For the first time in the United States, researchers have used gene editing to repair a mutation in human embryos.

Molecular scissors known as CRISPR/Cas9 corrected a gene defect that can lead to heart failure. The gene editor fixed the mutation in about 72 percent of tested embryos, researchers report August 2 in Nature. That repair rate is much higher than expected. Work with skin cells reprogrammed to mimic embryos had suggested the mutation would be repaired in fewer than 30 percent of cells.
In addition, the researchers discovered a technical advance that may limit the production of patchwork embryos that aren’t fully edited. That’s important if CRISPR/Cas9 will ever be used to prevent genetic diseases, says study coauthor Shoukhrat Mitalipov, a reproductive and developmental biologist at Oregon Health & Science University in Portland. If even one cell in an early embryo is unedited, “that’s going to screw up the whole process,” says Mitalipov. He worked with colleagues in Oregon, California, Korea and China to develop the embryo-editing methods.

Researchers in other countries have edited human embryos to learn more about early human development or to answer other basic research questions (SN: 4/15/17, p. 16). But Mitalipov and colleagues explicitly conducted the experiments to improve the safety and efficiency of gene editing for eventual clinical trials, which would involve implanting edited embryos into women’s uteruses to establish pregnancy.
In the United States, such clinical trials are effectively banned by a rule that prevents the Food and Drug Administration from reviewing applications for any procedure that would introduce heritable changes in human embryos. Such tinkering with embryo DNA, called germline editing, is controversial because of fears that the technology will be used to create so-called designer babies.

“This paper is not announcing the dawn of the designer baby era,” says R. Alta Charo, a lawyer and bioethicist at the University of Wisconsin Law School in Madison. The researchers have not attempted to add any new genes or change traits, only to correct a disease-causing version of a gene.

In the study, sperm from a man who carries a mutation in the MYBPC3 gene was injected into eggs from women with healthy copies of that gene. Carrying just one mutant copy of the gene causes an inherited heart problem called hypertrophic cardiomyopathy (SN: 9/17/16, p. 8). That condition, which strikes about one in every 500 people worldwide, can cause sudden heart failure. Mutations in the MYBPC3 gene are responsible for about 40 percent of cases. Doctors can treat symptoms of the condition, but there is no cure.

Along with the man’s sperm, researchers injected into the egg the DNA-cutting enzyme Cas9 and a piece of RNA to direct the enzyme to snip the mutant copy of the gene. Another piece of DNA was also injected into the egg. That hunk of DNA was supposed to be a template that the fertilized egg could use to repair the breach made by Cas9. Instead, embryos used the mother’s healthy copy of the gene to repair the cut.

Embryos’ self-healing DNA came as a surprise, because gene editing in other types of cells usually requires an external template, Mitalipov says. The discovery could mean that it will be difficult for researchers to fix mutations in embryos if neither parent has a healthy copy of the gene. But the finding could be good news for those concerned about designer babies, because embryos may reject attempts to add new traits.

Timing the addition of CRISPR/Cas9 is important, the researchers also discovered. In their first experiments, the team added the gene editor a day after fertilizing the eggs. Of 54 injected embryos, 13 were patchwork, or mosaic, embryos with some repaired and some unrepaired cells. Such mosaic embryos probably arise when the fertilized egg copies its DNA before researchers add Cas9, Mitalipov says.

Injecting Cas9 along with the sperm — before an egg had a chance to replicate its DNA — produced only one patchwork embryo. That embryo had repaired the mutation in all its cells, but some cells used the mother’s DNA for repair while others used the template supplied by the researchers.

None of the tested embryos showed any signs that Cas9 was cutting where it shouldn’t be. “Off-target” cutting has been a safety concern with the gene editor because of the possibility of creating new DNA errors.

The study makes progress toward using gene editing to prevent genetic diseases, but there’s still has a long way to go before clinical testing can begin, says Janet Rossant, a developmental biologist at the Hospital for Sick Children and the University of Toronto. “We need to be sure this can be done reproducibly and effectively.”

I heard it for the first time a few days ago: “She’s copying me!” my 4-year-old wailed in a righteous complaint about her little sister. And she most certainly was copying, repeating the same nonsense word over and over. While it was distressing to my older kid, I thought it was funny that it took her so long to realize her sister copies almost everything she does.

This egregious violation occurred just after I had read about an experiment that pitted young kids against bonobos in a test to see who might copy other individuals more. I’ll get right to the punch line: Kids won, by a long shot. The results, published online July 24 in Child Development, show that despite imitation annoying older siblings everywhere, it’s actually really important.

“Imitation is one of the most essential skills for being human,” says study coauthor Zanna Clay, a comparative psychologist at the University of Birmingham and Durham University, both in England. Learning how to talk, operating the latest iPhone and figuring out how to buy bulk goods at the local co-op — these skills all rely on imitation. Not only that, but imitation is also important for cementing social relationships. My daughter notwithstanding, “Humans like to be imitated, and we like those who imitate us,” Clay says.
Clay and her colleague Claudio Tennie tested just how strong the urge to imitate is in 77 children ages 3 to 5 and a group of 46 bonobos ages 3 to 29. In one-on-one trials, the researchers sat next to the kids and bonobos with a small wooden box about the size of a hand. Inside was a treat: a sticker for the kids and a bit of apple for the bonobos.

Before opening the box, the researcher performed nonsensical actions over it, either rubbing the box with the back of the hand and doing a wrist twist in the air or tracing a cross into the top of the box and then tracing the edges.

These hand motions were totally irrelevant to the actual opening of the box. Nonetheless, after seeing the gestures, the vast majority of the kids made the same motions before trying to open their own box. Not a single bonobo, though, copied the irrelevant actions.
What the bonobos did — not copying the meaningless gestures — “is the rational thing to do,” says Clay. “Yet the irrational thing that the kids did is part of the reason why human cultures have evolved so rapidly and so diversely.”

Such excessive imitation, called overimitation, is a special form of copying in which people perform actions that clearly serve no purpose. It may be behind rituals, social norms and language that keep our societies running smoothly.

And it may be unique to humans: Other studies have failed to spot overimitation among chimpanzees and orangutans. These findings hint that our powerful urge to imitate even nonsensical gestures may be one of the things that separate humans from other apes.

A growing band of digital characters that converse, read faces and track body language is helping humans to communicate better with one another. While virtual helpers that perform practical tasks, such as dealing with customer service issues, are becoming ubiquitous, computer scientist M. Ehsan Hoque is at the forefront of a more emotionally savvy movement. He and his team at the University of Rochester in New York create software for digital agents that recognize when a person is succeeding or failing in specific types of social interactions. Data from face-to-face conversations and feedback from professional counselors and interviewers with relevant expertise inform this breed of computer advisers.

One of Hoque’s digital helpers grooms people to be better public speakers. With words on a screen, this attentive app notes, for example, how many times in a practice talk a person says “um,” gestures inappropriately or awkwardly shifts vocal tone. With the help of Google Glass, the app even offers useful reminders during actual speeches. Another computerized helper, this one in the form of an avatar, helps people hone their job interviewing skills, flagging long-winded responses or inconsistent eye contact in practice interviews. In the works are computerized conversation coaches that can improve speech and communication skills among people with developmental conditions such as autism and mediate business meetings in ways that encourage everyone to participate in decision making.

“There has been some progress in artificial intelligence, but not much in developing emotional aspects of AI,” Hoque says. “We’re just cracking through the surface at this point.”
The U.S. Department of Defense and the U.S. Army have taken notice. With their financial support, Hoque is developing avatars that collaborate with humans to solve complex problems, and digital observers that monitor body language to detect when people are lying.
This is heady stuff for a 35-year-old who earned a doctoral degree just four years ago. Hoque, who was born in Bangladesh and immigrated to the United States as a teenager, did his graduate work with the MIT Media Lab’s Affective Computing research group. The group’s director, Rosalind Picard, helped launch the field of “affective computing” in the 1990s, which focuses on the study and development of computers and robots that recognize, interpret and simulate human emotions.

Hoque’s approach puts a service spin on affective computing. As a grad student, he developed software he dubbed MACH, short for My Automated Conversation coacH. This system simulates face-to-face conversations with a computer-generated, 3-D man or woman that sees, hears and makes decisions while conversing with a real-life partner. Digital analyses of a human partner’s speech and nonverbal behavior inform the avatar’s responses during a session. A simulated coach may, for instance, let a user know if smiles during an interview look forced or are mistimed. After a session, users see a video of the interaction accompanied by displays of how well or poorly they did on various interaction skills, such as keeping eye contact and nodding at appropriate times.

MACH got its start in trials that trained MIT undergraduates how to conduct themselves during interviews with career counselors. First, Hoque analyzed smiles and other behaviors that either helped or hurt the impressions job candidates left on experienced counselors in mock interviews. In a series of follow-up studies, his team developed an automated system that recognized impression-enhancing behaviors during simulated interviews. That pilot version of MACH was then put to the test. Women, but not men, who received MACH training and got feedback from their digital coach while watching videos of their initial interviews with a counselor displayed substantial improvement in follow-up interviews. MACH trainees who watched interview videos but got no feedback showed minimal improvement. Testing with larger groups of men and women is under way.
As he developed MACH, Hoque consulted MIT sociologist and clinical psychologist Sherry Turkle. That was a bold move, since Turkle has warned for 30 years that, despite its pluses, digital culture discourages person-to-person connections. Social robots, in particular, represent a way for people to escape the challenges of forging authentic relationships, Turkle contends.

But she came away impressed with Hoque, whose goals she calls refreshingly modest and transparent. “His avatars will be helpers and facilitators,” she says, “not companions, friends, therapists and pretend people.”

Hoque’s approach grew out of personal experience. He is the primary caregiver for his 16-year-old brother, Eshteher, who has Down syndrome and does not speak. Eshteher can make sounds to refer to certain things, such as food, and has limited use of sign language. “I’ve spent a lot of time with him and can read what he’s experiencing, like when he’s frustrated or repentant,” Hoque says.
So it’s not surprising that Hoque’s next-generation MACH, dubbed LISSA for Live Interactive Social Skill Assistance, is an avatar that conducts flexible, “getting acquainted” conversations while providing feedback on users’ eye contact, speaking volume, smiling and body movements via flashing icons.

LISSA has shown promise in preliminary tests aimed at improving the conversational chops of college students attending speed-dating sessions and individuals with autism spectrum disorders. Hoque plans to expand this technology for use with people suffering from social phobia and post-traumatic stress disorder. He’s also working on an avatar that trains doctors to communicate clearly and compassionately with patients being treated for life-threatening cancers.

Hoque’s work on emotionally perceptive avatars may eventually transform the young industry of digital assistants, currently limited to voices-in-a-box such as Apple’s Siri and Microsoft’s Cortana, says cognitive scientist Mary Czerwinski, a principal researcher at Microsoft Research Lab in Redmond, Wash. Avatar research “could lead to more natural, personable digital assistants,” Czerwinski predicts. Hoque agrees.

“In the future, we’ll all have digital, personalized assistants,” he says. If he gets his way, emotionally attuned helpers will make us more social and less isolated. That’s something to applaud — if we can manage to put down our smartphones.

One of the planet’s deadliest viruses makes an annual pass through the United States with little fanfare. It rarely generates flashy headlines or news footage of health workers in hazmat suits. There’s no sudden panic when a sick person shows up coughing and feverish in an emergency room. Yet before next spring, this season’s lethal germ will probably have infected millions of Americans, killing tens of thousands. Still, it’s often referred to as just the flu.

The influenza virus seems so normal to most Americans that only about half of us will heed those “time for your flu shot” banners that pop up at pharmacies and worksites every autumn. Those annual shots remain the best means of protection, but they must be manufactured months before flu season starts, based on a best educated guess of what strains of the virus will be circulating. That means even in a successful year, vaccine performance may not be impressive. During the 2015–2016 season, only about half of those immunized were protected, according to a study in the Aug. 10 New England Journal of Medicine. Some years’ vaccines are duds: For the 2014–2015 season, the vaccine protected only 19 percent of people who received it, based on U.S. Centers for Disease Control and Prevention data.
Scientists have long worked to develop a flu shot that works better and lasts longer. But, unlike the very stable measles virus, influenza is a moving target. While only a few strains of flu virus circulate worldwide in a typical year, dozens more may exist. Each one is highly likely to mutate from year to year, with just enough shape-shifting to be unrecognizable to the body’s defenses.

Now, after years of searching, scientists believe they have better strategies to attack the parts of the virus that stay the same from year to year, offering the hope of protection across multiple seasons. The vaccines being developed in laboratories around the world “offer more promise than we’ve ever had,” says Walter Orenstein, associate director of the Emory Vaccine Center in Atlanta. And there are new creative approaches: One research group is trying to make a kind of super shot by anticipating every possible mutation a circulating virus might undergo.

“I’m optimistic we are going to get to a vaccine,” says Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, or NIAID, in Bethesda, Md. Then, you may need to heed those “time for your flu shot” messages only once.
Researchers often describe the flu virus as looking like a ball with lollipops sticking out. Tucked inside the ball is RNA, which the virus needs to make copies of itself. The lollipops on the outside are proteins: hemagglutinin and neuraminidase. There are 18 different kinds of hemagglutinin and 11 kinds of neuraminidase. Each kind of flu virus is named for its particular combination of these proteins; the current forms circulating around the world are H1N1 and H3N2. Hemagglutinin attaches to human cells to launch an infection; neuraminidase is more important for spreading the virus once infection has occurred.

Flu viruses involved in human epidemics are divided into types A and B, and A viruses are sliced even further into group 1 and group 2. Influenza A, the most troublesome for vaccine scientists, travels the world among birds, pigs and humans. The bird and pig versions don’t easily infect people, but the virus is constantly mutating and even swapping genes with other influenza viruses it meets along the way. Sometimes these genetic changes create a version that allows a bird or pig flu to move directly into humans. In 2013, one called H7N9 moved into people in China (SN Online: 3/11/15). The virus has since infected more than 1,500 people. Mostly, though, the genetic changes are more subtle, with just enough alterations to evade the human immune system.
Like kids with a sweet tooth, the immune system gets most excited about the top part of the hemagglutinin lollipop, and makes antibodies against it. The top is, after all, the first thing the immune system notices once the virus slips inside the nose, mouth and lungs. Every year, genetic mutations in the virus slightly change the chemical flavor of the lollipop, making it more sweet or sour than last season’s — just different enough so the immune system doesn’t recognize it. That’s why most years there’s a new flu shot.

Sometimes, in the gene shuffling with viruses in birds and pigs, the changes are so great that the flavor changes completely. Those are pandemic years, when there is so little residual immunity that a large portion of the global population falls ill from the new virus. The devastating 1918 flu, which killed an estimated 50 million people globally, was caused by such a drastic genetic shift (SN Online: 4/29/14). The most recent pandemic occurred in 2009, with the appearance of the “swine flu,” so named because the virus was first found in pigs. By one analysis, it caused between 148,000 and 249,000 deaths around the world.

Attack the stem
The 2009 disaster helped provide a blueprint for some of the latest experimental vaccines. Researchers noticed that when people with swine flu developed antibodies to the virus, those antibodies did something odd: They favored the hemagglutinin stem — the stick of the lollipop. And, more important, they appeared to react broadly against two kinds of flu virus. Scientists had known that the hemagglutinin stem, or stalk, isn’t as apt to change as the lollipop top, which theoretically makes the stem a good target for a universal vaccine. But in a usual flu season, the human body isn’t inclined to make infection-fighting antibodies against the stem.

“Unfortunately, the immune system preferentially recognizes the head, and we don’t know why it does that,” says Adrian McDermott, an immunologist at NIAID. So after infection, the biggest share of antibodies flocks to the hemagglutinin head. (Neuraminidase, the bigger player in disease after infection, is a target for influenza treatments but not a major focus for vaccine development.)

But in a study reported in the Journal of Experimental Medicine in 2011, a team of scientists from Emory and elsewhere found that antibodies to the so-called swine flu behaved unexpectedly. “If you have a head that the immune system hasn’t seen, you potentially redirect to a stalk response,” McDermott says. “That was an aha! moment.”
Researchers investigated further. For one study in 2012 in Frontiers in Immunology, scientists from Canada injected these stem-recognizing antibodies into mice to see if the mice were shielded from a different strain of flu. Not only were the mice protected from lethal doses of flu virus, but the protection was also in large part due to the absence of familiar antibodies against the head, the researchers found. Without the distraction of a head it recognized, the immune system seemed to rally against the stem.

Then came the what ifs: What if a vaccine produced just antibodies to the stem? Would that be enough protection? For the last few years, McDermott and others have been trying to develop vaccines made of “headless stalks” — just the sticks of the lollipops. With no head in place to hoard the immune response, the vaccine might coax the body to make enough stem-focused antibodies to protect against flu, the researchers hoped, regardless of the seasonal mutations occurring at the top.

Several groups soon found that headless stalks are difficult to make. Without the top to stabilize it, the molecular assembly tended to break apart. Two teams working independently reported in 2015 their success in keeping the stalk in one piece. NIAID scientists and their partners held the stalks together by anchoring them to the protein ferritin, which can assemble itself into nanoparticles. In a study in Nature Medicine, the team reported that vaccinated mice and ferrets appeared to be protected from dying of the H5N1 bird flu after receiving the vaccine, even when they developed symptoms. Unvaccinated mice and ferrets died.

The second team, from the Janssen Center of Excellence for Immunoprophylaxis in Leiden, the Netherlands, and the Scripps Research Institute in La Jolla, Calif., glued the stalk together by creating a series of genetic mutations at its top. In Science, the researchers reported that the vaccine reduced the symptoms of flu in vaccinated monkeys.

“We realized that the stem has much less variability than the head, and then we developed the capability to use it for a possible vaccine,” says Fauci, commenting on both efforts. “These were two important things that came together.”

Despite progress, these stalk-focused vaccines haven’t yet been put to human tests that would show whether they could protect broadly against many mutations of flu circulating annually, which is the ultimate test. And some stalk-directed antibodies might be better than others. In July in Science Immunology, McDermott and colleagues reported that the stalk antibodies against group 2 of the A viruses appear to be more broadly effective than those against group 1 viruses.

Other researchers have stabilized the stalk by attaching a new hemagglutinin head — a lollipop flavor that the human immune system has never tasted. In this case, researchers from the Icahn School of Medicine at Mount Sinai in New York City took tops from two flu strains that circulate only in birds, and connected each one to a human hemagglutinin stalk. This experimental vaccine consists of two doses. The first dose prompts the immune system to make antibodies against the stalk with the first top, and a second dose produces a second round of antibodies against the stalk with the second top. The idea is that the abundance of stem-focused antibodies — amplified from the two shots of vaccine — will come to the rescue during a natural infection from a virus that possesses a third, totally different head.
“The human immune system will try to find something it has seen before,” says Peter Palese, chairman of microbiology at Mount Sinai. In theory, the only antibodies in play will be the ones responding to the parts of the stalk that the immune system recognizes, known as the “conserved domains.”

“The $64,000 question,” according to Palese: “Will the immune response to these conserved domains be enough to elicit a broad immune system reaction?”

In 2016, Palese and colleagues described a test of the vaccine in the Journal of Virology. Six ferrets given the two doses were housed with six ferrets infected with H1N1 flu. Within 10 days, the vaccinated animals had become infected but had no symptoms or signs of being able to easily spread virus to others. A report in June in the same journal described tests of the vaccine in mice against influenza B viruses; the animals were protected from normally lethal doses of flu.

What’s not known is whether the stem-focused antibodies are enough to protect people from all virus variants. The vaccine from the Mount Sinai researchers is entering the first human safety trials with drugmaker GlaxoSmithKline.

Unhide and seek
Another approach incorporates proteins that don’t tend to mutate like the hemagglutinin head but are hidden from the immune system under normal circumstances. When these proteins are made visible to types of white blood cells called T cells, the immune system wakes up. T cells don’t make antibodies, but certain T cells hold on to a memory of foreign molecules seen before. When these pre-programmed T cells recognize an infection, they destroy the invader.

This work began in the 1990s, when researchers at the Weizmann Institute of Science in Rehovot, Israel, set out to find parts of the virus that remain unchanged from year to year. The team identified stable regions in three proteins — hemagglutinin, plus one from the virus membrane and one from the virus core. In 2003, a company called BiondVax Pharmaceuticals formed to develop and test, in humans, an experimental vaccine that takes these proteins and packages them in a way that the immune system can recognize them.

So far, almost 700 volunteers have participated in six small trials, all of which showed signs of a lasting immune response among most volunteers. Writing in February in Vaccine, the researchers reported that the stored serum of elderly volunteers who received the vaccine in 2011 showed an immune response to new strains of flu that were circulating three years later. The company is starting larger trials to see if the vaccine can actually protect people from getting sick.
Out of many, one
Other experimental vaccines take a different approach. Rather than relying on precision to hit a narrow target, microbiologist Ted Ross and colleagues at the University of Georgia in Athens are attempting to cast a wide net. The researchers are taking hemagglutinin mutations from every flu strain that has ever circulated, dumping them into a kind of scientific blender and attaching them to particles that can form the basis of a vaccine.

“The question we asked is, how can we make a vaccine against a strain we don’t even know exists?” Ross says. The technique he uses is called COBRA for computationally optimized broadly reactive antigen. A computer compiles all seemingly possible genetic iterations of a particular flu type — in this case H1N1 — and then bundles them into one molecule. It’s kind of like taking every novel in your local library and combining them into one giant book.

Last year in the Journal of Virology, Ross and colleagues described a COBRA-derived vaccine that represented almost all forms of H1N1 that have been around for the last 100 years. The vaccine protected mice against infection from strains of H1N1 that the mice had never been exposed to. “We took a bunch of different hemagglutinins and mixed them into one hemagglutinin molecule,” Ross says. “It protected against any strain of H1N1 we could throw at it.”

The study caught the attention of vaccine maker Sanofi Pasteur, which plans to test the vaccine in clinical trials. Ross’ lab is now using the same strategy to develop a vaccine against H3N2 strains, the other dominant kind of flu circulating around the world. Same approach, different library.

Meanwhile, the virus isn’t waiting around. Based on the heavy flu season in the Southern Hemisphere, some experts are predicting this year’s epidemic could be severe. It’s still too early to know whether the current vaccine will provide good protection, but someday, a super shot may remove the guesswork altogether.

To craft a new color-switching material, scientists have again taken inspiration from one of nature’s masters of disguise: the chameleon.

Thin films made of heart cells and hydrogel change hues when the films shrink or stretch, much like chameleon skin. This material, described online March 28 in Science Robotics, could be used to test new medications or possibly to build camouflaging robots.

The material is made of a paper-thin hydrogel sheet engraved with nanocrystal patterns, topped with a layer of living heart muscle cells from rats. These cells contract and expand — just as they would inside an actual rat heart to make it beat — causing the underlying hydrogel to shrink and stretch too. That movement changes the way light bounces off the etched crystal, making the material reflect more blue light when it contracts and more red light when it’s relaxed.
This design is modeled after nanocrystals embedded in chameleon skin, which also reflect different colors of light when stretched (SN Online: 3/13/15).

When researchers treated the material with a drug normally used to boost heart rate, the films changed color more quickly — indicating the heart cells were pulsating more rapidly. That finding suggests the material could help drug developers monitor how heart cells react to new medications, says study coauthor Luoran Shang, a physicist at Southeast University in Nanjing, China. Or these kinds of films could also be used to make color-changing skins for soft robots, Shang says.

The center of the Milky Way may be abuzz with black holes. For the first time, a dozen small black holes have been spotted within the inner region of the galaxy in an area spanning just a few light-years — and there could be thousands more.

Astrophysicist Charles Hailey of Columbia University and his colleagues spotted the black holes thanks to the holes’ interactions with stars slowly spiraling inward, the team reports in Nature on April 4. Isolated black holes emit no light, but black holes stealing material from orbiting stars will heat that material until it emits X-rays.
In 12 years of telescope data from NASA’s orbiting Chandra X-ray Observatory, Hailey and colleagues found 12 objects emitting the right X-ray energy to be black holes with stellar companions. Based on theoretical predictions of how many black holes are paired with stars, there should be up to 20,000 invisible solo black holes just in that small part of the galaxy.
The discovery follows decades of astronomers searching for small black holes in the galactic center, where a supermassive black hole lives (SN: 3/4/17, p. 8). Theory predicted that the galaxy should contain millions or even 100 million black holes overall, with a glut of black holes piled up near the center (SN: 9/16/17, p. 7). But none had been found.
“It was always kind of a mystery,” Hailey says. “If there’s so many that are supposed to be jammed into the central parsec [about 3.26 light-years], why haven’t we seen any evidence?” Finding the 12 was “really hard,” he admits.

It’s unclear how the black holes got to the galaxy’s center. Gravity could have tugged them toward the supermassive black hole. Or a new theory from Columbia astronomer Aleksey Generozov suggests black holes could be born in a disk around the supermassive black hole.

The researchers ruled out other objects emitting X-rays, such as neutron stars and white dwarfs, but acknowledged that up to half of the sources they found could be fast-spinning stellar corpses called millisecond pulsars rather than black holes. That could add to the debate over whether a mysterious excess in gamma rays at the galactic center is from pulsars or dark matter (SN: 12/23/17, p. 12).

“The theorists are going to have to slug it out and figure out what’s going on,” Hailey says.

Every few years, a buzz fills the air in the southeastern United States as adolescent cicadas crawl out from the soil to molt and make babies. After a childhood spent sipping tree sap underground, some species emerge every 13 years, others every 17 years, rarely overlapping. Yet somehow in this giant cicada orgy, hybridization happens between species that should be out of sync.

Researchers have sought to explain how the two life cycle lengths developed. A new study published online April 19 in Communications Biology fails to pin the difference on genetics, but finds some interesting things along the way.
Cicadas fall into three species groups that diverged from one another about 3.9 million to 2.5 million years ago. Within each of those groups, species on a 13-year schedule diverged from 17-year-cycle cicadas about 200,000 to 100,000 years ago, the researchers from the United States and Japan report.

But the researchers also found that the 17-year and 13-year broods within each group share genetic code — evidence of hybridization. It’s possible that neighboring broods swapped DNA when their emergence overlapped — something that happens every 221 years — or if stragglers emerged early or late.

Everybody agrees that medical treatments should be based on sound evidence. Hardly anybody agrees on what sort of evidence counts as sound.

Sure, some people say the “gold standard” of medical evidence is the randomized controlled clinical trial. But such trials have their flaws, and translating their findings into sound real-world advice isn’t so straightforward. Besides, the best evidence rarely resides within any single study. Sound decisions come from considering the evidentiary database as a whole.
That’s why meta-analyses are also a popular candidate for best evidence. And in principle, meta-analyses make sense. By aggregating many studies and subjecting them to sophisticated statistical analysis, a meta-analysis can identify beneficial effects (or potential dangers) that escape detection in small studies. But those statistical techniques are justified only if all the studies done on the subject can be obtained and if they all use essential similar methods on sufficiently similar populations. Those criteria are seldom met. So it is usually not wise to accept a meta-analysis as the final word.

Still, meta-analysis is often a part of what some people consider to be the best way of evaluating medical evidence: the systematic review.

A systematic review entails using “a predetermined structured method to search, screen, select, appraise and summarize study findings to answer a narrowly focused research question,” physician and health care researcher Trisha Greenhalgh of the University of Oxford and colleagues write in a new paper. “Using an exhaustive search methodology, the reviewer extracts all possibly relevant primary studies, and then limits the dataset using explicit inclusion and exclusion criteria.”

Systematic reviews are highly focused; while hundreds or thousands of studies are initially identified, most are culled out so only a few are reviewed thoroughly with respect to the evidence they provide on a specific medical issue. The resulting published paper reaches a supposedly objective conclusion often from a quantitative analysis of the data.
Sounds good, right? And in fact, systematic reviews have gained a reputation as a superior form of medical evidence. In many quarters of medical practice and publishing, systematic reviews are considered the soundest evidence you can get.

But “systematic” is not synonymous with “high quality,” as Greenhalgh, Sally Thorne (University of British Columbia, Vancouver) and Kirsti Malterud (Uni Research Health, Bergen, Norway) point out in their paper, accepted for publication in the European Journal of Clinical Investigation. Sometimes systematic reviews are valuable, they acknowledge. “But sometimes, the term ‘systematic review’ allows a data aggregation to claim a more privileged position within the knowledge hierarchy than it actually deserves.”

Greenhalgh and colleagues question, for instance, why systematic reviews should be regarded as superior to “narrative” reviews. In a narrative review, an expert in the field surveys relevant publications and then interprets and critiques them. Such a review’s goal is to produce “an authoritative argument, based on informed wisdom,” Greenhalgh and colleagues write. Rather than just producing a paper that announces a specific conclusion, a narrative review reflects the choices and judgments by an expert about what research is worth considering and how to best interpret the body of evidence and apply it to a variety of medical issues and questions. Systematic reviews are like products recommended to you by Amazon’s computers; narrative reviews are birthday presents from friends who’ve known you long and well.

For some reason, though, an expert reviewer’s “informed wisdom” is considered an inferior source of reliable advice for medical practitioners, Greenhalgh and colleagues write. “Reviews crafted through the experience and judgment of experts are often viewed as untrustworthy (‘eminence-based’ is a pejorative term).”

Yet if you really want the best evidence, it might be a good idea to seek the counsel of people who know good evidence when they see it.

A systematic review might be fine for answering “a very specific question about how to treat a particular disease in a particular target group,” Greenhalgh and colleagues write. “But the doctor in the clinic, the nurse on the ward or the social worker in the community will encounter patients with a wide diversity of health states, cultural backgrounds, illnesses, sufferings and resources.” Real-life patients often have little in common with participants in research studies. A meaningful synthesis of evidence relevant to real life requires a reviewer to use “creativity and judgment” in assessing “a broad range of knowledge sources and strategies.”

Narrative reviews come in many versions. Some are systematic in their own way. But a key difference is that the standard systematic review focuses on process (search strategies, exclusion criteria, mathematical method) while narrative reviews emphasize thinking and interpretation. Ranking systematic reviews superior to narrative reviews “elevates the mechanistic processes of exhaustive search, wide exclusion and mathematical averaging over the thoughtful, in-depth, critically reflective processes of engagement with ideas,” Greenhalgh and collaborators assert.

Tabulating data and calculating confidence intervals are important skills, they agree. But the rigidity of the systematic review approach has its downsides. It omits the outliers, the diversity and variations in people and their diseases, diminishing the depth and nuance of medical knowledge. In some cases, a systematic review may be the right approach to a specific question. But “the absence of thoughtful, interpretive critical reflection can render such products hollow, misleading and potentially harmful,” Greenhalgh and colleagues contend.

And even when systematic reviews are useful for answering a particular question, they don’t serve many other important purposes — such as identifying new questions also in need of answers. A narrative review can provide not only guidance for current treatment but also advice on what research is needed to improve treatment in the future. Without the perspective provided by more wide-ranging narrative reviews, research funding may flow “into questions that are of limited importance, and which have often already been answered.”

Their point extends beyond the realm of medical evidence. There is value in knowledge, wisdom and especially judgment that is lost when process trumps substance. In many realms of science (and life in general), wisdom is often subordinated to following rules. Some rules, or course, are worthwhile guides to life (see Gibbs’ list, for example). But as the writing expert Robert Gunning once articulated nicely, rules are substitutes for thought.

In situations where thought is unnecessary, or needlessly time-consuming, obeying the rules is a useful strategy. But many other circumstances call for actual informed thinking and sound judgment. All too often in such cases the non-thinkers of the world rely instead on algorithms, usually designed to implement business models, with no respect for the judgments of informed and wise human experts.

In other words, bots are dolts. They are like a disease. Finding the right treatment will require gathering sound evidence. You probably won’t get it from a systematic review.

Genetic modifications to a plant that makes artemisinin, a key compound used in malaria drugs, more than tripled the amount of the ingredient naturally produced in leaves.

Previous attempts to genetically engineer Artemisia annua to increase the yield of artemisinin had failed. So Kexuan Tang, a plant scientist at Shanghai Jiao Tong University, and colleagues determined A. annua’s entire genetic instruction book and identified three genes crucial to artemisinin production. Genetic modifications to increase the activity of these genes boosted the artemisinin level in leaves from 0.1–1 percent of their dry weight to 3.2 percent, the researchers report April 24 in Molecular Plant.
Malaria kills about 440,000 people worldwide every year. The scientists hope to save lives by increasing and stabilizing the global supply of artemisinin, which has been in shortage due to unstable supply, Tang says. Seeds of these modified plants have been shipped to Madagascar, which grows the most A. annua in Africa, as part of a field trial.

“This is a milestone paper for artemisinin,” says Akhil Vaidya, an immunologist at Drexel University in Philadelphia who was not involved in the research. Artemisinin was discovered by Chinese chemist Youyou Tu in 1972, as she was investigating thousands of traditional Chinese remedies. The discovery, which has saved millions of lives, earned her the 2015 Nobel Prize in medicine (SN Online: 10/5/15).

Drug companies have used genetically modified yeast to produce semisynthetic artemisinin (SN: 5/4/13, p. 20), which is also effective against malaria. But artemisinin from plants is cheaper, Vaidya says. “Let the sun shine. Let the plants do their job,” he says.

Toastier nest temperatures, rather than sex chromosomes, turn baby turtles female. Now, a genetic explanation for how temperature determines turtles’ sex is emerging: Scientists have identified a temperature-responsive gene that sets turtle embryos on a path to being either male or female. When researchers dialed down that gene early in development, turtle embryos incubating at the cooler climes that would normally yield males turned out female instead, researchers report in the May 11 Science.

Scientists have struggled since the 1960s to explain how a temperature cue can flip the sex switch for turtles and other reptiles (SN Online: 1/8/18). That’s partly because gene-manipulating techniques that are well-established in mice don’t work in reptiles, says study coauthor Blanche Capel, a developmental biologist at Duke University School of Medicine. Previous studies showed certain genes, including one called Kdm6b, behaving differently in developing male and female turtles. But until recently, nobody had been able to tweak those genes to directly test which ones controlled sex.
“This is the first venture down that path,” says Clare Holleley, an evolutionary geneticist at the Australian National Wildlife Collection in Canberra who wasn’t part of the study. “It’s really quite a breakthrough.”

In the new study, Capel’s lab collaborated with a group of Chinese researchers led by Chutian Ge of Zhejiang Wanli University in Ningbo. Ge’s team recently developed a way to lessen the activity of particular reptilian genes by injecting viruses bearing snippets of artificial RNA into developing eggs.

The researchers used the technique to weaken the effects of the Kdm6b gene in the embryos of red-eared slider turtles (Trachemys scripta elegans) before the gonads formed, then tracked the embryos’ development at 26° Celsius.

“To my delight, it resulted in complete sex reversal,” Capel says. That temperature should have yielded all male turtles. Instead, in two separate experiments done with different gene-silencing viruses, 80 and 87 percent of the surviving embryos became female.
Still, something as complex as sex determination can’t be boiled down to a single gene. Kdm6b controls a gene called Dmrt1, which had already been shown to direct male development, Capel’s team also found. And while Kdm6b does behave differently as temperatures rise, it doesn’t show the same response in all tissues. That suggests that the gene doesn’t directly sense temperature, but is instead receiving messages from some higher-up gene that reacts directly to temperature and directs Kdm6b’s behavior in different tissues, the researchers propose.

Whether Kdm6b plays the same role in other reptiles remains to be seen. A 2017 study in Science Advances coauthored by Holleley found that the gene influenced bearded dragons’ sexual fate (SN Online: 6/14/17). But other genes in the same family, Jumonji genes, are also known to influence development in both reptiles and mammals. And those genes might not work exactly the same way in other reptiles.

“There’s this huge diversity of sex determining modes in reptiles,” Holleley says. Even if Kdm6b is an important switch in other reptiles, “the genes that Jumonji genes are activating are probably going to be different in every reptile.”

There are other wrinkles, too. “This is really exciting finding, but we need to remember that everything in a lab is controlled,” says Itzel Sifuentes-Romero of Florida Atlantic University in Boca Raton. Wild turtle eggs are subject to fluctuations in temperature and moisture as they incubate, she says, which means the signals that temperature-sensitive genes are receiving are far more muddled.