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How an ancient microbial arms race remodeled human cells

Science

At a recent symposium on the evolution of infectious diseases, University of California, San Diego (UCSD), pathologist Nissi Varki noted that humans suffer from a long list of deadly diseases—including typhoid fever, cholera, mumps, whooping cough, and gonorrhea—that don't afflict apes and most other mammals. All of those pathogens follow the same well-trodden pathway to break into our cells: They manipulate sugar molecules called sialic acids. Hundreds of millions of these sugars stud the outer surface of every cell in the human body—and the sialic acids in humans are different from those in apes. Varki and an international team of researchers have now traced how evolution may have scrambled to construct new defenses after that molecular vulnerability emerged in our distant ancestors. By analyzing modern human genomes and ancient DNA from our extinct cousins, the Neanderthals and Denisovans, the researchers detected a burst of evolution in our immune cells that occurred in an ancestor of all three types of human by at least 600,000 years ago. As the researchers report in the current issue of Genome Biology and Evolution , these genetic changes may have sharpened the body's defenses against the pathogens that evolved to exploit sialic acids—but created new vulnerabilities. In an added irony, they note, humans' distinctive sialic acids were themselves once a defense against disease. The evolutionary saga is a vivid illustration of the competition between humans and microbes, says microbiologist Christine Szymanski of the University of Georgia, Athens, who is not a co-author. “This gives us a human perspective on how we have to keep changing to keep pace.” The arena for this evolutionary arms race is the glycocalyx, a sugar coating that protects the outer membrane of all cells. It consists of a forest of molecules that sprout from the cell membrane. The sialic acids are at the tip of the tallest branches, sugar chains called glycans, which are rooted to fats and proteins deeper in the membrane. Given their prominence and sheer number, sialic acids are usually the first molecules that invading pathogens encounter. Human cells are coated with one type of sialic acid, N-acetylneuraminic acid (Neu5Ac). But apes and most other mammals also carry a different one, N-glycolylneuraminic acid (Neu5Gc). More than 2 million years ago, according to multiple molecular clock methods that estimate when mutations arose, a mutation in a gene on chromosome six made it impossible for human ancestors to make Neu5Gc anymore; instead, they made more of another sialic acid, Neu5Ac ( Science , 4 September 1998, p. [1432][1]). “We now know we had an ancient complete makeover of the surface of the human cells,” says evolutionary biologist Pascal Gagneux of UCSD, a co-author of the new paper. Birds, some bats, ferrets, and New World monkeys all separately made the same evolutionary change. The change likely evolved as a defense against malaria, says UCSD physician-scientist Ajit Varki, senior author of the paper and Nissi Varki's spouse. Malarial parasites that infect chimpanzees were no longer able to bind with the altered sialic acids on our red blood cells ( Science , 24 September 2010, p. 1586). But in the next million years or so, that mutation became a liability, as Neu5Ac became a portal for a flurry of other pathogens. At the infectious disease symposium organized by UCSD's Center for Academic Research and Training in Anthropogeny, researchers described how multiple diseases evolved to use Neu5Ac to enter cells or to evade immune cells. Coronaviruses appear to be no exception. “Most coronaviruses infect cells in two steps—first by recognizing abundant sialic acids as binding sites to gain a foothold, and then seeking out the higher affinity protein receptors like ACE2,” Ajit Varki says. “Think of it like an initial handshake or introduction that is required before one can ask for a date.” Two preprints suggest the novel coronavirus, SARS-CoV-2, also docks with sialic acids before binding with the ACE2 receptor to pierce human cells. In past studies, Ajit Varki and Gagneux suggested the makeover of the cell and the loss of Neu5Gc may have even contributed to the origin of a new species in our genus Homo . If a woman with only Neu5Ac sialic acids mated with a man who still expressed Neu5Gc, her immune system may have rejected that man's sperm or the fetus that developed from it. This fertility barrier might have helped divide Homo populations into different species more than 2 million years ago, the researchers speculated. But the sialic acid change also sparked a new arms race between pathogens and our ancestors. In the new study, the researchers scanned DNA for immune genes in six Neanderthals, two Denisovans, and 1000 humans, and looked at dozens of chimps, bonobos, gorillas, and orangutans as well. They found evolutionary changes that “markedly altered” one class of proteins—sialic acid-binding immunoglobulin-type lectins, or Siglecs—that usually sit on the surface of human immune cells and recognize sialic acids. ![Figure][2] Battle at the cell surface Some pathogens use sialic acids, which sit on the outer edge of the cell membrane, to invade a cell. Pathogens sometimes coat themselves in humanlike sialic acids to trick signaling molecules called sialic acid-binding immunoglobulin-type lectins (Siglecs) into inhibiting immune responses. But other Siglecs can instead turn on an immune response if they sense sialic acids on pathogens. GRAPHIC: PASCAL GAGNEUX/UCSD, ADAPTED BY N. DESAI/ SCIENCE Siglecs are molecular sentries: They probe sialic acids to see whether they are familiar parts of our own bodies or foreign invaders. If Siglecs spot sialic acids that are damaged or missing, they signal immune cells to activate, rousing an inflammatory army to attack potential invaders or clean up damaged cells. If sialic acids instead appear to be normal parts of our own cells, other, inhibitory Siglecs throttle back immune defenses so as not to attack our own tissues (see graphic, below). The researchers identified functional changes in the DNA of eight out of 13 Siglecs encoded by genes on chromosome 19 in humans, Neanderthals, and Denisovans. This hot spot of evolution appears only in Siglec gene variants, not in nearby genes on the chromosome, suggesting natural selection favored these changes, presumably because they helped fight pathogens that target Neu5Ac. Apes did not show these changes, says first author Naazneen Khan, an evolutionary biologist now at the University of Kentucky. Given the mutations' presence in archaic hominins, this burst of evolution must have happened before our lineages diverged 600,000 years ago, but after the mutation in that altered sialic acid arose more than 2 million years ago, perhaps in Homo erectus , thought to be an ancestor of modern humans and Neanderthals. Most Siglecs are found on immune cells, but in the new paper, the team reports that several of the human Siglecs that underwent evolutionary changes are expressed in other types of human cells, including some in the placenta, cervix, pancreas, gut, and brain. Siglec changes may have been a side effect of intense battles with pathogens that infected these tissues, Nissi Varki suggests. Although the recently mutated Siglecs protect us from pathogens, they may also contribute to other diseases. Some of the genetically changed Siglecs are associated with inflammation and autoimmune disorders such as asthma and with meningitis. The researchers suggest the altered Siglecs are constantly on high alert and do not dampen immune responses against our own tissues; they may even make some individuals more prone to the runaway inflammation seen in severe COVID-19. Other researchers say the work underscores broad evolutionary principles. “This nicely shows that … natural selection is not always going for the optimal solution, because the optimal solution is changing all the time,” says Rita Gerardy-Schahn, a glycobiologist at Hannover Medical School in Germany, who was not part of the new work. “What is best for natural selection in the short run may be the wrong selection tomorrow.” [1]: http://www.sciencemag.org/content/281/5382/1432 [2]: pending:yes


News at a glance

Science

SCI COMMUN### Conservation A company seeking to build a controversial gold and copper mine in Alaska won a major victory on 24 July when the U.S. Army Corps of Engineers issued an environmental analysis saying the mine wouldn't endanger the world's most productive sockeye salmon fishery. The decision clears the way for the Corps to issue permits needed by promoters of the Pebble Mine, located at the headwaters of two major watersheds that form part of the Bristol Bay salmon runs, just north of the Aleutian Islands. Environmental and Native Alaskan groups and some salmon scientists blasted the new study, saying it understated risks by focusing on the mine's small, initial footprint over 20 years of mining rather than its potential impacts if it expands to become one of the world's largest gold and copper mines, as its promoters hope. Mine backers have said such an expansion would get a closer environmental review later if they pursue it. Scientists have raised concerns that even the smaller mine could have wide impacts, because the resilience of the salmon runs hinges on access to a wide variety of spawning habitats. Environmental groups have vowed to file lawsuits to block the project. 90% —Accuracy of a new artificial intelligence system trained to identify individual weaver birds, which human birders generally cannot tell apart unless they are tagged ( Methods in Ecology and Evolution ). ### Planetary science China's first independent mission to Mars blasted off from the Xichang Satellite Launch Center on 23 July. To arrive in February 2021, Tianwen-1, a “quest for heavenly truth,” comprises an orbiter, lander, and rover. Only the United States and the Soviet Union have successfully landed on Mars. Instruments on the three Tianwen-1 craft will study the planet's magnetic field and atmosphere, map its surface, and characterize its geology. Tianwen-1 is the second in a trio of fresh martian missions: The United Arab Emirates launched its Hope orbiter on 19 July, and NASA planned to launch its Perseverance rover as early as 30 July, after Science went to press. ### Funding A bill in France would increase research spending over the next 10 years and add tenure-track faculty positions, a novelty in France. But critics say the plan's increases would be too small and slow. By 2030, the annual public research budget would rise by about one-third, to €20 billion, toward a goal of lifting overall R&D spending from 2.2% of gross domestic product to 3%. The National Research Agency, which funds researchers through competitive calls, would get €1 billion more over 7 years, reaching about €1.7 billion in 2027, to help raise its grant success rates from 16% to a target of 30%. The new, nonpermanent tenure-track positions would complement the permanent entry-level research positions traditionally offered by the French system, but critics fear the growth may lead to a decline in the permanent ones. Parliament is expected to approve the bill. ### Drug trials A monoclonal antibody given to babies has strongly protected them from severe disease caused by respiratory syncytial virus (RSV), a leading cause of infant death. As reported this week in The New England Journal of Medicine , a placebo-controlled study of nearly 1500 babies born preterm—who are at higher risk of severe symptoms of RSV—in 23 countries found that a single injection of the antibody before RSV season starts in the fall led to 78.4% fewer hospitalizations for lower respiratory infections associated with the disease. The antibody, being developed by AstraZeneca and Sanofi Pasteur, could replace one now on the market that is rarely used. (It is recommended only for infants at highest risk, requires five shots, and is very expensive.) The companies plan to seek regulatory approval of the new prophylaxis if larger studies now underway in preterm and full-term infants confirm that it is safe and effective. ### Graduate studies The American Astronomical Society last week launched the Astronomy Genealogy Project, which maps 5000 astronomers to their academic “descendants”—the 28,000 doctorate recipients they supervised. The discipline's family tree, at astrogen.aas.org, stretches back to 1766, but half of the listed doctorates were awarded since 2002. Organizers hope the data will help historians and sociologists of science analyze patterns across countries, universities, and subfields. U.S. universities awarded slightly more than half of the doctorates listed, and about two-thirds of the theses are online. ### Climate Environmental groups last week denounced as weak a plan announced by the U.S. Environmental Protection Agency (EPA) to limit greenhouse gas emissions from aircraft. The new standard would match an existing one adopted in 2016 by a U.N. body, the International Civil Aviation Organization (ICAO), that required emissions cuts by 2028. But recently manufactured planes already meet the standard, and EPA conceded its new rule would not reduce overall airplane emissions. Manufacturers have supported such a U.S. regulation to help them meet ICAO certification requirements. IACO has predicted that even under its standard, airplane emissions will grow by at least 3% a year globally. U.S. aviation accounts for 3% of the country's greenhouse gas emissions. ### Extreme life Bacteria from seafloor sediments buried 101 million years ago have been grown in the lab, raising the possibility they are as old as their muddy home. They had somehow survived in an area of the Pacific Ocean almost devoid of organic matter or other nutrients most bacteria need, although the sediments recovered do contain oxygen, the researchers report in Nature Communications . The finding pushes back the documented age of bacteria living in marine sediment from 15 million years and provides new insights on the limits of life under extreme conditions. A team led by researchers from the Japan Agency for Marine-Earth Science and Technology harvested the microbes from core samples drilled up to 5700 meters below sea level and took precautions against contaminating them with modern bacteria. The group argues the microbes likely didn't have enough food to keep replicating, and instead may have survived for eons without dividing by repairing age-related cellular damage. The microbes identified are known members of more than eight bacterial groups, many of which are commonly found elsewhere on Earth. ### Biotechnology Scientists announced last week that they used CRISPR gene editing to modify a cow embryo so that the resulting calf, named Cosmo, should produce more offspring bearing male traits. Bulls are 15% more efficient than cows at converting feed into weight gain, so the new method may allow cattle farmers to raise fewer cattle, benefiting the environment, say the researchers at the University of California, Davis. The researchers inserted a gene called SRY , which initiates male development and is normally found on the male sex chromosome, into an embryo's chromosome 17. Next, the researchers plan to determine whether Cosmo's offspring that inherit the SRY gene look and grow like males. Fifty percent of the calf's progeny will naturally be male; another 25% will be genetically female but will carry the SRY gene. ### Conservation Florida's governor this month signed a bill to establish a 162,000-hectare marine sanctuary in the Gulf of Mexico and protect one of the state's last remaining stretches of seagrass. Florida's coast boasts the most continuous expanse of seagrass beds in the United States, but these diverse habitats, home to blue crabs and manatees, have been damaged by nutrient-driven algal blooms and boat propellers. Authorities plan to create a management plan for the new Nature Coast Aquatic Preserve to balance protection with ecotourism, boating, and fishing. ### A magic ride for science In 1984, artist Bruce Degen met writer Joanna Cole at a publisher's office in New York City to discuss creating a children's book about science. They went on to collaborate and publish 13 colorful, zany books in The Magic School Bus series, featuring the ebullient, intrepid teacher Ms. Frizzle (above, right), who takes her students on fantastic adventures into the ocean, across the Solar System, and through the human body, for example. Cole died on 12 July at age 75. But the series continues to teach young readers and their parents about the natural world. > Q: Did you expect to create such a legacy? > A: I was in art school doing very serious art, and I realized that, in my heart of hearts, I wanted to do children's books. In the beginning, it was darn hard work. Some book sketch dummies have five layers of rewrites and reillustrations. The first book was a one-book contract to see if this would work. [The reception] was like the world was waiting for somebody to make this happen. People say, “[As a child,] I [used to] read these books, now I read them to my kids!” I could never have imagined it. > Q: Does scientific accuracy get in the way of storytelling? > A: Frequently. You have to tell kids what is true, but you can't give them all the truth—it's too much. For example, the evolution book goes from now [back] to the beginning of the Earth. I [initially] tried to show every era, year, and life form. It was too complicated. So it ended up as a nice, open spiral with a few representations of each era. > Q: Why use the format of adventures? > A: By following the story, it gave kids a mental filing system—they could retrieve and remember information because it was given to them in a memorable trip. ### Dispatches from the pandemic Read additional Science coverage of the pandemic at [sciencemag.org/tags/coronavirus][1]. #### U.S. vaccine efficacy trials begin The first large-scale efficacy trials of COVID-19 vaccines in the United States began last week. On 27 July, the National Institutes of Health, working with Moderna, announced the start of one that aims to recruit 30,000 people. Later that day, a partnership between Pfizer and BioNTech announced separately it was launching a similarly sized study at sites in the United States and elsewhere. Both the Moderna and the Pfizer/BioNTech vaccines contain messenger RNA that prompts cells to make a protein that studs the surface of the COVID-19 virus. If the vaccines work, this viral protein will safely teach the immune system how to battle the virus if a person later is exposed to it. Operation Warp Speed, the Trump administration's push to accelerate development of a COVID-19 vaccine, has committed nearly $3 billion to these two R&D projects, about half its total investment. Other efficacy trials of various COVID-19 vaccines have begun in Brazil, the United Arab Emirates, and the United Kingdom. Results are expected in late fall at the earliest. #### CDC slammed over school rules Guidance issued by the U.S. Centers for Disease Control and Prevention (CDC) last week for safely reopening schools downplays risks that teachers, other staff members, and students will spread or contract COVID-19, many public health specialists say. Provoking claims that CDC's advice had been politicized, the agency revised an earlier draft that President Donald Trump had panned as “very tough and expensive.” The nonbinding recommendations, released 23 July, emphasize the social and developmental benefits of in-person schooling and highlight that young children are at low risk for contracting the disease and transmitting the virus that causes it. The document also recommends against screening students for symptoms. Nevertheless, the Trump administration did advise communities with high infection rates to consider not beginning in-person classes. Large school districts, such as those in Atlanta, Houston, Los Angeles, and San Diego, have already announced that they will begin the 2020–21 school year with online instruction only. #### Anti-Fauci TV segment canceled Following heavy criticism from scientists and others, Sinclair Broadcast Corp. this week canceled plans for its chain of local TV stations to air a segment featuring widely challenged accusations that Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, intentionally created the virus responsible for COVID-19 and sent it to China. Fauci has helped lead the U.S. effort to control the pandemic despite tangling with President Donald Trump. The allegation came from Judy Mikovits, a virologist and antivaccine activist who appears in a documentary about the coronavirus that was also widely debunked as false and misleading (). The Sinclair segment, a new interview with Mikovits, was available online until the company pulled it for review on 25 July, after Media Matters reported its existence. Sinclair announced on 27 July that it would not air the segment on the nearly 200 TV stations it owns or operates in 89 U.S. markets—but not before one in Charleston, West Virginia, had broadcast it. [1]: http://sciencemag.org/tags/coronavirus


Coronavirus pandemic has sparked interest in online swinging, dating app data shows

FOX News

The number of messages sent per user in New York City between April and June was three times that of San Diego, the app reported. The coronavirus pandemic has sparked a surge in online swingers across the country -- with New York City topping the list, according to a report. Threesome dating app "3Fun" reported a steady uptick in the number of messages sent between its 721,927 active users since lockdowns began in March. "Social distancing makes offline meetings tough … That means most open-minded people are trying to meet new friends online during the pandemic," spokeswoman Jennifer White said in a statement. Dating app "3Fun" reported a steady uptick in the number of messages sent between its 721,927 active users since lockdowns began in March.


Using AI to identify the aggressiveness of prostate cancer

#artificialintelligence

These promising results indicate that the deep learning system has the potential to support expert-level diagnoses and expand access to high-quality cancer care. To evaluate if it could improve the accuracy and consistency of prostate cancer diagnoses, this technology needs to be validated as an assistive tool in further clinical studies and on larger and more diverse patient groups. However, we believe that AI-based tools could help pathologists in their work, particularly in situations where specialist expertise is limited. Our research advancements in both prostate and breast cancer were the result of collaborations with the Naval Medical Center San Diego and support from Verily. Our appreciation also goes to several institutions that provided access to de-identified data, and many pathologists who provided advice or reviewed prostate cancer samples.


Google claims its AI system can grade prostate cancer samples with 72% accuracy

#artificialintelligence

In a study published today in the journal JAMA Oncology, Google researchers claim to have developed an AI system that accurately identifies signs of prostate cancer in biopsies. Building on an algorithm that grades large, surgically removed cancerous segments of prostates, they say their system -- which was developed with support from the Naval Medical Center in San Diego and Verily, Alphabet's life sciences division -- works on the smaller samples extracted during the initial part of cancer care to get diagnoses and prognoses. Prostate cancer biopsies are commonly taken to better evaluate tumors' aggressiveness. The Gleason score, a grading system that classifies cancer cells based on how closely they resemble normal prostate gland tissue, is used to detect problematic masses. But determining which of three Gleason patterns a tumor falls into and assigning a grade based on the relative amounts of pattern in the whole sample is a challenging task -- one that relies on subjective visual inspection and experience.


AIhub coffee corner – the future of conferences

AIHub

This month we discuss conferences and whether they will ever be the same again now we've had a taste of the virtual. Joining the discussion this week are: Kamalika Chaudhuri (University of California, San Diego), Tom Dietterich (Oregon State University), Sabine Hauert (University of Bristol), Carles Sierra (CSIC). Carles Sierra: I think we will see more and more of these virtual conferences. We could probably work as well as we did when meeting physically, although some aspects will be different. Sabine Hauert: Last week I gave three talks, at three separate conferences, and never had to leave the home, which is really great for work-life balance and childcare responsibilities.


Experimental Blood Test Detects Cancer up to Four Years before Symptoms Appear

#artificialintelligence

For years scientists have sought to create the ultimate cancer-screening test--one that can reliably detect a malignancy early, before tumor cells spread and when treatments are more effective. A new method reported today in Nature Communications brings researchers a step closer to that goal. By using a blood test, the international team was able to diagnose cancer long before symptoms appeared in nearly all the people it tested who went on to develop cancer. "What we showed is: up to four years before these people walk into the hospital, there are already signatures in their blood that show they have cancer," says Kun Zhang, a bioengineer at the University of California, San Diego, and a co-author of the study. "That's never been done before."


Arrow Electronics and Taoglas Join Forces to Boost IoT and AI Initiatives – Tech Check News

#artificialintelligence

SAN DIEGO–( BUSINESS WIRE)–Taoglas, a leading enabler of digital transformation using IoT, today announced their collaboration with Arrow Electronics. This includes a new global distribution agreement focused on AI and IoT products and services. Taoglas will use Arrow's sales and services organization to expand their customer base, grow ecosystem partnerships, and improve supply chain services. Taoglas and @ArrowGlobal announce new global distribution agreement for Taoglas leading portfolio of #IoT solutions, #antenna and #RF design services and products. Tweet this "Our customers need both products and services to support […]


Artificial Intelligence Allows Rapid COVID-19 Lung Imaging Analysis – IAM Network

#artificialintelligence

July 16, 2020 – UC San Diego recently announced that its health radiologists and other physicians are now leveraging artificial intelligence (AI) to augment lung-imaging analysis in a clinical research study aimed at COVID-19 lung imaging analysis. The cause of death for most COVID-19 patients is pneumonia, which often requires long hospital stays in intensive care units and assistance breathing with ventilators. Last year, Albert Hsiao, MD, PhD, associate professor of radiology at University of California San Diego School of Medicine and radiologists at UC San Diego Health, and his team, developed a machine learning algorithm that allowed radiologists to use AI to enhance their own abilities to spot pneumonia on chest X-rays. The algorithm was trained with 22,000 notations by radiologists and overlays X-rays with color-coded maps that indicate pneumonia probability, researchers explained. "Pneumonia can be subtle, especially if it's not your average bacterial pneumonia, and if we could identify those patients early, before you can even detect it with a stethoscope, we might be better positioned to treat those at highest risk for severe disease and death," Hsiao said.


NASA to Use Machine Learning to Enhance Search for Alien Life on Mars – IAM Network

#artificialintelligence

Phil Duffy, is the VP of Product, Program & UX Design at Brain Corp a San Diego-based technology company specializing in the development of intelligent, autonomous navigation systems for everyday machines.The company was co-founded in 2009 by world-renowned computational neuroscientist, Dr. Eugene Izhikevich, and serial tech entrepreneur, Dr. Allen Gruber. The company is now focused on developing advanced machine learning and computer vision systems for the next generation of self-driving robots.Brain Corp powers the largest fleet of autonomous mobile robots (AMRs) with over 10,000 robots deployed or enabled worldwide and works with several Fortune 500 customers like Walmart and Kroger.What attracted you initially to the field of robotics?My personal interest in developing robots over the last two decades stems from the fact that intelligent robots are one of the two major unfulfilled dreams of the last century--the other dream being flying cars.Scientists, science-fiction writers, and filmmakers all predicted we would have intelligent robots doing our bidding and helping us in our daily lives a long time ago.