach to his own work. In addition to working with GV, hes a cardiologist at Brigham and Womens Hospital, and the chief data officer at Broad Institute of Harvard and MIT.)

As Decibels CEO, Steve Holtzman explains of the companys modus operandi: If you make investments in a broad discovery and translational medicine platform for drug discovery not just take a shot on goal with a single drug or assay you have a better chance to dominate the space.

Indeed, Holtzman who is focused first on hearing loss in millennials but who has ambitions to tackle hearing loss across the age spectrum says Decibel is working on drugs to reduce against drug toxicity [which can cause hearing loss], drugs to repair hair cells [in the inner ear] , drugs that are looking at other aspects of hearing that may involve the [central nervous system], and drugs focused on regeneration [versus just cellular repair].

Our play is much broader than that of any other firm, adds Holtzman, who has worked in the biotech industry for roughly 30 yearsand helped co-found the company with Third Rock.

Holtzman doesnt mention Frequency Therapeutics specifically, but its probably no coincidence that Frequency which recently raised $32 million in Series A led by CoBro Ventures, an investment firm formed by tech entrepreneur Marc Cohen and his brother Alain is taking a rather different approach.

The vision for the company started three years ago, says CEO David Lucchino. Bob Langer, a renowned biomedical engineer at MIT, had teamed up with peer Jeffrey Karp of Harvard Medical school on research showing that cells in the inner ear theyre called progenitor cells, and each of us is born with a fixed number of them could potentially be manipulated to create new inner ear cells.

Why thats important: these inner ear hair cells absorb sound and convert it to electrical impulses.

Frequencys lead program is focused on treating chronic hearing loss by regenerating cochlear hair cells with combinations of easily made drug molecules. But one challenge, among many, is whether this growth can happen in vivo. Why no one yet knows: Langer and Karps earlier findings involved human cochlear tissue that had been removed from a 40-year-old, whod had to have it removed in order for surgeons to get to a tumor.

Though the researchers witnessed an encouraging response from the tissue after dosing it with drugs, shooting medicine directly into someones ear and getting it to grow new cells is a giant leap from that starting point. Lucchino acknowledges, too, that determiningwhat amount of medicine to inject, or how often to inject it, would present a whole new host of other obstacles to overcome.

Given the various unknowns, its perhaps no surprise that Lucchino who worked as a venture capitalist with Polaris Partners before founding an earlier biosciences company 10 years ago says Frequency plans to focus on more than hearing eventually.

Its our first focus, but we view ourselves as a next-generation regenerative medicine player. And hearing is a wonderful place for us to start.

Either way, Frequency might find encouragement in other initiatives that are making meaningful strides. For example, two projects similarly involving endogenous cells (meaning already present in the body), are now in clinical development at the Swiss company Novartis.

The programs which came out of the small-molecule regenerative program of Scripps Research Institute of La Jolla, Calif. are focused on other areas, including treating multiple sclerosis and gastrointestinal problems. Some academics see the approach as potentially very powerful, however. If only it works. Stay tuned.

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Sunscreen made from DNA would last forever – Popular Science

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A DNA-based sunscreen that not only stops harmful ultraviolet (UV) light, but also becomes more protective the longer you expose it to UV rays? Thats the dazzling premise behind a recent study published in the journal Science Reports.

While sunscreen isnt the only form of sun protection (theres always protective clothing and floppy hats), the reality is that most of us just skip it. A 2015 study in Journal of the American Academy of Dermatology found that only 14.3 percent of men and 29.9 percent of women routinely use sunscreen when they are in outside for more than an hour. This wouldnt be a problem, except, Ultraviolet light is a carcinogen, Guy German a biomedical researcher at Binghamton University in New York and an author on the study, tells PopSci. We know it can give you a tan, but it can also cause cancer as well.

While dermatoepidemiologists (scientists who study diseases of the skin) suspect that sunlight causes cancer because it damages DNA in our cells, German and his colleagues were looking at DNA in an entirely different way. They wondered what would happen if they exposed DNA film, essentially a thin sheet of the stuff, to the same kind of ultraviolet light we get from walking in sunshine.

If youve ever taken glue and spread it on a surface and then let it dry to create a sheet or film, then you understand the basics of the material the researchers made: They took a liquid solution of DNA, smeared it on a piece of glass, and let it dry to create the film. The DNA, in case you were wondering, comes from salmon sperm. It was not that we chose salmon sperm, says German. It's just one of the readily available DNA sources.

German, along with the lead author on the study, Alexandria Gasperini, then exposed the film to UVA and UVB light to see how much, if any, radiation the films would allow to pass. UVA light makes up around 95-percent of the suns radiative light; it can penetrate deep into the skin, has long-been thought to be a culprit in premature aging, and is increasingly believed to play a key role in the formation of skin cancer. UVB, the radiation that makes us tan (and burn), also plays a role in skin cancer.

This was a fundamental study to see how UV light interacts with DNA films," says German, "Also, you know subsequently how the UV light can actually alter DNA films.

To measure these effects, the team used a device called a spectrophotometer, which allows them to control the amount and wavelength of light that they put through the films. A receptor on the other side measured how much of the light passed made it through. The DNA film did not allow up to 90 percent of UVB light and 20-percent of UVA light to cross through. Perhaps even more amazing: The DNA film seemed to grow strongerthat is, it seemed to allow less light to pass through the longer it was exposed to UV light. German and his team, however, aren't sure if the films achieve this by absorbing light or reflecting it.

We discovered two possible mechanisms, says German to explain how the DNA cells appear to achieving this feat. One is called hypochromicity, that is the increased ability of DNA molecules to absorb UV light, but also we found that the results that we got suggest a crosslinking density of the cells themselves.

Under a microscope, the film's crystalline structure got denser, or developed more crosslinks, as it was exposed to more light. The results suggest that, if a film has more crosslinks, its potentially going to absorb or scatter more UV light.

As an added bonus, the team also found that when they coated the film on human skin samples procured from elective surgeries, it also helped the skin retain moisture.

To be clear, what German and his team tested is not sunscreen, at least not in the traditional sense of a liquid or paste smeared onto the skin. You cant pick this up at the supermarket, at least not anytime soon. But between the ecological and health concerns of chemical sunscreens, and the lack of efficacy of mineral sunscreens, what they uncovered, might make its way into products in the future. Who wouldnt want a sunscreen that you apply once? That grows stronger the longer you frolic in the sun? It would, in a sense, act as a sacrificial layer, taking one for the team and allowing your own skin to go unscathed.

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She thought she was Irish until a DNA test opened a 100-year-old mystery – Chicago Tribune

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Five years ago, Alice Collins Plebuch made a decision that would alter her future or really, her past.

She sent away for a "just-for-fun DNA test." When the tube arrived, she spit and spit until she filled it up to the line, and then sent it off in the mail. She wanted to know what she was made of.

Plebuch, now 69, already had a rough idea of what she would find. Her parents, both deceased, were Irish-American Catholics who raised her and her six siblings with church Sundays and ethnic pride. But Plebuch, who had a long-standing interest in science and DNA, wanted to know more about her dad's side of the family. The son of Irish immigrants, Jim Collins had been raised in an orphanage from a young age, and his extended family tree was murky.

After a few weeks during which her saliva was analyzed, she got an email in the summer of 2012 with a link to her results. The report was confounding.

About half of Plebuch's DNA results presented the mixed British Isles bloodline she expected. The other half picked up an unexpected combination of European Jewish, Middle Eastern and Eastern European. Surely someone in the lab had messed up. It was the early days of direct-to-consumer DNA testing, and Ancestry.com's test was new. She wrote the company a nasty letter informing them they'd made a mistake.

But she talked to her sister, and they agreed she should test again. If the information Plebuch was seeing on her computer screen was correct, it posed a fundamental mystery about her very identity. It meant one of her parents wasn't who he or she was supposed to be and, by extension, neither was she.

Eventually, Plebuch would write to Ancestry again. You guys were right, she'd say. I was wrong.

We are only just beginning to grapple with what it means to cheaply and easily uncover our genetic heritage.

Over the past five years, as the price of DNA testing kits has dropped and their quality has improved, the phenomenon of "recreational genomics" has taken off. According to the International Society of Genetic Genealogy, nearly 8 million people worldwide, but mostly in the United States, have tested their DNA through kits, typically costing $99 or less, from such companies as 23andMe, Ancestry.com and Family Tree DNA.

The most popular DNA-deciphering approach, autosomal DNA testing, looks at genetic material inherited from both parents and can be used to connect customers to others in a database who share that material. The results can let you see exactly what stuff you're made from as well as offer the opportunity to find previously unknown relatives.

For adoptees, many of whom can't access information about their birthparents because of closed adoption laws, DNA testing can let them bypass years, even decades, of conventional research to find "DNA cousins" who may very well lead them to their families.

But DNA testing can also yield uncomfortable surprises. Some testers, looking for a little more information about a grandparent's origins, or to confirm a family legend about Native American heritage, may not be prepared for results that disrupt their sense of identity. Often, that means finding out their dad is not actually their dad, or discovering a relative that they never knew existed perhaps a baby conceived out of wedlock or given up for adoption.

In 2014, 23andMe estimated that 7,000 users of its service had discovered unexpected paternity or previously unknown siblings a relatively small fraction of overall users. The company no longer provides data on surprise results. However, its customer base has more than doubled since 2014, and now contains more than 2 million people and as more people get involved with recreational genomics, bloodline surprises are certain to become a more common experience. The 2020s may turn out to be the decade that killed family secrets, for better and for worse.

"We see it every day," says CeCe Moore, a genetic genealogist and consultant for the PBS series "Finding Your Roots." She runs a 54,000-person Facebook group, DNA Detectives, that helps people unravel their genetic ancestries. "You find out that a lot of things are not as they seem, and a lot of families are much more complex than you assume."

Alice Plebuch found herself in this place in the summer of 2012. To solve the mystery of her identity, she needed more help than any DNA testing company could offer. After all, genetic testing gives you the what, but not the why.

Plebuch would turn out to be uniquely suited to the role of private eye in her own detective story. Now living in the suburbs of Vancouver, Washington, she worked as an IT manager for the University of California before her retirement. "I did data processing most of my life, and at a fairly sophisticated level," she says. Computers do not intimidate her, and neither do big questions that require the organization and analysis of complex information. She likes to find patterns hidden in the chaos.

Just the skills necessary to solve a very old puzzle.

After the initial shock of her test results, Plebuch wondered if her mother might have had an affair. Or her grandmother, perhaps? So, she and her sister, Gerry Collins Wiggins, both ordered kits from DNA testing company 23andMe.

The affair scenario seemed unlikely certainly out of character for her mom, and besides, all seven Collins children had their father's hooded eyes. But she couldn't dismiss it. "My father, he was in the Army and he was all over the world, and it was just one of those fears that you have when you don't know," she says.

As they waited for their results, they wondered. If the Ancestry.com findings were right, it meant one of Plebuch's parents was at least partly Jewish. But which one?

They had a gut sense that it was unlikely to be their mother, who came from a large family, filled with cousins Plebuch and her siblings all knew well. Dad, who died in 1999, seemed the likelier candidate. Born in the Bronx, Jim Collins was a baby when his mother died. His longshoreman father, John Collins, was unable to care for his three children and sent them to live in orphanages. He died while Jim was still a child, and Jim had only limited contact with his extended family as an adult.

But still, the notion Jim could somehow be Jewish seemed far-fetched. His parents had come to the United States from Ireland, and that history was central to Jim's sense of himself. "He was raised in an orphanage; he didn't have anything else," Plebuch says. "He had his Irish identity."

She plunged into online genealogy forums, researching how other people had traced their DNA and educating herself about the science. She and her sister came up with a plan: They would persuade two of their first cousins to get tested their mother's nephew and their father's nephew. If one of those cousins was partly Jewish, they'd know for sure which side of the family was contributing the mysterious heritage.

The men agreed. The sisters sent their kits and waited.

Then Plebuch's own 23andMe results came back. They seemed consistent with her earlier Ancestry.com test, indicating lots of Ashkenazi Jewish ancestry from areas such as Belarus, Russia, Ukraine and Lithuania. She also discovered that her brother Bill had recently taken a 23andMe test. His results were a relief sort of.

"No hanky-panky," as Plebuch puts it. They were full siblings, sharing about 50 percent of the relevant DNA, including the same mysterious Jewish ancestry. This knocked out another theory they had considered that Plebuch might have been adopted.

Plebuch found a feature on 23andMe's website showing what segments along her chromosomes were associated with Ashkenazi Jews. Flipping back and forth, comparing her DNA to her brother's, she had a sudden insight.

There was a key difference between the images, lurking in the sex chromosomes. Along the X chromosome were blue segments indicating where she had Jewish ancestry, which could theoretically have come from either parent because females inherit one X from each. But males inherit only one X, from their mothers, along with a Y chromosome from their fathers, and when Plebuch looked at her brother's results, "darned if Bill's X chromosome wasn't lily white." Clearly, their mother had contributed no Jewish ancestry to her son.

"That was when I knew that my father was the one," Plebuch says.

The next day, her sister Gerry Wiggins's results came back: She, too, was a full sibling who also displayed significant Jewish ancestry. Then, Plebuch got an email from a retired professor known for his skill at interpreting ancestry tests, to whom she'd sent hers. "What you are is 50 percent Jewish," he wrote. "This is in fact as solid as DNA gets, which in this case is very solid indeed."

But how could their father have been Jewish? Could Jim Collins's parents have been secret Irish Jews? Or maybe Jews from Eastern Europe who passed themselves off as Irish when they came to the country as immigrants?

Now they really needed the data from the cousin on their father's side. If he also had Jewish ancestry, Plebuch figured, that could point to a family secret buried in Europe.

They waited for months, through a series of setbacks problems in the lab, problems with the mail. Meanwhile, the sisters emailed back and forth.

Plebuch asked her younger sister: Did this revelation about their father's ethnicity unnerve her? They'd been so certain of their family roots, and "now we know nothing," she wrote.

"It is the first thing I think about when I wake up in the morning," Wiggins replied, "and the last thing I think about as I drift off to sleep."

At last, Plebuch was alerted that her cousins' results were ready. The data from their mom's nephew revealed that he was a full first cousin, as expected sharing about 12.5 percent of his DNA with Plebuch.

But the results from her dad's nephew, Pete Nolan, whose mother was Jim Collins' sister, revealed him to be a total stranger, genetically speaking. No overlap whatsoever with Plebuch or, by extension, with her father.

In other words, Plebuch's cousin wasn't actually her cousin.

And her dad's sister wasn't actually his sister.

Plebuch was devastated. This finding knocked out the secret-Jews theory but if it put Plebuch closer to the truth, she still felt unmoored. She was deeply fond of Nolan, with whom she shared a birthday. "I was afraid he was going to reject me because we were no longer biological cousins."

She called Nolan to share the results of his DNA test. "He was sad," Plebuch says, "but he also told me I was the best cousin he ever had."

Plebuch and Wiggins came to the stunned conclusion that their dad was somehow not related to his own parents. John and Katie Collins were Irish Catholics, and their son was Jewish.

"I really lost all my identity," Plebuch says. "I felt adrift. I didn't know who I was you know, who I really was."

For Wiggins, the revelation confirmed a long, lingering sense that something was amiss with her father's story. Studying the family photographs on her wall, she'd thought for years that their paternal grandfather looked like no one in her immediate family. Visiting Ireland in 1990, she had searched the faces for any resemblance to her 5-foot-4, dark-haired father. "There was nobody that looked like my dad," Wiggins says.

The sisters set about methodically pursuing several theories. With Jim Collins and his parents long dead, Plebuch knew she needed to unravel his story through the living. She signed up to take a class in Seattle on how to use DNA to find her father's relatives.

If the woman Jim called his sister was not his sister, was there evidence of an actual sibling out there somewhere? Might that sibling have children? Might Plebuch and her siblings have first cousins they'd never known about?

---

The dystopian novelistMargaret Atwood is fond of saying that all new technologies have a good side, a bad side, and a "stupid side you hadn't considered." Doing DNA testing for fun can carry consequences few of us might anticipate. It requires little investment at the outset, but it has the potential to utterly change our lives.

After researching her family history, Laurie Pratt decided five years ago to enhance her genealogical knowledge by testing herself and her parents. This was how she discovered that her dad was not related to her.

Pratt, 52, an airline ground operations supervisor in Orange County, California, went to her mother, who at first said the results were "impossible." But over time, her mother divulged hazy memories of a short-lived relationship during a period when she and her husband were briefly separated.

Her mother couldn't recall a name before she died. The man who raised Pratt also died; she never told him he was not, biologically speaking, her father.

She searched over several years, eventually identifying a potential candidate within the family tree of previously unknown cousins she found through DNA matching. She sent this man a letter and days later, in February of this year, he suddenly popped up in the Ancestry.com database, identified by a saliva test as her biological father.

The man called her, and they spoke briefly on the phone. Though he was unmarried when Pratt was conceived, he fretted over the idea that he had abandoned a baby without knowing it. Pratt asked if they could meet, and the man agreed, but asked if he could take some time first to process the news and tell his wife and daughter.

Two days later, Pratt logged onto Ancestry.com and discovered that the man's test had been deleted.

Reactions to DNA testing surprises vary dramatically. Moore, the genetic genealogist, says that, in her experience, even those who are initially dismayed end up glad that "they learned about the truth of themselves."

But seekers may be a self-selecting bunch, and those who find the truth thrust upon them by someone else's quest are not always happy about it. Gaye Sherman Tannenbaum, an adoptee who spent decades searching for her birthparents and now helps others on their quests, says in some instances, people are "outright hostile" when they learn of a newly discovered relative.

The reaction is understandable: DNA surprises often imply extramarital affairs, out-of-wedlock births and decades-old secrets.

Researchers from theUniversity of Leuven in Belgium recently examined the English-language websites of 43 direct-to-consumer DNA testing companies and found that few companies warn consumers about the possibility of discovering "misattributed paternity."

23andMe is unusual in offering multiple warnings. ("Unexpected relationships may be identified that could affect you and your family.") "We are as transparent as possible," says Kate Black, the privacy officer for 23andMe, brought on in 2015after the company was criticized for failing to prepare consumers for such surprises. "We try to educate and inform people in every tool."

Still, consumers may skim those warnings, or refuse to believe such surprises might lurk within their own families. Jennifer Utley, the director of research at Ancestry.com, says that even though she had seen many cases of surprise relatives in her work, she still found herself in "complete shock" when she tested her own DNA and discovered a first cousin she hadn't known existed.

"I had no idea who this person was," says Utley, who has since learned that her cousin was the product of a teenage relationship, raised by an adoptive family. Of her family, she now concludes: "We're the best secret-keepers on the planet."

Pratt says she doesn't regret testing her DNA. She found herself both "devastated and curious" after the initial discovery about her genetic heritage. But, of course, that discovery was not hers alone, because her genes are not hers alone. Cases of unexpected paternity and secret adoptions implicate other people.

"I think this jars him," she says of her biological father. "He goes to bed the good guy he's always been very religious, very Catholic. And he wakes up, he's Mick Jagger. He has a baby. It blew his mind a little bit."

In late April, Pratt sent the man another letter. She had "no desire to push myself into your family," she wrote, nor make a financial claim. What she sought were stories about him and his family, to help her build a sense of where she came from. Just one meeting, a few hours, was all she asked.

She still hasn't heard back.

By early 2013, the Collins children were hot on the trail of a hundred-year-old mystery.

They had their father's birth certificate, indicating that he'd been born on Sept. 23, 1913. They wrote to his orphanage and learned that their dad had been sent there by the New York Society for the Prevention of Cruelty to Children.

Plebuch wondered if Jim Collins, just a baby at the time, had somehow been confused with another child when he was taken from his father's home.

She found a forensic artist said to be skilled in understanding how faces change over time. She sent her a picture of her dad sitting on his father's lap when he was about 11 months, along with photos of him as an adult. Were these of the same person?

Probably, the forensic artist ruled. The ears hadn't changed, and the mouth, chin and facial proportions seemed the same.

If the mystery of their father didn't begin with his parents' life in Ireland, nor with his own time in the orphanage, Plebuch and her sister concluded it must have happened shortly after Jim was born. Unusually for the era, his mother gave birth not at home but at Fordham Hospital in the Bronx.

Could something have happened there?

Wurts Bros./Museum of the City of New York

By this time, the sisters were using techniques developed by Moore and others to help adoptees try to find relatives in a vast universe of strangers' spit. Every time a site like 23andMe informed them of what Plebuch calls a "DNA cousin" on their Jewish side someone whose results suggested a likely cousin relationship they would ask to see that person's genome. If the person agreed, the site would reveal any places where their chromosomes overlapped.

The idea, Plebuch explains, was to find patterns in the data. A group of people who share segments on the same chromosome probably share a common ancestor. If Plebuch could find a group of relatives who all shared the same segment, she might be able to use that along with their family trees, family surnames, and ancestors' home towns in the old country to trace a path into her father's biological family.

The work was slow and painstaking, complicated by the fact that Ashkenazi Jews frequently marry within the group and often are related in multiple ways. This can make distant relatives look like a closer match than they actually are. But the sisters forged on, sending at least 1,000 requests for genome-sharing to DNA cousins through 23andMe. It became Plebuch's full-time job.

Some ignored their overtures, while others were drawn in by the saga and devoted their own efforts to helping the sisters untangle it. It was as if the Collins sisters had plugged into a larger family, a web of strangers who wanted to help because generations before, their ancestors had shared soup, shared heartache, slept in the same bed.

One DNA cousin made a clever suggestion: Why not search for evidence of a baby born around the same time under a common Jewish surname, Cohen? He reasoned that the nurses, perhaps relying on an alphabetical system, might have confused a Collins baby with a Cohen baby. CeCe Moore was by now volunteering to advise Plebuch, and with additional help from Tannenbaum and the New York City Birth Index of 1913, Plebuch found a Seymour Cohen born in the Bronx on Sept. 23. DNA cousins fanned out on the Internet, tracking down a descendant of Seymour's sister.

Plebuch wrote to the woman, a professor in North Carolina, and offered to pay for her test kit if she'd contribute something completely free and absolutely priceless: her saliva. The woman agreed.

Weeks later, the results came back. No relation.

After that red herring, Plebuch decided to dive deeper into the 1913 birth index, to find babies who were in the hospital at the same time as her father. It was no easy task: The list of children born in the Bronx in 1913 ran 159 pages, was not ordered by date, and didn't distinguish hospital births from home births. But she manage to isolate all the male children born on Sept. 23, as well as the day after and the day before. She further narrowed the list to names that sounded either Jewish or ethnically neutral 30 babies in all.

Her hope was that one of those babies would share a surname with one of the people that the DNA matching sites identified as a likely relative. So she searched methodically.

"Appel" nothing. "Bain" nothing. "Bamson" nothing.

It was another dead end.

The sisters went back to the chromosome segment matching, both at 23andMe and Family Tree DNA, where they had also uploaded their genetic data. They bought at least 21 DNA test kits for themselves, relatives and strangers suspected of being relations. Plebuch found she and her siblings matched to 6,912 likely DNA relatives, with 311,467 "segment matches" among them segments along the chromosomes that overlapped with those of the Collins children. Which is to say, 311,467 potential clues.

The data they had kept on spreadsheets quickly became overwhelming, so their brother Jim, a retired software and systems engineer who had worked on NASA supercomputers, designed an iPad app called DNAMatch to help them and other seekers keep their data straight.

Plebuch was determined, and unusually well suited to the task of solving a puzzle hidden in big data. She and Wiggins searched this way for two and a half years. But she was having no luck finding someone closely related to her father's biological family they simply weren't in the system.

Perhaps they didn't know about DNA testing, or couldn't afford it, or weren't interested.

All the sisters could do was keep working and waiting, hoping the DNA testing revolution would make its way to strangers who shared their blood.

---

Ultimately, the crack in the case came not through Plebuch's squad of helpful DNA cousins, but through a stranger with no genetic connection.

It was Jan. 18, 2015, a Sunday, and Plebuch was feeling down. She was writing an email to her cousin Pete Nolan the beloved relative it turned out she wasn't really related to to update him on her stalled search.

As administrator of his 23andMe account, she had permission to check the list of his DNA relatives yet rarely did so, since new relatives rarely showed up. But she decided to check it this day and this time, there was a new person. A stranger had just had her saliva processed, and she showed up as a close relative of Nolan.

Plebuch emailed the woman and asked if she would compare genomes with Nolan. The woman agreed, and Plebuch could see the segments where her cousin and the stranger overlapped. Plebuch thanked her, and asked if her results were what she expected.

"I was actually expecting to be much more Ashkenazi than I am," the woman wrote. Her name was Jessica Benson, a North Carolina resident who had taken the test on a whim, hoping to learn more about her Jewish ethnicity. Instead, she wrote, she had discovered "that I am actually Irish, which I had not expected at all."

Plebuch felt chills. She wrote back that her father had been born at Fordham Hospital on Sept. 23, 1913. Had anyone in the Benson family been born on that date?

Jessica replied. Her grandfather, Phillip Benson, might have been born around that date, she wrote.

Plebuch began to cry.

She started combing through her list of baby names from the 1913 Index. No "Benson" born that day in the Bronx. But then, well after midnight, she found it:

The New York City Birth Index had a "Philip Bamson," born Sept. 23 one of the names she had searched among her DNA cousins. This had to be Phillip Benson, his name misrecorded on his birth certificate.

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The DNA of ancient Canaanites lives on in modern-day Lebanese, genetic analysis shows – Los Angeles Times

Posted: at 6:46 pm

The Canaanites lived at the crossroads of the ancient world. They experienced wars, conquests and occupations for millennia, and as a result evolutionary geneticists expected that their DNA would become substantially mixed with incoming populations.

Astonishingly, new genetic analysis shows that scientists were wrong. According to a new study in the American Journal of Human Genetics, todays Lebanese share a whopping 93% of their DNA with the ancient Canaanites.

The study also found that the Bronze Age inhabitants of Sidon, a major Canaanite city-state in modern-day Lebanon, have the same genetic profile as people living 300 to 800 years earlier in present-day Jordan.

Later known as Phoenicians, the Canaanites have a murky past. Nearly all of their own records have been destroyed over the centuries, so their history has been mostly pieced together from archaeological records and the writings of other ancient peoples.

Archaeologists at the Sidon excavation site have been unearthing ancient Canaanite secrets for the last 19 years in the still-inhabited Lebanese port city. The team has uncovered 160 burials from the Canaanite period alone, said Claude Doumet-Serhal, director of the excavation. They have found people of all ages in these Canaanite burials, she said children were buried in jars and adults were placed in sand.

Claude Doumet-Serhal / The Sidon Excavation

An aerial view of the Sidon excavation site.

An aerial view of the Sidon excavation site. (Claude Doumet-Serhal / The Sidon Excavation)

Aided by new DNA sampling techniques, a team of evolutionary geneticists including Marc Haber and Chris Tyler-Smith from the Wellcome Trust Sanger Institute stepped in.

They sequenced the whole genomes of five individuals found in Sidon who lived about 3,700 years ago. The team then compared the genomes of these ancient Canaanites with those of 99 Lebanese people currently living in the country, along with the previously published genetic information from modern and ancient populations across Europe and Asia.

First, they investigated the genetic ancestry of the Canaanites themselves. They found that these Bronze Age inhabitants of Sidon shared about half their DNA with local Neolithic peoples and the other half with Chalcolithic Iranians. Interestingly, this genetic profile is nearly identical to the one evolutionary geneticist Iosif Lazaridis and his team found last year in Bronze Age villagers near Ain Ghazal in modern-day Jordan.

This suggests that Canaanite-related ancestry was spread across a wide region during the Bronze Age and was shared between urban societies on the coast and farming societies further inland. This evidence supports the idea that different Levantine cultural groups such as the Moabites, Israelites, and Phoenicians may have had a common genetic background, the authors said.

The researchers were also able to determine that the genetic mixing of the Levantine and Iranian peoples happened between 6,600 and 3,550 years ago, a range they would be able to narrow down with more ancient DNA samples from the region.

Claude Doumet-Serhal / The Sidon Excavation

The buried remains of a Canaanite adult whose DNA was sequenced in the study.

The buried remains of a Canaanite adult whose DNA was sequenced in the study. (Claude Doumet-Serhal / The Sidon Excavation)

Next, the team wanted to compare the Canaanite genome with the genetic makeup of the people who currently inhabit the ancient Canaanite cities. To do this, they collected DNA from 99 Lebanese people Druze, Muslim, and Christian alike.

As expected, they found some new additions to the modern Lebanese genome since the Bronze Age. About 7% of modern Lebanese DNA originates from eastern Steppe peoples found in what is now Russia, but wasnt represented in the Bronze Age Canaanites or their ancestors. What surprised the team was what was missing from their genetic data.

If you look at the history of Lebanon after the Bronze Age, especially it had a lot of conquests, Haber said. He and Tyler-Smith expected to see greater genetic contributions from multiple conquering peoples, and were surprised that as much as 93% of the Lebanese genome is shared with their Canaanite predecessors.

Though a 7% genetic influx from the Steppe seems very small, that number might be covering some hidden complexities, said Lazaridis, who worked on the Bronze Age Jordanian samples but was not involved in the new study.

Not much is known about the migrations of these eastern Steppe populations, he said. If the genomes of the incoming people were only half Steppe, for example, 14% of the Lebanese genome could have come from the new migrants.

Haber and Tyler-Smith said they want to explore this complexity further. Who were those eastern migrants? Where did they come from? And why did they migrate toward the Levant region? Haber asked. Analyzing more samples from different locations and periods could lead to an answer.

The team also wanted to know if the individuals from Sidon are more similar to modern-day Lebanese than to other modern Eurasian populations.

Despite small genetic variations between the three religious groups caused by preferential mating over time, the Lebanese genome is not widely varied. As a whole, the Lebanese people have more genetic overlap with the Canaanites from Sidon than do other modern Middle Eastern populations such as Jordanians, Syrians or Palestinians.

The difference is small, but its possible that the Lebanese population has remained more isolated over time from an influx of African DNA than other Levantine peoples, Lazaridis suggested.

Claude Doumet-Serhal - The Sidon Excavation

An archaeologist sorts pottery at the Sidon excavation site.

An archaeologist sorts pottery at the Sidon excavation site. (Claude Doumet-Serhal - The Sidon Excavation)

The findings have powerful cultural implications, Doumet-Serhal said. In a country struggling with the ramifications of war and a society fiercely divided along political and sectarian lines, religious groups have often looked to an uncertain history for their identities.

When Lebanon started in 1929, Doumet-Serhal said, the Christians said, We are Phoenician. The Muslims didnt accept that and they said, No, we are Arab.

But from this work comes a message of unity. We all belong to the same people, Doumet-Serhal said. We have always had a difficult past but we have a shared heritage we have to preserve.

mira.abed@latimes.com

Twitter: @mirakatherine

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Salk Institute, UCSD scientists decode DNA’s 3D shape – The San … – The San Diego Union-Tribune

Posted: at 6:46 pm

DNA is compressed in the nucleus in a disorderly way that allows flexibility in how genes are turned on and off, according to a study by scientists from the Salk Institute and University of California San Diego.

This discovery was made with a new imaging technology devised by Salk researchers led by Clodagh OShea and carried out by UCSD researchers led by Mark Ellisman.

Published in Science, the study is available at j.mp/salkdna. OShea is listed as senior author with Ellisman as collaborator. The first author was Horng Ou, a researcher in OSheas lab.

Understanding DNAs 3D structure is expected to yield a better understanding of how defects in that structure relate to senescence and diseases, according to a perspective piece published along with the study.

In the nucleus, DNA is bound to proteins called histones to make a complex called chromatin, which in turn forms chromosomes. The degree of compression is extreme. Stretched out to form a line, the DNA in a single cell would extend about two meters, or about 6 1/2 feet. It must all fit into a nucleus of about 10 millionths of a meter.

What that means is that not all your DNA is accessible, OShea said. So even though the same DNA sequence is in every cell in your body, its structure in any cell nucleus can be different, which determines whether those DNA sequences can be accessed and used.

The fundamental question then is, well what's the structure of DNA in the nucleus, she said.

Existing models envision DNA as being grouped in increasingly large fibers, one inside another. But determining whether these models are correct has been stymied by the lack of imaging technology that can visualize chromatin.

Electron microscopy, one of the common tools to visualize such minute structures, doesnt work well with chromatin, OShea said. Thats because the chemical elements in chromatin dont provide sufficient contrast.

The Salk team solved that problem by using a fluorescent dye to stain the chromatin. When the dye was illuminated, it caused a metal to coat the DNA and associated proteins so they can be more easily detected by electron microscopy. They call this method ChromEMT.

The dye was already known, but it was the Salk teams idea to use it for imaging chromatin. The actual imaging, called "multi-tilt electron tomography" was performed by colleagues at University of California San Diego.

They found that chromatin is packed in clusters of various densities. The denser clusters are not as accessible as the looser cluster, OShea said. This provides a mechanism for allowing selective access to genes.

Previous hierarchy-based models didnt fit the experimental evidence of gene activation and suppression, OShea said. These models suggested that access would be allowed or denied at predictable, periodic intervals. The trouble with that is that one error would cause the whole intricate structure to fail.

By allowing DNA to be compressed into many separate clusters, with no grand structure, gene regulation can be take place independently. Moreover, a defect in one cluster wouldnt affect other clusters.

bradley.fikes@sduniontribune.com

(619) 293-1020

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University of Maryland scientists research gene linked to depression – Baltimore Sun

Posted: at 6:44 pm

Although medications exist to treat depression, many scientists arent sure why theyre effective and why they dont work for everyone.

Researchers at the University of Maryland School of Medicine believe they may have found a key to the puzzle of major depression that could lead to therapies for those who dont respond to medications already on the market.

A new study by the researchers has identified the central role a gene known as Slc6a15 plays in either protecting from stress or contributing to depression, depending on its level of activity in a part of the brain associated with motivation, pleasure and reward seeking.

Published in the Journal of Neuroscience in July, the study is the first to illuminate in detail how the gene works in a kind of neuron that plays a key role in depression, according to the University of Maryland School of Medicine.

Specifically, the researchers found that mice with depression had reduced levels of the genes activity, while those with high levels of the genes activity handled chronic stress better.

Though senior researcher Mary Kay Lobos primary studies were done with mice, she also examined the brains of people who had committed suicide and found reduced levels of the genes activity, confirming a likely link.

She hopes now that drugs could be developed that would encourage the genes activity.

I thought it was fascinating we had this system in place that allows us to go after things or be motivated or have pleasure and I was interested in how it becomes dysfunctional in certain diseases like depression, Lobo said. I hope that we can identify molecules that could potentially be therapeutically treated or targeted to treat depression.

Lobo and her colleagues have been examining the gene for years. In 2006, they discovered that it was more common among specific neurons in the brain that they later learned were related to depression. Five years later, other researchers learned the gene played a role in depression and Lobo and her research colleagues decided to investigate what that role is in those specific neurons.

About 15 million adults, or 6.7 percent of all U.S. adults, experience major depression in a given year, according to the Anxiety and Depression Association of America. It is the leading cause of disability for Americans aged 15 to 44. It is more prevalent in women and can develop at any age, but the median age of onset is 32.5.

David Dietz, an associate professor in the Department of Pharmacology and Toxicology at the State University of New York at Buffalo, said little was known previously about the biological basis of depression in the brain. Many drugs used to treat depression were discovered serendipitously, he said, and it wasnt clear why they worked.

Were starting to really get an idea of what does the depressed brain look like, Dietz said. When you put the whole puzzle together, you see where the problem is. For too long weve been throwing things at individual pieces. Its so complex and we have so little information that it was almost bound to be that way. For the first time this is one of those bigger pieces you can slide into the jigsaw puzzle.

Lobo said its not clear yet how Slc6a15 works in the brain, but she believes it may be transporting three types of amino acids into a subset of neurons called D2 neurons in a part of the brain called the nucleus accumbens. The nucleus accumbens and D2 neurons are known to play a role in pleasure, activating when one eats a delicious meal, has sex or drinks alcohol.

The amino acids would then be synthesized into neurotransmitters. Depression previously has been linked to imbalances of the neurotransmitters serotonin, norepinephrine and dopamine.

So even though people may have proper levels of amino acids in their bodies, the neurons in their brains that need them may not be getting enough if the transporter is not working as it should.

This gene is critical for putting very specific amino acids in the right place so that neurotransmitters can be synthesized, said A.J. Robison, an assistant professor in the Department of Physiology at Michigan State University. Its the location, location, location idea. Its not the amino acids, its where theyre at and in which cells.

Robison said Lobos next step would be discovering more about how the transporter gene works.

The fact that this transporter seems to be important is what the paper shows and how it does it is not shown, and thats a challenge for her, he said. Figuring out the how of it is the next step and Dr. Lobo is particularly positioned to do it.

Lobos team was able to use gene therapy, a form of therapy in the early stages of being studied in humans, in the mice to boost the genes activity. The mice were exposed to larger, more aggressive mice, which usually causes depressive symptoms. But the gene therapy helped protect the mice against the stress, the team found. When the team reduced the genes activity in the mice, just one day of exposure to the aggressive mice was enough to cause symptoms of depression.

Gene therapy is starting to be used in the treatment of some types of cancers, but Lobo said science had not yet advanced to the point where it can be used for treating neurological issues in human patients. A more likely treatment would be a drug that targets the genes activity directly, she said.

I think this is a major step toward our understanding of the precise maladaptive changes that occur in response to stress, said Vanna Zachariou, an associate professor in the Department of Neuroscience at the Icahn School of Medicine at Mount Sinai. It can be a more efficient way to target depression because its not simply targeting monoamine receptors or dopamine but targeting molecular adaptations that occur. It doesnt act necessarily as the drugs we have available, so it might create an alternative avenue to treat depression.

Lobo said she wouldnt refer to Slc6a15 as a depression gene, saying the disease was complex and could have many factors.

I wouldnt say theres one depression gene she said. A number of things play a role, and also theres no depression neuron, theres multiple depression neurons.

There also may be different types of depression with different symptoms, she said. With the disease, some sufferers sleep a lot, while others sleep a lot less, for example.

With all these complex diseases, its hard to link it to something, she said. Like Huntingtons disease, we know theres a specific gene that causes Huntingtons disease. For depression we dont have that.

cwells@baltsun.com

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