# News this Week

Science  18 Dec 2015:
Vol. 350, Issue 6267, pp. 1446
1. # News at a glance

### Syrian refugees struggle with TB

Lebanon, Jordan, and Iraq are struggling to detect and treat tuberculosis (TB) in the nearly 2 million refugees who have fled to these countries from Syria. “The national TB programs operating in conflict-affected regions are strained and they need help,” Aleksandar Galev of the International Organization for Migration explained last week at the 46th Union World Conference on Lung Health. In Lebanon, which hosts half the refugees, more than 20% of those diagnosed with active TB cases are “lost to follow-up” and don't complete the 6-month treatment needed for a cure. “The refugees move from country to country and even across the seas,” said Galev, who is based in Amman. But this shouldn't deter countries from taking Syrian refugees, says Gilles Cesari of the Global Fund to Fight AIDS, Tuberculosis and Malaria in Geneva, Switzerland. “The refugees are not vectors of disease,” says Cesari, who stresses that their TB rates are much lower than those of hard-hit populations in sub-Saharan Africa and Asia. “They're just at a greater risk of being sick because of poor nutrition, being tired and on the move, and living with many people in one room.”

### African dragonfly boom

They call themselves “bionauts”—explorers not of space, but of life on Earth. In one fell swoop, a team of three naturalists has added 60 new species of dragonfly and damselfly to the 700 previously known in Africa. Worried that increasing development was threatening the insect's freshwater habitat, Klaas-Douwe Dijkstra, a systematist at the Naturalis Biodiversity Center in Leiden, the Netherlands, along with a high school teacher and a former mining mechanic, spent 15 years tracking down as many species on the African continent as they could. “We want to wow the world with so many new dragonflies but also deliver them to the doormats of those who care most about them,” Dijkstra says. Describing so many new species at once required a special 230-page issue of Odonatologica, a journal devoted to the large, delicate, long-winged insects. http://scim.ag/dragonflyboom

### Overhaul in the works for aging U.S. Antarctic station

The U.S. National Science Foundation (NSF) is planning a $300 million overhaul of McMurdo Station, the biggest of its three Antarctic research stations. The redesign, called the Antarctic Infrastructure Modernization for Science, would replace and reconfigure various scientific, operational, and logistics support facilities at McMurdo as part of a larger plan to upgrade all Antarctic stations. NSF's Office of Polar Programs presented its latest draft at a 4 December meeting of the National Academies' Polar Research Board. The planned redesign is in response to a 2012 report by a blue-ribbon panel convened to study NSF's science facilities on the southernmost continent. Funding would come from NSF's Major Research Equipment and Facilities Construction account, and not from its$300 million annual budget for Antarctic logistics and infrastructure. The overhaul, which is to have no direct impact on ongoing scientific activities, would start in fiscal year 2019 and take about 8 years. http://scim.ag/McMurdoStation

“It's just worthless words. There's no action, just promises. As long as fossil fuels appear to be the cheapest fuels out there, they will continue to be burned.”

Columbia University climate scientist James Hansen to The Guardian on last week's global deal for cutting carbon emissions.

### By the numbers

6 million—Number of pregnancies in the United States in 2010, the lowest annual tally since 1976, the Centers for Disease Control and Prevention reported last week. Girls under 14 saw the biggest decline in pregnancy rate.

\$1 billion—Amount of money Silicon Valley investors—including SpaceX's Elon Musk—have committed to OpenAI Inc., a nonprofit firm whose stated goal is to “advance digital intelligence in the way that is most likely to benefit humanity,” not shareholders.

213—Number of “unequivocal” references to Bob Dylan's lyrics snuck into biomedical papers by authors at the Karolinska Institute since 1970. The references were the result of a long-running bet among the scientists (The BMJ).

## Around the world

### Bethesda, Maryland

NIH to unveil strategic plan

The National Institutes of Health (NIH) this week was on track to release its first agency-wide strategic plan in more than 20 years. (It had not been released by the time Science went to print.) The plan, previewed in draft form last week, describes four objectives: advancing opportunities by funding basic and applied science, setting priorities, enhancing stewardship, and “managing for results.” Among other changes, the plan ends a tradition of setting aside 10% of NIH's budget for AIDS research. It further pledges to improve how the agency looks at the public health burden of a disease to guide funding. It also lays out several bold goals for 2020, such as a universal influenza vaccine that works against all virus strains.

### Silver Spring, Maryland

New drug from GM chicken eggs

The U.S. Food and Drug Administration (FDA) last week approved Kanuma, a new drug produced in the eggs of genetically engineered chickens. The drug treats lysosomal acid lipase (LAL) deficiency, a rare genetic disorder that prevents the body from breaking down fat and typically causes fatal organ damage in infants. Alexion Pharmaceuticals of Cheshire, Connecticut, modified chickens to produce a human form of LAL, which can be extracted from egg whites and given to patients as an intravenous infusion. The chickens were approved separately from the drug by FDA's Center for Veterinary Medicine.

### Mexico City

Mexico approves dengue vaccine

Mexico last week became the first country to approve a vaccine for dengue fever, a mosquito-borne disease that causes excruciating muscle and joint pain and kills more than 10,000 people every year. The new vaccine—developed by Sanofi Pasteur—targets each of four distinct virus serotypes. In clinical trials, the vaccine reduced the incidence of severe dengue, which sometimes results when patients are infected a second time with a different serotype. But the vaccine provided limited protection against dengue serotype 2, a common version of the virus. Despite that shortcoming, the approval is “a milestone in our efforts to prevent and control dengue,” says Duane Gubler of the Duke-NUS Graduate Medical School in Singapore. Sanofi is awaiting approval in several other countries.

### Geneva, Switzerland

The most dangerous pathogens

The World Health Organization (WHO) last week released a short list of the world's most dangerous pathogens—eight viruses “likely to cause severe outbreaks in the near future,” for which few or no medical countermeasures exist. The list, which includes viruses causing Ebola, Marburg, SARS, Middle East respiratory syndrome, Nipah, Lassa fever, Rift Valley fever, and Crimean Congo hemorrhagic fever, is part of a push to develop vaccine and drug candidates for dangerous emerging pathogens before a major outbreak. “Many of these diseases have not received the funding or the attention they require,” says Cathy Roth, a science policy adviser at WHO. Three other diseases were ranked as “serious”: chikungunya, severe fever with thrombocytopaenia syndrome, and Zika. http://scim.ag/WHOpathogens

### The Hague, Netherlands

Dutch get open access

A standoff between Dutch universities and publishing giant Elsevier ended last week with a compromise: Elsevier says it will allow 30% of Dutch research in its 2500 journals to be free to the public by 2018. “It's not the 100% that I hoped for,” says Gerard Meijer, the president of Radboud University in Nijmegen, the Netherlands, and the lead negotiator on the Dutch side. “But this is the future. No one can stop this anymore.” The agreement follows a year of negotiations between the publisher and a coalition of 14 Dutch universities. http://scim.ag/ElsevierOpenAccess

### Washington, D.C.

NIH to end monkey experiments

The National Institutes of Health (NIH) decided last week to phase out controversial monkey experiments at its Poolesville, Maryland, facility. The work—which includes separating young rhesus macaques from their mothers, measuring their addiction to alcohol, and monitoring their long-term stress levels—has been the target of an intense campaign by People for the Ethical Treatment of Animals, but the agency says the group had nothing to do with its decision. Rather, NIH says the facility had become too expensive to maintain. About 300 monkeys will leave the lab for other facilities over the next 3 years, where they may still be used in research. http://scim.ag/Poolesville

## Newsmakers

### Biodefense lab overseer out

The head of a federal program that oversees safety and security at U.S. labs that work with risky pathogens has been replaced. Since 2006, Robbin Weyant had directed the Atlanta-based U.S. Centers for Disease Control and Prevention's (CDC's) Division of Select Agents and Toxins (DSAT), which regulates labs working with viruses, bacteria, and toxins that could be used as bio weapons. Last week, USA Today reported that on 9 November, Weyant moved to a different position at CDC. Weyant's departure comes in the wake of several high-profile mishaps with select agents, including mistaken shipments of live anthrax from CDC and an Army lab. CDC's Daniel Sosin is now acting director of DSAT.

## Findings

### First ‘test tube puppies’

Dogs' reproductive systems are so quirky that researchers have been trying to produce puppies through artificial fertilization since the 1970s without success. But now, scientists have used a new set of techniques to give rise to the world's first “test tube puppies,” a litter of beagles and beagle mixes. To bring the new litter into the world, researchers collected mature eggs from the canine equivalent of the fallopian tubes—a trickier prospect than collecting them from ovaries (as is done in humans). Once they had the eggs, the team experimented with different conditions for fertilization and incubation, finally coaxing seven embryos to grow in a surrogate mother hound, they reported last week in PLOS ONE. The pups, now 5 months old and thriving with their adoptive human families, could offer hope for endangered species like red wolves and African wild dogs, the researchers write. Dog in vitro fertilization could also be used to study heritable traits and diseases, many of which are shared by dogs and humans.

2. # Making the cut

1. John Travis

CRISPR genome-editing technology shows its power.

It was conceived after a yogurt company in 2007 identified an unexpected defense mechanism that its bacteria use to fight off viruses. A birth announcement came in 2012, followed by crucial first steps in 2013 and a massive growth spurt last year. Now, it has matured into a molecular marvel, and much of the world—not just biologists—is taking notice of the genome-editing method CRISPR, Science's 2015 Breakthrough of the Year.

CRISPR has appeared in Breakthrough sections twice before, in 2012 and 2013, each time as a runner-up in combination with other genome-editing techniques. But this is the year it broke away from the pack, revealing its true power in a series of spectacular achievements. Two striking examples—the creation of a long-sought “gene drive” that could eliminate pests or the diseases they carry, and the first deliberate editing of the DNA of human embryos—debuted to headlines and concern. Each announcement roiled the science policy world. The embryo work (done in China with nonviable embryos from a fertility clinic) even prompted an international summit this month to discuss human gene editing. The summit confronted a fraught—and newly plausible—prospect: altering human sperm, eggs, or early embryos to correct disease genes or offer “enhancements.” As a genetic counselor quipped during the discussion: “When we couldn't do it, it was easy to say we shouldn't.”

What sets CRISPR apart? Its competitors—designer proteins called zinc finger nucleases and TALENs—also precisely alter chosen DNA sequences, and several companies are already exploiting them for therapeutic purposes in clinical trials. But CRISPR has proven so easy and inexpensive that Dana Carroll of the University of Utah, Salt Lake City, who spearheaded the development of zinc finger nucleases, says it has brought about the “democratization of gene targeting.” Quoted in a recent issue of The New Yorker, bioethicist Hank Greely of Stanford University in Palo Alto, California, compares CRISPR to the Model T Ford: far from the first automobile, but the one whose simplicity of production, dependability, and affordability transformed society. “Any molecular biology lab that wants to do CRISPR can,” says Harvard University's George Church, whose lab was one of the first to show that it efficiently edits human and other eukaryotic cells.

Already, the nonprofit group Addgene has distributed about 50,000 plasmids—circlets of DNA—containing genetic code for the two basic components of CRISPR, the “guide RNA” used to target a specific DNA sequence and the DNA-cutting enzyme, or nuclease, usually one called Cas9. “It's going to be like PCR, a tool in the toolbox,” says Jennifer Doudna of the University of California, Berkeley, whose group, in collaboration with one led by Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology in Berlin, published the first report that CRISPR could cut specific DNA targets.

Their work grew out of a surprising observation that bacteria could remember viruses. Researchers had found remnants of genes from past infections, sandwiched between odd, repeated bacterial DNA sequences—the “clustered regularly interspaced short palindromic repeats” that give CRISPR its name. The viral scraps serve as an infection memory bank: From them, bacteria create guide RNAs that can seek out the DNA of returning viruses before chopping up the viral genes with a nuclease. Once this mechanism was understood, Doudna and Charpentier, among others, raced to adapt it to editing DNA in higher organisms.

### ON OUR WEBSITE

For more on the Breakthrough of the Year, including a video and a podcast, go to http://scim.ag/breakthru15.

A torrent of applications followed. One of them—the CRISPR-powered gene drive—is a case study in the power, and potential risks, of genome-editing technology. In 2003, Austin Burt, an evolutionary biologist at Imperial College London, envisioned attaching a gene for a desired trait to “selfish” DNA elements that could copy themselves from one chromosome spot to another. That would bias the offspring of a parent carrying the trait to inherit it, quickly spreading it throughout a population. Earlier this year, a U.S. team adapted CRISPR to just that purpose, succeeding well beyond the original vision.

In a method ominously dubbed “mutagenic chain reaction,” the researchers drove a pigmentation trait in lab-grown fruit flies to the next generation with 97% efficiency. They then teamed up with another research group to create a gene drive that, unleashed in a lab population of mosquitoes, spread genes that prevent the insects from harboring malaria parasites. Weeks later, working with another malaria-carrying mosquito, Burt and colleagues reported the same thing with genes that rendered the females infertile and could quickly wipe out a population. Debates are now erupting over the benefits and ecological risks of releasing such insects into the wild—and whether gene drives could also thwart invasive species such as Asian carp and cane toads, or combat other animal-borne pathogens such as the one causing Lyme disease.

In other labs, researchers harnessed the technique to create a growing menagerie of genetically engineered animals and plants: extramuscular beagles, pigs resistant to several viruses, and wheat that can fend off a widespread fungus. Longer-lasting tomatoes, allergen-free peanuts, and biofuel-friendly poplars are all on the drawing board. Depending on how it's wielded, CRISPR can do its work without leaving any foreign DNA behind, unlike earlier techniques for genetically modifying organisms, which poses a challenge for regulations based on the presence of foreign DNA.

There is much, much more. By making “dead” versions of Cas9, scientists eliminated CRISPR's DNA-cutting ability but preserved its talent for finding sequences. Tack molecules onto Cas9 and CRISPR suddenly becomes a versatile, precise delivery vehicle. Several groups, for example, have outfitted dead Cas9s with various regulatory factors, enabling them to turn almost any gene on or off or subtly adjust its level of activity. In one experiment this year, a team led by another CRISPR pioneer, Feng Zhang of the Broad Institute in Cambridge, Massachusetts, targeted the 20,000 or so known human genes, turning them on one by one in groups of cells to identify those involved in resistance to a melanoma drug.

The biomedical applications of CRISPR are just starting to emerge. Clinical researchers are already applying it to create tissue-based treatments for cancer and other diseases. CRISPR may also revive the moribund concept of transplanting animal organs into people. Many people feared that retroviruses lurking in animal genomes could harm transplant recipients, but this year a team eliminated, in one fell swoop, 62 copies of a retrovirus's DNA littering the pig genome. And the international summit saw many discussions of CRISPR's promise for repairing genetic defects in human embryos, if society dares to cross what many regard as an ethical threshold and alter the human germline.

In short, it's only slightly hyperbolic to say that if scientists can dream of a genetic manipulation, CRISPR can now make it happen. At one point during the human gene-editing summit, Charpentier described its capabilities as “mind-blowing.” It's the simple truth. For better or worse, we all now live in CRISPR's world.

## People's choice

Visitors to Science's website voted on our 10 Breakthrough finalists. Their top picks:

1. Pluto 35%

2. CRISPR 20%

3. Lymphatic system in the central nervous system 15%

4. Ebola vaccine 10%

5. (Tie) Psychology replication/quantum entanglement 6%

For the second year in a row, the public weighed in through the Internet, voting for its top discovery while the Breakthrough team was hammering out its choices. High on the list, the results mirrored Science staffers' own deliberations. CRISPR surged to an early lead, as high-profile meetings and magazine articles focused public attention on the genome-editing technique. Pluto, a media darling in July when the New Horizons probe swooped past it en route to points beyond, was a distant second.

But the dwarf planet rallied, as New Horizons scientists blitzed Twitter with get-out-the-vote tweets. When the final returns were in, Pluto finished comfortably ahead of CRISPR in the popular vote.

Further down the list, it was a bad year for old bones. Homo naledi (a new human species!) finished in seventh place, and Kennewick Man, the ancient Native American whose DNA was recently sequenced, was dead last. Better luck next time, O my people.

### Making the Cut

Special Collection: The CRISPR Revolution

### People's choice

R. Coontz, “Vote for your scientific breakthrough of the year winner!Science (1 December 2015).

Correction: This article has been edited to remove the assertion that the researchers who found CRISPR sequences were already looking for a way that bacteria remember viruses.

3. # Runners-up

In addition to its Breakthrough of the Year, Science named nine runners-up as significant scientific achievements of 2015.

## A big year for small worlds

It was the year of the dwarf planet. Two NASA spacecraft, two encounters, two fuzzy orbs that bloomed in vivid detail before robotic eyes. In March, Dawn went into orbit around Ceres, the largest object in the asteroid belt. And in July, New Horizons zoomed past Pluto, one of the largest objects in the Kuiper belt.

At Pluto, scientists found a place sculpted both in the present day, by the extreme seasons of an elliptical orbit and a 248-year-long year, and billions of years ago, as the dwarf planet cooled and cracked. Scaly textures in a veneer of nitrogen frost bore witness to patterns of sublimation and deposition, as the thin atmosphere breathed through cycles of expansion and collapse. Mountains of water ice towered above smooth plains, jumbled together as if ancient tectonic forces had pushed them across a sea of soft nitrogen ice like drifting icebergs. Two mountains with deep holes in their middles may have been “cryovolcanoes” spewing ice from a warmer interior.

Ceres, closer to the sun, was shaped by different forces. Dark as asphalt, its surface has been brutalized by impacts. Above mysterious bright spots in some of its impact craters floats a haze of dust and water vapor—a hint that Ceres is “outgassing” like a comet on its last legs. Dawn also found ammonia, typical of comets, in surface minerals, adding to the evidence that Ceres is actually a giant dead comet that began its life in the outer solar system, closer to Pluto (see Scorecard, p. 1461). This month, Dawn lowered itself to its final, lowest, mapping orbit, less than 380 kilometers above the surface.

A third small body awaits, as New Horizons heads toward a 2019 rendezvous with a Kuiper belt object called 2014 MU69. After that, New Horizons will glide on, exiting the solar system in a few decades, while Dawn will orbit Ceres for centuries or more.

Eric Hand

## Kennewick Man's kin

From the beginning, the bones of the so-called Kennewick Man have sparked contention. Since the 8500-year-old skeleton was discovered on the shore of the Columbia River in Kennewick, Washington, in 1996, anthropologists have debated its relationship to today's Native Americans. Meanwhile, local tribes, regarding “The Ancient One” as an ancestor, have demanded that he be handed over to them and ceremonially reburied. In 2004, the U.S. government granted researchers permission to study the skeleton.

This year, the story took an ironic twist, when experts in ancient DNA succeeded in sequencing Kennewick Man's nuclear genome. The result: The Ancient One is closely related to at least one of the five Washington area tribes that originally fought to reclaim him. More important to scientists, the genome confirms earlier findings, based on DNA from even older human remains, that today's Native Americans are direct descendants of Asian peoples who crossed the Bering land bridge at least 15,000 years ago. Thus, Kennewick Man's genome contradicts suggestions that today's Native Americans stem from later migrants, as well as claims that the first Americans came from Europe rather than Asia.

In a dispute often portrayed as pitting science against cultural traditions, it appears that the Native Americans—who are now renewing their efforts to have The Ancient One turned over to them—may well have had science on their side all along.—Michael Balter

## Reproducibility in psychology

This year caps a transformation for psycho logical science. The field was mired in scandal just a few years ago. But a band of revolutionaries is turning psychology into a beacon for scientific reproducibility.

Concerns that false positive results might be common in psychology, where studies often involve small numbers of subjects and statistically weak effects, boiled over in 2011. The scandal spurred psychologists to clean up their field—both by replicating key studies and by creating new models of scholarly publication and peer review to restore confidence in published research.

The first crop of replications, in 2013, brought reassuring news: Ten of 13 experiments obtained the same results as the original study. Last year, however, an even larger replication—involving nearly 100 researchers around the world repeating 27 published psychological experiments—proved painful: Not only did about one-third of the follow-up studies fail to replicate, but some of the original authors felt unfairly singled out.

Undaunted, this year the replicators pulled off the biggest do-over yet. In a report published in Science in August, 270 psychologists orchestrated a repeat of 100 studies published in three top journals. On the downside, only 39% passed the test. But this time, the process went so smoothly that psychology journal editors announced that the publication of direct replications should become routine.

The innovation that may have the largest effect on the rest of science, however, lies in the design of the replication efforts. The researchers followed a procedure called preregistration, publishing the methods and rationale of each study before the experiments were undertaken. Then they reported the results and statistical analysis no matter what the outcome. That prevents researchers from teasing out positive results from their data or leaving negative results unpublished. If everyone followed that protocol, false positives might all but disappear from journals.—John Bohannon

## Homo naledi comes out of the dark

The human family gained a new member in 2015, with the unveiling of a strange new species of hominin from a cave in South Africa. In the first of what promise to be many papers, an international team of 60 researchers described 1500 fossils from at least 15 individuals found by spelunkers deep in the Rising Star cave system northwest of Johannesburg, South Africa.

It was the largest trove of hominin fossils ever discovered in Africa. All of them, the team proposed, belonged to a single species, which they named Homo naledi after the word for “star” in the local Sotho language. The fossils are still undated, which makes it hard to know whether H. naledi lived while our genus, Homo, was emerging about 2 million years ago or more recently.

Regardless of their age, the fossils are important because they reveal a profoundly new kind of Homo. An initial portrait reveals relatively tall individuals whose modern-looking feet and wrists suggest they walked upright like us and may even have made tools. But they were very primitive in other ways, with small brains and long, curving fingers that, together with weird thumbs, suggest that, like earlier hominins, they still had to climb trees to avoid predators.

How they ended up deep in a cave without other animal bones remains puzzling. But researchers hope other fossils still buried in the caves will provide some answers. —Ann Gibbons

## Deep mantle plumes rise to the test

Island chains like Hawaii are a clue to Earth's deep stirrings: plumes of hot rock percolating up from its interior. As a tectonic plate crawls over a plume and volcanic eruptions spew material onto the plate, island after island takes shape over geological time.

But for more than 40 years, there has been a debate as hot as the plumes themselves. Do plumes stretch nearly 3000 kilometers down to the base of Earth's rocky mantle? Or could they be fed by shallower reservoirs of magma? To find out, researchers have used seismic waves from earthquakes—which bend and change speed as they encounter boundaries—to probe the mantle like a CT scan. But the images of the deep earth have been frustratingly fuzzy.

Now, geophysicists can see down more clearly, and lo: They have found 28 plumes, stretching all the way to the core. The new studies rely on a computer-intensive technique called “whole waveform tomography,” which yields the highest resolution images ever of Earth's interior. Whereas previous studies only used the initial bursts of energy from an earthquake, the new ones now incorporate information from all the squiggles in a seismogram.

The plumes, as thick as 800 kilometers, are three times fatter than theorized, so models of how Earth's core is cooling will need some rethinking. Geophysicists hope the new technique will eventually reveal other details of Earth's interior, including the diving slabs of subducting ocean crust and their presumed resting place in deep mantle “graveyards.” —Eric Hand

## A vaccine against Ebola

The unprecedented campaign to develop drugs and vaccines to fight the Ebola epidemic yielded disappointingly few tangible results. But one potential game changer in future outbreaks emerged in 2015. An Ebola vaccine developed by scientists at the Public Health Agency of Canada—known to work in monkeys, and adopted by the Merck pharmaceutical company at the height of last year's epidemic—proved remarkably successful in a clinical study in Guinea led by the World Health Organization.

Because the trial was launched after the epidemic had begun to dwindle, the vaccine—an innocuous livestock virus with an Ebola surface protein stitched in—was tested in a highly unusual ring vaccination strategy that maximized the chance of detecting an effect. That gamble paid off: A paper published online in The Lancet on 31 July showed Merck's vaccine to be between 75% and 100% protective. Another leading vaccine candidate, developed by GlaxoSmithKline, was tested in a traditional setup that ran out of cases and failed to show efficacy.

Regulators such as the European Medicines Agency will need more data before they can give the vaccine their blessing. But Ebola flares up every few years, and even without formal approval, the shots will probably be deployed in the next outbreak on an experimental basis. They may help prevent the West African tragedy from ever happening again. —Martin Enserink

## Yeast engineered to brew opioids

This year, biologists in the United States engineered yeast to convert sugar into the makings of opioid painkillers. The feat of biosynthesis, once unique to opium poppies, might lead to better pharmaceuticals—or, more darkly, to home-brewed morphine and heroin.

In a bioengineering tour de force, the researchers altered yeast to express an additional 21 genes. Those genes originally came from a diverse set of species, including three types of poppies, a plant called Goldthread, bacteria, and even a rat. The result was an organism that could turn sugar into thebaine, normally derived from poppies—the precursor of synthetic painkillers such as hydrocodone and oxycodone. With two additional genes, the yeast could make hydrocodone as well.

The U.S. team and others had previously engineered different yeast strains to carry out either the first or second half of this complex pathway. This year, they took the final steps: performing a single chemical transformation to link the two halves, and putting all the genes together in one strain of yeast.

The newly engineered yeasts are far from efficient: Producing one dose of painkiller would probably take thousands of liters of culture. (Reassuringly, the researchers found that a home-brew setup couldn't make enough opioid to be detectable.) Medicinal chemists are now working to increase the yeasts' output and trying to tweak their biochemistry to produce safer, more effective drugs. —Robert F. Service

## Lymphatic vessels: The brain's well-hidden secret

To anatomists who thought they had the body's systems mapped out, this summer's discovery was like sighting a new continent. An unexpected finding revealed that the lymphatic system—a web of vessels that helps clear waste and transport immune cells in the body—extends into the brain instead of stopping in the neck as most scientists had assumed.

More than 2 centuries ago, an Italian physician, Paolo Mascagni, proposed that the brain has the same lymphatic plumbing as the rest of the body. His claim was largely ignored, but this year, researchers exploring the role of immune cells in the brains of mice spotted a suspiciously well-organized set of T cells in an outer layer of the brain. Nearby vessels seemed to be guiding the cells, and biomarkers showed that the mystery tubes were extensions of the mouse's lymphatic system. Since then, tissue evidence has suggested that human brains harbor similar vessels.

Tucked away in the meninges, the outermost layer covering the brain, the well-hidden vessels may offer insights into how the immune system and brain interact. Scientists had thought that brains had their own, self-contained immune defenses, sealed off from the rest of the body. The discovery—or rediscovery—of a physical link could open new avenues for exploring neurodegenerative and neuroinflammatory diseases like Alzheimer's, multiple sclerosis, and meningitis. But researchers say that for now, their top priority is fathoming the basic structure and function of the newly discovered network. —Hanae Armitage

## Quantum weirdness confirmed

It may be the strangest idea in quantum mechanics: Measuring the property of one quantum particle, such as a photon, can instantly determine the state of another quantum particle, even if it's light-years away. Albert Einstein balked at such “spooky action at a distance” because it seemed to clash with his postulate that nothing can travel faster than light. But this year, many researchers say, physicists in the Netherlands demonstrated beyond a reasonable doubt that such remote influence exists.

The strange quantum linkage is called entanglement. When particles are entangled, their states are completely uncertain but nonetheless correlated. For example, an electron can be prepared so that if you measure it, you'll have a 50% chance of finding it spinning in one direction, and a 50% chance of finding it spinning the opposite way. But you can entangle two such electrons so that if you measure the state of the first one and find it spinning one way, you will know instantly that the state of the other photon has “collapsed” to the opposite spin.

Einstein and others hoped particles like electrons would turn out to harbor “local hidden variables” that determine each entangled particle's state from the beginning, eliminating the need for any kind of remote influence. In 1964, the U.K. theorist John Bell realized that subtle statistical measurements could reveal whether hidden variables were at work.

Earlier versions of Bell's test jibed with the quantum theory and not with hidden variables, but technical loopholes left room for doubt. This year's experiment—which entangled electrons 1.3 kilometers apart—closes the loopholes and drives a stake through local hidden variables. The result won't surprise many physicists, but it could pave the way for exotic technologies such as a quantum Internet.

It also leaves relativity intact, in spite of Einstein's fears. As Bell noted when he first proposed the test, even though the “action at a distance” happens instantaneously, it can't be used to send signals faster than light. —Adrian Cho

Corretion (17 December 2015): The story has been corrected to indicate that the group that conducted the new experiment is based in the Netherlands, not Germany.

### A big year for small worlds

E. Hand, “Scientists may have solved mystery of dwarf planet's enigmatic bright spot,” Science (17 March 2015).

S. A. Stern et al., “The Pluto system: Initial results from its exploration by New Horizons Science,” Science 350, 6258 (15 October 2015).

E. Hand, “Late harvest from Pluto reveals a complex world,” Science 350, 6258 (16 October 2015).

E. Hand, “Mission controller,” Science 348, 6242 (26 June 2015).

### Kennewick Man's kin

M. Balter, “Ancient infant was ancestor of today's Native Americans,” Science 343, 6172 (14 February 2014).

M. Balter, “Critics assail notion that Europeans settled Americas,” Science 335, 6074 (16 March 2012).

M. Balter, “Mystery solved: 8500-year-old Kennewick Man is a Native American after all,” Science (18 June 2015).

M. Rasmussen et al., “The ancestry and affiliations of Kennewick Man,” Nature 523, 455 (23 July 2015).

### Reproducibility in psychology

M. Enserink, “Final report: Stapel affair points to bigger problems in social psychology,” Science (28 November 2012).

J. Bohannon, “Second look at psychology experiments offers reassurance,” ScienceInsider (27 November 2013).

J. Bohannon, “Replication effort provokes praise—and 'bullying' charges,” Science 344, 6186 (23 May 2014).

J. Bohannon, “Many psychology papers fail replication test,” Science 349, 6251 (28 August 2015).

### Homo naledi comes out of the dark

L. Berger et al., “Homo naledi, a new species of the genus Homo from the Dinaledi Chamber, South Africa,” eLife 2015;4:e09560 (10 September 2015).

A. Gibbons, “New human species discovered,” Science 349, 6253 (11 September 2015).

NOVA/National Geographic, “Dawn of Humanity” (2015).

### Deep mantle plumes rise to the test

E. Hand, “Mantle plumes seen rising from Earth's core,” Science 349, 6252 (4 September 2015).

S. French and B. Romanowicz, “Broad plumes rooted at the base of the Earth's mantle beneath major hot spots,” Nature 525, 95 (3 September 2015).

### A vaccine against Ebola

M. Enserink, “High hopes for Guinean vaccine trial,” Science 347, 629 (16 January 2015).

A. M. Henao-Restrepo, “Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial,” The Lancet 386, 9996 (29 August 2015).

P. R. Krause, “Interim results from a phase 3 Ebola vaccine study in Guinea,” The Lancet 386, 9996 (29 August 2015).

A. Marzi et al., “VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain,” Science 349 649 (14 August 2015).

M. Enserink, “Unusual Ebola vaccine study pays off in Guinea,” Science 349, 6248 (7 August 2015).

J. Cohen and M. Enserink, “Ebola vaccines face daunting path to approval,” Science 349, 6254 (18 September 2015).

### Yeast engineered to brew opioids

R. F. Service, “Modified yeast produce opiates from sugar,” Science 349, 6249 (14 August 2015).

R. F. Service, “Final Step in Sugar to Morphine Deciphered,” News from Science (25 June 2015).

R. F. Service, “Researchers closer to engineering yeast that make morphine, spurring worries,” ScienceInsider (18 May 2015).

D. Endy et al., “Complete absence of thebaine biosynthesis under home-brew fermentation conditions,” bioRxiv (13 August 2015).

### Lymphatic vessels: The brain's well-hidden secret

A. Louveau et al., “Structural and functional features of central nervous system lymphatic vessel,” Nature 523, 337 (1 June 2015).

A. Aspelund et al., “A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules,” Journal of Experimental Medicine 212, 991 (15 June 2015).

### Quantum weirdness confirmed

B Hensen et al., “Loophole-free Bell inequality violation using electron spins separated by 1.3 kilometres,” Nature 526 682 (29 October 2015).

A. Cho, “More evidence to support quantum theory's 'spooky action at a distance,” Science (28 August 2015).

Stanford Encyclopedia of Philosophy, “The Einstein-Podolsky-Rosen argument in quantum theory.”

Stanford Encyclopedia of Philosophy, “Bell's Theorem.”

4. # Scorecard for 2015

Looking back at items last year's Breakthrough staff expected to make news in 2015.

In every Breakthrough section, staff members record scientific developments they think we'll be talking about in the next year. Our forecasts for 2015 turned out fairly well; next year's are on p. 1464.

## ARCTIC SEA ICE

Scientists are still debating whether—and, if so, how—warming in the Arctic and dwindling sea ice influence extreme weather events at midlatitudes. Model limitations, scarce data on the warming Arctic, and the inherent variability of the systems make answers elusive. But a flurry of studies, workshops, and meetings over the past year is ramping up the hunt for an atmospheric link.

## SOLAR SYSTEM HISTORY

Could the dwarf planets Ceres and Pluto be twins separated at birth? Scientists have long suspected that Ceres, closer in composition to icy Pluto and its ilk, may be something of an interloper in the asteroid belt. In December, NASA's Dawn spacecraft provided evidence: Mixed with Ceres's surface minerals is ammonia, a compound that could have been stable only in the colder reaches of the outer system. Either the ammonia reached Ceres early on in a fusillade of small impactors, or Ceres formed in the outer solar system and was flung inward to its current locale, perhaps because of the gravitational disruptions of a wandering Jupiter.

## LHC RESTART

As expected, after 2 years of repairs, the world's largest atom-smasher, Europe's Large Hadron Collider (LHC), ran at close to its design energy instead of the half-energy that it had coasted at from 2010 to 2013. However, the LHC collected less than half the data envisioned. The hunt for new particles should heat up in the next few years. The future of accelerator-based particle physics may hinge on its success.

## COMBINED IMMUNOTHERAPY

Last year we had our eyes on cancer drug combinations that relied at least partly on immunotherapy, using the immune system to target tumors. That research continues to flourish, but there aren't many hard results yet. Still, in September the U.S. Food and Drug Administration approved a combination of two immunotherapy treatments, ipilimumab and nivolumab, for advanced melanoma, and there are hints that some patients respond better to certain combinations still in trials. Keep an eye out in 2016 for more findings in this very active field.

## SCORECARD

### ARCTIC SEA ICE

D. Coumou et al., “The weakening summer circulation in the Northern Hemisphere mid-latitudes,” Science 348, 6232 (17 April 2015).

J. Francis and N. Skific, “Evidence linking rapid Arctic warming to mid-latitude weather patterns,” Philosophical Transactions of the Royal Society A 373 (July 2015).

J. A. Screen et al., “Reduced Risk of North American Cold Extremes due to Continued Arctic Sea Ice Loss,” Bulletin of the American Meteorological Society 96 1489 (September 2015).

### SOLAR SYSTEM HISTORY

E. Hand, “Scientists may have solved mystery of dwarf planet's enigmatic bright spot,” Science (17 March 2015).

S. A. Stern et al., “The Pluto system: Initial results from its exploration by New Horizons Science,” Science 350, 6258 (15 October 2015).

E. Hand, “Late harvest from Pluto reveals a complex world,” Science 350, 6528 (16 October 2015).

E. Hand, “Mission controller,” Science 348, 6242 (26 June 2015).

### LHC RESTART

A. Cho, “Excitement, anxiety greet LHC restart,” Science 347, 6227 (13 March 2015).

### IMMUNOTHERAPY

J. Larkin et al., “Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma,” The New England Journal of Medicine, 373 (2 July 2015).

5. # Areas to watch in 2016

Our editors scan the horizon for next year's hottest topics in science.

News writers live partly in the future. They may not know exactly what lies ahead, but, like old-time whalers, they do keep a sharp eye on the horizon. Here are a few items on the Breakthrough team's “watch list” for the next year.

## FALLING BODIES

French researchers plan to launch a satellite that in the next 2 years will recreate in space possibly the most famous experiment that never happened. Most likely, Galileo didn't really drop balls made of two different materials from the Leaning Tower of Pisa—his legendary demonstration that all objects accelerate at the same rate under the pull of gravity. However, physicists with MicroSCOPE (an acronym for the French equivalent of the Drag-Compensated Microsatellite for the Observation of the Equivalence Principle) actually will test whether two free-falling cylinders of different materials, titanium and platinum-rhodium, experience a different pull from Earth's gravity and orbit at ever-so-slightly different heights. Any difference would violate the equivalence principle, which says that gravitational mass equals inertial mass and lies at the heart of Einstein's general theory of relativity. The experiment's a long shot, but a fun one.

## WHO LET THE DOGS IN?

Could 2016 be the year we finally figure out where dogs came from? For decades, scientists have debated where and when wolves were domesticated into our canine pals. The proposed epicenters range from Europe to Asia, and the time frames span 15,000 to more than 30,000 years ago. In 2013, the major warring factions declared a truce and began pooling their resources and scouring the globe for every ancient wolf and dog specimen they could get their hands on. Now, they may be close to a definitive answer, one that could solve one of the greatest mysteries of domestication. One of the collaboration's leaders says significant findings should come next year.

## GRAVITATIONAL WAVES

Newly upgraded detectors could finally give physicists a glimpse of gravitational waves: ripples in space and time set off by, say, two neutron stars spiraling into each other. This year, scientists with the Laser Interferometer Gravitational-Wave Observatory (LIGO) completed rebuilds of their kilometers-long facilities in Livingston, Louisiana, and Hanford, Washington, to make them up to 10 times more sensitive than when they ran from 2002 to 2010. LIGO took 3 months' worth of data this year. However, the physicists are still tuning up their detectors and will make a longer data run later next year. Meanwhile, European researchers plan to bring their upgraded VIRGO detector near Pisa, Italy, on line. Scientists say that when LIGO and VIRGO reach their design sensitivities in a few years, they are virtually certain to pick up a passing ripple. With luck, they might see one sooner.

## AREAS TO WATCH

### Falling Bodies

Adrian Cho, “Drop Test,” Science 347, 6226 (6 March 2015).

### Who let the dogs in?

D. Grimm, “Dawn of the dog,” Science 348, 6232 (17 April 2005).

### Gravitational waves

Adrian Cho, “To catch a wave,” Science 347, 6226 (6 March 2015).

A. Cho, “Video: Take a whirl above the massive LIGO gravitational wave detector,” Science (5 March 2015).

P. Bagla, “India to join hunt for gravity waves,” ScienceInsider (5 February 2014).

6. # Breakdown of the year: Assault on the past

1. Elizabeth Culotta

Science's Breakdown of the Year was the Islamic State's efforts to erase the past by destroying antiquities and murdering scholars. Other setbacks for science included revelations of sexist attitudes and sexual harassment, and a court-ordered halt to construction of a giant telescope.

For 2000 years, the imposing colonnades of the great temple of Baal rose from the desert in the ancient city of Palmyra, in today's Syria. The temple's friezes recorded the story of this ancient crossroads of East and West, and had weathered centuries of conflict, from the warrior queen Zenobia's ill-fated rebellion against Rome to two world wars. But in August 2015, a lethal combination of 21st century explosives and a twisted, 7th century worldview erased that history, when the group known as the Islamic State (IS) group deliberately blew up the temple.

“Palmyra symbolizes everything that extremists abhor—cultural diversity, dialogue between cultures, the encounter of peoples of all origins in this caravan city between Europe and Asia,” UNESCO Director-General Irina Bokova said in October, after the group, also known as Daesh, felled the ancient city's iconic Arch of Triumph.

Palmyra, a UNESCO World Heritage Site, was but one of the archaeological wonders that suffered this year as the IS group rampaged through parts of Syria and Iraq, brutalizing local populations and destroying their culture, including archaeological sites. What wasn't destroyed was often plundered and sold, lost either way to humanity and to archaeological research. “I believe [it] is the worst cultural heritage crisis since World War II,” says Michael Danti, academic director at the Cultural Heritage Initiative of the American Schools of Oriental Research.

The region is the birthplace of some of humanity's greatest innovations—among them the first agricultural societies, the first writing, and the first empires; it's also home to major World Heritage Sites from later periods. So archaeologists were horrified when, in February, the IS group released a video of men taking sledgehammers to statues in the Mosul Museum in northern Iraq, and drilling away the features of a great winged bull, a Neo-Assyrian sculpture dating to the 8th century B.C.E. In early April, the group destroyed monuments and bulldozed ruins in the World Heritage Site of Hatra, Iraq, then raced on to do the same at Nimrud, an ancient Assyrian city and also a World Heritage Site. Claiming to wish to “purify” the region of anything “un-Islamic,” the militants have also systematically destroyed countless smaller sites, including mosques, churches, and shrines that testify to the diversity of religions both now and in ancient times.

Many of the major sites had previously suffered looting and collateral damage from conflict. But the IS group treated them as targets in a campaign of cultural cleansing. At major sites, explosions were set off as scripted performance pieces, with the release of photos and videos timed for maximum public relations value. Meanwhile, the group has set up industrial-scale looting operations to dig up and sell artifacts, which provide a sizable portion of its income. Satellite images show looters' holes pocking key sites, signaling a loss of priceless archaeological knowledge.

In May, in a raid in eastern Syria, U.S. special forces killed a militant known as Abu Sayyaf who was apparently deeply involved in the antiquities trade. They found a cache of archaeological objects, including coins, suggesting large-scale looting. Some turned out to be fakes, but others still bore inventory numbers from an Iraqi museum. Much of the looting has been market-driven, Danti says, with Hellenistic, Roman, and Byzantine periods especially targeted.

In Palmyra, the IS group wove the attacks on archaeology into its brutal treatment of locals. The group executed 50 captured soldiers in the ancient city's amphitheater and tied captives to columns, then exploded the columns. The group also beheaded Khaled al-Asaad, an 82-year-old Syrian archaeologist who had spent his life studying and protecting Palmyra's ruins. Many other Iraqis and Syrians have risked and lost their lives to protect sites.

UNESCO and several partners now have a program to put 5000 cameras on the ground to document threatened sites and artifacts, including many in the Middle East. Agencies are also working to reduce the trade in looted objects. Another program, run by the University of Pennsylvania Museum of Archaeology and Anthropology and partner institutions, has trained Iraqi locals to protect threatened sites and swiftly pack up artifacts, employing techniques last widely used during WWII. When the conflict raged around the Ma'arra museum outside Aleppo in June, its delicate frescoes had been sandbagged and mostly survived—a minor victory in a terrible year for world heritage.

## Breakdown runners-up

### SEXISM IN SCIENCE

This year exposed an underbelly of sexist attitudes in science. In April, a Twitterstorm erupted when a reviewer for PLOS ONE suggested that what two (female) scientists really needed to improve their paper was a male co-author. Twitter exploded again in June, when Nobel laureate Tim Hunt told an audience that when women are in the lab, “you fall in love with them and they fall in love with you,” although many defenders argued that his remarks were a failed joke. Then in October, prominent University of California, Berkeley (UC), astronomer Geoff Marcy was found to have repeatedly violated the university's sexual harassment policy over a decade, groping, kissing, and touching female students. Despite the bad news barrage, the revelations had a salutary effect: PLOS ONE removed the reviewer and editor involved, and women countered Hunt under the hashtag #distractinglysexy, posting photos of themselves doing science bedecked in field and lab gear. As for Marcy, the national tide of outrage proved too great, and he resigned from the UC system on 14 October.

### THIRTY METER TELESCOPE

This year, a project to build the largest optical telescope on U.S. soil collided head-on with the rights and beliefs of indigenous people.

The builders of the Thirty Meter Telescope (TMT) got an inkling of trouble in October 2014, when protesters disrupted the project's groundbreaking ceremony on the Hawaiian mountain of Mauna Kea. The mountain is considered sacred in the Hawaiian religion, and—although 13 telescopes already crowd the summit—opponents claim the enormous TMT would desecrate it.

Since March 2015, protesters have been blocking construction crews from reaching the site, and dozens have been arrested. A 1-week halt in construction has grown into an indefinite hiatus. Then, in December, Hawaii's Supreme Court ruled that the TMT's construction permit was invalid because opponents hadn't been given time to make their case before it was awarded in 2011—a setback that could delay construction for years. The outlook for the telescope—meant to deliver some of the clearest ever views of the cosmos—appears distinctly cloudy.

### BREAKDOWN OF THE YEAR: Assault on the past

A. Lawler, “Militants leave trail of destruction at Iraqi sites,” Science 347, 6227 (13 March 2015).

AAAS Geospatial Technologies Project, “Ancient History, Modern Destruction: Assessing the Current Status of Syria's World Heritage Sites Using High-Resolution Satellite Imagery.”

Institute for Digital Archaeology, “Million Image Database.”

Penn Cultural Heritage Center, “Syria.”

### Breakdown Runners-up

#### Sexism in science

Science News Staff, “Geoff Marcy, prominent astronomer, resigns academic position after sexual harassment judgment,” ScienceInsider (14 October 2015).

A. Ghorayshi, “Famous Berkeley astronomer violated sexual harassment policies over many years,” BuzzFeedNews (9 October 2015).

R. Bernstein, “PLOS ONE ousts reviewer, editor after sexist peer-review storm,” ScienceInsider (1 May2015).

C. Gramling, “Nobel laureates say the dumbest things,” Slate (10 June 2015).

### Thirty Meter Telescope

L. Xin, “Protestors greet opening ceremony of Hawaii telescope,” ScienceInsider (9 October 2014).

I. Loomis, “Hawaii protests force pause in construction of world's largest telescope,” ScienceInsider (15 December 2015).

I. Loomis, “In symbolic blow, Native Hawaiian panel withdraws support for world's largest telescope,” ScienceInsider (1 May 2015).

I. Loomis and A. Cho, “Telescope clash deeply rooted in Hawaii's past,” Science 348, 6235 (8 May 2015).

A. Cho, “Affirming support for Thirty Meter Telescope, Hawaii's governor calls for closing others,” Science Insider (27 May 2015).

A. Cho and I. Loomis, “Hawaii's governor proposes telescope swap,” ScienceInsider (2 June 2015).

Science News Staff, “Astronomers to restart construction of controversial telescope in Hawaii,” ScienceInsider (21 June 2015).

I. Loomis, “Protestors block effort to restart work on controversial Hawaii telescope; 11 arrested,” ScienceInsider (25 June 2015).

Science News Staff, “Hawaii's high court blocks construction of giant telescope,” ScienceInsider (2 December 2015).