Speed has its limits — on the open road and the Serengeti. Midsize animals tend to be the speedsters, even though, in theory, the biggest animals should be the fastest. A new analysis that relates speed and body size in 474 species shows that the pattern holds for animals whether they run, fly or swim (see graphs below) and suggests how size becomes a liability.

This relationship between speed and size has long stumped scientists. Big animals have longer legs or flippers to get from point A to point B. And bigger bodies have higher metabolic rates and more fast-twitch muscle cells, needed to convert chemical energy into mechanical energy and rapidly accelerate. So, why aren’t wildebeests faster than cheetahs?
The make-or-break factor is the time it takes an animal to accelerate to its top theoretical speed, an upper limit based on mass and metabolic rate, researchers report July 17 in Nature Ecology & Evolution. Fast-twitch muscle cells provide the power for acceleration but tire quickly. When an animal gets too big, it takes too long to accelerate, and these cells use up their energy before hitting top speeds. More modestly built critters need less time to accelerate to those speeds.

The researchers gathered speed and size data from past lab and field studies. The animals (some shown as icons in the slideshow below) ranged in mass from 30-microgram Spanish mites to a blue whale weighing 108 metric tons.

Maybe it’s more than reptile fashion. The high percentage of citified sea snakes wearing black might be a sign that pollution is an evolutionary force.

Off the coasts of Australia and New Caledonia, some turtle-headed sea snakes (Emydocephalus annulatus) sport pale bands on their dark skins. Others go all black. In 15 places surveyed, the all-black form was more likely to predominate in waters near cities, military sites or industrial zones than along reefs near less built-up coastlines, says evolutionary ecologist Rick Shine of the University of Sydney.
That trend plus some analysis of trace elements in snakes’ skin suggests that the abundant dark forms could turn out to be an example of industrial melanism, Shine and his colleagues propose August 10 in Current Biology.

The most famous example of this evolutionary phenomenon comes from a dark form of peppered moth that overtook pale populations in 19th century England (SN: 6/25/16, p. 6). Dark wings created better camouflage from hungry birds in the grimy industrializing landscape.
Shine doesn’t think the sea snakes are going for camouflage, though. Instead, the snakes could be more like the dark-feathered pigeons of Paris. The melanin that gives that city’s feral birds their urban chic also does a great job of binding traces of toxic metals such as zinc, explains evolutionary ecologist Marion Chatelain of the University of Warsaw. When birds molt, getting rid of darker feathers lets them unload more of the unhealthful urban pollutants, she and colleagues have reported.
This could explain why marine biologist and study coauthor Claire Goiran has so many dark turtle-headed sea snakes in a lagoon not far from her campus, the University of New Caledonia in Nouméa. Earlier studies had found only downsides to dark coloration: Seaweed spores preferentially settle on dark snakes and sprout fuzz that can cut swimming speed by 20 percent and cause a snake to shed its skin more often than normal.
To test a scenario of industrial melanism, or darkening due to pollution, the researchers collected data on skin colors for a total of about 1,450 snakes, both live and museum specimens, from 15 sites in New Caledonia and Australia. Higher percentages of all-dark snakes wriggled around the nine polluted sites surveyed. At one, a remote Australian reef that the military had long used as a bombing range, all 13 specimens were dark.

To test shed skins for trace metals, Goiran and Shine enlisted Paco Bustamante of the University of La Rochelle in France, who studies trace metal contamination in marine life.

Researchers managed to collect sloughed skins from 17 turtle-headed snakes, which inconveniently shed their skin underwater. To compare light and dark patches, the scientists turned to two local species of sea kraits, which have banded skin and visit land to shed it.
Overall, skins held concentrations of trace elements higher than those that can cause health problems in birds and mammals, the researchers report. In the krait skins, dark zones had slightly more of some contaminants, such as zinc and arsenic, than the pale bluish-white bands did.

The idea that polluted water favors melanized sea snakes “is a reasonable hypothesis based on what we know,” Chatelain says. Definitive tests will require more data and different approaches. Genetic testing, for example, would clarify whether dark populations arose instead from small groups of pioneers that happened to have a lot of black snakes.

That testing could be a long way off. Sea snakes are evolutionary cousins of cobras and mambas, and some of the species swimming around Australia and New Caledonia are “bowel-looseningly large,” Shine says. At least the little turtle-headed ones, which eat eggs of small reef fishes, have venom glands that have atrophied and “probably couldn’t fit a human finger in their mouths.” But until someone figures out how to keep them alive in captivity for more than a few days, Shine isn’t expecting definitive genetics.

China’s first emperor broke the mold when he had himself buried with a terra-cotta army. Now insight into the careful crafting of those soldiers is coming from the clays used to build them. Custom clay pastes were mixed at a clay-making center and then distributed to specialized workshops that cranked out thousands of the life-size figures, new research suggests.

Roughly 700,000 craftsmen and laborers built Emperor Qin Shihuang’s palatial mausoleum in east-central China between 247 B.C. and 210 B.C. A portion of those workers gathered clay from nearby deposits and prepared it in at least three forms, researchers propose in the August Antiquity. On-site or nearby workshops used different signature clay recipes for terra-cotta warriors, parts of mostly bronze waterfowl figures and paving bricks for pits in which the soldiers originally stood.
Around 7,000 ceramic foot soldiers, generals and horses — equipped with a variety of bronze weapons — make up the army, which was accidentally discovered in 1974 by farmers digging a well. The emperor would have regarded the ceramic statues as a magic army that would protect him as he ruled in the afterlife, many researchers suspect.

Building and assembling the multitude was an enormous task. Workers poured clay mixtures into casts of torsos, limbs and other body parts, and then assembled the bodies, taking care to create different facial features for each soldier. Finished statues, now mostly gray, were covered in colored lacquers and likely fired in kilns. Most figures were placed inside one giant pit. Earthen walls formed 11 parallel corridors where statues stood in battle-ready rows.

Still, no workshops or debris firmly linked to the statue-making process have been found. As a result, the number, size, location and organization of workshops involved in producing the emperor’s ceramic troops remain uncertain.

Archaeologist Patrick Quinn of University College London and three Chinese colleagues studied the composition of clay samples from the site. The pieces were taken from 12 terra-cotta warriors, two acrobat statues found in a second pit, five clay bricks from the floor of the largest pit, clay fragments from inside three bronze waterfowl statues found in a third pit and part of an earthen wall in the acrobat pit.

Microscopic analysis of the samples revealed that the clay came from deposits near the tomb’s location, the scientists say. But the recipes for different parts varied. Paving bricks contained only a mixture of dark and light clays, while the clay used for warriors and acrobats had sand worked in. Sand and plant fragments were folded into a clay mixture that formed the core of the bronze waterfowl.
Sand may have made the clay more malleable for shaping into ornate figures and increased statues’ durability, the researchers speculate. Plant pieces may have helped reduce the weight of birds’ clay cores. A clay-processing site at or just outside the emperor’s mausoleum must have doled out the appropriate clay pastes to an array of workshops where potters made statues, bricks or other objects, the scientists propose.

What’s more, many statue and waterfowl samples show signs of having been slowly heated in kilns at maximum temperatures of no more than 750˚ Celsius. That’s lower by 150˚ C or more than some previous estimates, the investigators say. Fires set in an attack on the tomb after the emperor’s death may have refired some of the clay, accounting for the temperature discrepancy, the researchers say.

“I’m not at all surprised by the new findings,” says East Asian art historian Robin D.S. Yates of McGill University in Montreal. Legal and administrative documents previously found at two other Qin Empire sites describe workshops that specialized in various types of craft production, Yates says.

In some cases, artisans’ stamps and inscriptions on terra-cotta warriors match those on excavated roof tiles from Emperor Qin’s mausoleum. The markings suggest that some workshops made several types of ceramic objects, says East Asian art historian Lothar Ledderose of Heidelberg University in Germany. Inscriptions on statues also indicate that artisans working at off-site factories during the Qin Empire collaborated with potters at local workshops to produce the terra-cotta army, Ledderose says.

Early in Inferior, science writer Angela Saini recalls a man cornering her after a signing for her book Geek Nation, on science in India. “Where are all the women scientists?” he asked, then answered his own question. “Women just aren’t as good at science as men are. They’ve been shown to be less intelligent.”

Saini fought back with a few statistics on girls’ math abilities, but soon decided that nothing she could say would convince him. It’s a situation that may feel familiar to many women. “What I wish I had was a set of scientific arguments in my armory,” she writes.
So she decided to learn the truth about what science really does tell us about differences between the sexes. “For everyone who has faced the same situation,” she writes, “the same desperate attempt to not lose control but have at hand some real facts and a history to explain them, here they are.”

In Inferior, Saini marshals plenty of facts and statistics contradicting sexist notions about women’s bodies and minds. She cites study after study showing little or no difference in male and female capabilities.

But it’s the book’s historical perspective that makes it most compelling. Only by understanding the cultural context of the men whose studies and ideas first pointed to gender imbalances can we see how deeply biases run, Saini argues.

Charles Darwin’s influential ideas reflected his times, for instance. In The Descent of Man, he wrote that “man has ultimately become superior to woman” via evolution. To a woman active in her local women’s movement, Darwin wrote, “there seems to me to be a great difficulty from the laws of inheritance … in [women] becoming the intellectual equals of man.”

If that idea sounds absurd now, don’t fool yourself into thinking it has vanished. Saini’s book is full of examples right up to today of scientists who have started from this and other flawed premises, which have led to generations of flawed studies and results that reinforce stereotypes. But the tide has been turning, as more women have entered science and more scientists of both sexes seek to remove bias from their work.
Saini does an excellent job of dissecting research on evolution, neuroscience and even the long-standing notion that women’s sexual behavior is driven by their interest in stable, monogamous relationships. By the end, it’s clear that science doesn’t divide men and women; we’ve done that to ourselves. And as scientists become more rigorous, we get closer to seeing ourselves as we really are.

A tiny, shimmying cantilever wiggles a bit more than expected in a new experiment. The excess jiggling of the miniature, diving board–like structure might hint at why the strange rules of quantum mechanics don’t apply in the familiar, “classical” world. But that potential hint is still a long shot: Other sources of vibration are yet to be fully ruled out, so more experiments are needed.

Quantum particles can occupy more than one place at the same time, a condition known as a superposition (SN: 11/20/10, p. 15). Only once a particle’s position is measured does its location become definite. In quantum terminology, the particle’s wave function, which characterizes the spreading of the particle, collapses to a single location (SN Online: 5/26/14).
In contrast, larger objects are always found in one place. “We never see a table or chair in a quantum superposition,” says theoretical physicist Angelo Bassi of the University of Trieste in Italy, a coauthor of the study, to appear in Physical Review Letters. But standard quantum mechanics doesn’t fully explain why large objects don’t exist in superpositions, or how and why wave functions collapse.

Extensions to standard quantum theory can alleviate these conundrums by assuming that wave functions collapse spontaneously, at random intervals. For larger objects, that collapse happens more quickly, meaning that on human scales objects don’t show up in two places at once.

Now, scientists have tested one such theory by looking for one of its predictions: a minuscule jitter, or “noise,” imparted by the random nature of wave function collapse. The scientists looked for this jitter in a miniature cantilever, half a millimeter long. After cooling the cantilever and isolating it to reduce external sources of vibration, the researchers found that an unexplained trembling still remained.

In 2007, physicist Stephen Adler of the Institute for Advanced Study in Princeton, N.J., predicted that the level of jitter from wave function collapse would be large enough to spot in experiments like this one. The new measurement is consistent with Adler’s prediction. “That’s the interesting fact, that the noise matches these predictions,” says study coauthor Andrea Vinante, formerly of the Institute for Photonics and Nanotechnologies in Trento, Italy. But, he says, he wouldn’t bet on the source being wave function collapse. “It is much more likely that it’s some not very well understood effect in the experiment.” In future experiments, the scientists plan to change the design of the cantilever to attempt to isolate the vibration’s source.

The result follows similar tests performed with the LISA Pathfinder spacecraft, which was built as a test-bed for gravitational wave detection techniques. Two different studies found no excess jiggling of free-falling weights within the spacecraft. But the new cantilever experiment tests for wave function collapse occurring at different rate and length scales than those previous studies.
Theories that include spontaneous wave function collapse are not yet accepted by most physicists. But interest in them has recently become more widespread, says physicist David Vitali of the University of Camerino in Italy, “sparked by the fact that technological advances now make fundamental tests of quantum mechanics much easier to conceive.” Focusing on a simple system like the cantilever is the right approach, says Vitali, who was not involved with the research. Still, “a lot of things can go wrong or can be not fully controlled.”

To conclude that wave function collapse is the cause of the excess vibrations, every other possible source will have to be ruled out. So, Adler says, “it’s going to take a lot of confirmation to check that this is a real effect.”

Air pollution is a drag for renewable energy. Dust and other sky-darkening air pollutants slash solar energy production by 17 to 25 percent across parts of India, China and the Arabian Peninsula, a new study estimates. The haze can block sunlight from reaching solar panels. And if the particles land on a panel’s flat surface, they cut down on the area exposed to the sun. Dust can come from natural sources, but the other pollutants have human-made origins, including cars, factories and coal-fired power plants.

Scientists collected and analyzed dust and pollution particles from solar panels in India, then extrapolated to quantify the impact on solar energy output in all three locations. China, which generates more solar energy than any other country, is losing up to 11 gigawatts of power capacity due to air pollution, the researchers report in the Aug. 8 Environmental Science & Technology Letters. That’s a loss of about $10 billion per year in U.S. energy costs, says study coauthor Mike Bergin of Duke University. Regular cleaning of solar panels can help. Cleaning the air, however, is harder.

Sea stars and their relatives eat, breathe and scuttle around the seafloor with tiny tube feet. Now researchers have gotten their first-ever look at similar tentacle-like structures in an extinct group of these echinoderms.

It was suspected that the ancient marine invertebrates, called edrioasteroids, had tube feet. But a set of unusually well-preserved fossils from around 430 million years ago, described September 13 in Proceedings of the Royal Society B, provides proof.

Usually, when an echinoderm dies, “the tube feet are the first things that go,” says Colin Sumrall, a paleobiologist at the University of Tennessee, Knoxville who wasn’t part of the study. “The thing that’s so stunning is that they didn’t rot away.”
An abundance of soft-bodied creatures from the Silurian Period, which lasted from 444 million to 419 million years ago, are preserved in a fossil bed in Herefordshire, England. The edrioasteroids found in this bed were probably buried alive by volcanic ash, entrapped before their soft tissues could break down, says study coauthor Derek Briggs, a paleontologist at Yale University. Decaying tissue then left a void that was filled in by minerals, which preserved the shape of the appendages.
Briggs and his collaborators slowly ground three fossils down, taking pictures layer-by-layer to build up a three-dimensional view. The specimens are a new genus and species, the analysis revealed. Unlike relatively flat sea stars and sand dollars, the species — dubbed Heropyrgus disterminus — had a conical body about 3 centimeters long. Its narrower end anchored in the seabed. The other end sported a set of five plates partially covering dozens of tube feet arranged in a pentagonal ring.
Today’s echinoderms use hydraulic pressure in a water vascular system to extend and retract their tube feet, which serve a variety of roles. The feet can help animals pull in tiny particles of food, filter water or gases, and even inch along the seafloor. Based on the placement of H. disterminus’s tube feet (and the fact that it’s stuck in one place), the animal probably used the appendages mostly for feeding and gas exchange, Briggs suggests. The fossils didn’t preserve the internal tubing that hooks up to the tube feet, but Briggs’ team thinks that it’s a series of canals arranged like spokes connected to a wheel hub.

Sumrall isn’t surprised that this edrioasteroid had tube feet. “It’s exactly what we would have expected,” he says. But all other preserved tube feet to date come from classes of echinoderms that still have living relatives today. Edrioasteroids are less closely related to modern echinoderms, so this find broadens the range of species that scientists know sported the structures.

H. disterminus does have a few surprises, though: Its tube feet are found in two sets, in an arrangement not seen in any other echinoderms. And while it has five-point symmetry in its fleshy top part (like most other echinoderms), that transitions to eight-point symmetry in its long, columnar body.

For certain HIV antibodies, having a buddy or two makes a big difference in the fight against the virus.

Combining the antibodies, called broadly neutralizing antibodies, may stop more strains of HIV than any single one can do alone, two new studies suggest. A “triple-threat” antibody molecule can bind to three different spots on the virus, researchers report online September 20 in Science. In Science Translational Medicine, a second team describes a cocktail of two single antibodies that each target a different region of the virus. Both methods prevented infection from multiple strains of an HIV-like virus in monkeys.
“We have known for many years that broadly neutralizing antibodies are extremely powerful antibodies,” says molecular biologist Nancy Haigwood of the Oregon Health & Science University in Portland, who was not involved in either study. Using more than one of these antibodies “is the most promising approach” to block HIV infection in humans because it offers more coverage, she says.

This extra coverage is needed because HIV is a master of mutation. “It’s really adopted every bit of what I would call molecular trickery to outwit our immune system, and it’s a constant battle,” says Gary Nabel, coauthor of the study in Science and chief scientific officer of Sanofi in Cambridge, Mass. The immune system keeps trying to recognize parts of the virus, but mutations in the virus can alter those sites. “You really want to have this broadside attack against the virus that hits multiple targets,” he says.

Broadly neutralizing antibodies are powerful because they can bind to multiple strains of HIV (SN: 8/19/17, p.7). The antibodies stop HIV from getting into cells to infect them. Still, “there is no single antibody” that can block all strains, says virologist Dan Barouch of Beth Israel Deaconess Medical Center in Boston.

Barouch and colleagues tackled the issue by mixing two of the antibodies together. The researchers divided 20 rhesus monkeys into four groups, giving one group the cocktail, two groups the individual antibodies and one group a saline solution with no antibodies. A day later, all of the monkeys were exposed to a mix of two simian-human immunodeficiency virus, or SHIV, strains. The outer protein that surrounds HIV, where antibodies bind, is the same in SHIV. None of the five animals that received the antibody cocktail became infected, while all of the other animals did, the researchers report in Science Translational Medicine.

Nabel and colleagues took a different tack: They developed a molecule that combines the binding talents of three antibodies into one. The researchers tested their “tri-specific” antibody in rhesus monkeys, giving eight animals the trio antibody while two other groups each received just one of the broadly neutralizing antibodies that inspired the molecule. The animals were exposed to a mix of SHIV strains five days later. Of the 16 monkeys in the solo antibody groups, 11 developed infections. None of the eight animals dosed with the trio antibody did.
Both teams’ antibody approaches “show impressive protection against a combination of viruses, suggesting that they would be effective” against diverse HIV strains in humans, Haigwood says.

Virologist David Margolis of the University of North Carolina School of Medicine in Chapel Hill notes that the approaches are most likely to have preventative potential, but they also may be therapeutic. The antibody combinations might “replace oral antiretroviral therapy, or stand in for oral therapy in medical situations where pills cannot be taken,” he says.

The next step for both methods is to test the combination antibodies in people, the authors say. Whether the strategy is most effective as a preventative measure, treatment or both, the papers suggest that “to achieve optimal protection in humans,” multiple antibodies or antibody targets are going to be needed, Barouch says.

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.