Dental plaque preserved in fossilized teeth confirms that Neandertals were flexible eaters and may have self-medicated with an ancient equivalent of aspirin.
DNA recovered from calcified plaque on teeth from four Neandertal individuals suggest that those from the grasslands around Beligum’s Spy cave ate woolly rhinoceros and wild sheep, while their counterparts from the forested El Sidrón cave in Spain consumed a menu of moss, mushrooms and pine nuts.
The evidence bolsters an argument that Neandertals’ diets spanned the spectrum of carnivory and herbivory based on the resources available to them, Laura Weyrich, a microbiologist at the University of Adelaide in Australia, and her colleagues report March 8 in Nature.
The best-preserved Neandertal remains were from a young male from El Sidrón whose teeth showed signs of an abscess. DNA from a diarrhea-inducing stomach bug and several gum disease pathogens turned up in his plaque. Genetic material from poplar trees, which contain the pain-killing aspirin ingredient salicylic acid, and a plant mold that makes the antibiotic penicillin hint that he may have used natural medication to ease his ailments.
The researchers were even able to extract an almost-complete genetic blueprint, or genome, for one ancient microbe, Methanobrevibacter oralis. At roughly 48,000 years old, it’s the oldest microbial genome sequenced, the researchers report.
When Tommy the chimpanzee first came to London’s zoo in the fall of 1835, he was dressed in an old white shirt.
Keepers gave him a new frock and a sailor hat and set him up in a cozy spot in the kitchen to weather the winter. Visitors flocked to get a look at the little ape roaming around the keepers’ lodge, curled up in the cook’s lap or tugging on her skirt like a toddler. Tommy was a hit — the zoo’s latest star. Six months later, he was dead.
Tommy’s sorrowful story comes near the middle of Isobel Charman’s latest book, The Zoo, a tale of the founding of the Gardens of the Zoological Society of London, known today as the London Zoo. The book lays out a grand saga of human ambition and audacity, but it’s the animals’ stories — their lives and deaths and hardships — that catch hold of readers and don’t let go.
Charman, a writer and documentary producer, resurrects almost three decades of history, beginning in 1824, when the zoo was still just a fantastical idea: a public menagerie of animals “that would allow naturalists to observe the creatures scientifically.”
It was a long, hard path to that lofty dream, though: In the zoo’s early years, exotic creatures were nearly impossible to keep alive. Charman unloads a numbing litany of animal misery that batters the reader like a boxer working over a speed bag. Kangaroos hurl themselves at fences, monkeys attack each other in cramped, dark cages and an elephant named Jack breaks a tusk while smashing up his den. Charman’s parade of horrors boggles the mind, as does the sheer number of animals carted from all corners of the world to the cold, wet enclosures of the zoo.
Her story is an incredible piece of detective work, told through the eyes of many key players and famous figures, including Charles Darwin. Charman plumbs details from newspaper articles, diaries, census records and weather reports to craft a narrative of the time. She portrays a London that’s gritty, grimy and cold, where some aspects of science and medicine seem stuck in the Dark Ages. Doctors still used leeches to bleed patients, and no one had a clue how to care for zoo animals. Zoo workers certainly tried — applying liniment to sores on a lion’s legs, prescribing opium for a sick puma and treating a constipated llama with purgatives. But nothing seemed to stop the endless conveyor belt that brought living animals in and carried dead ones out. Back then, caring for zoo animals was mostly a matter of trial and error, Charman writes. What seems laughably obvious now — animals need shelter in winter, cakes and buns aren’t proper food for elephants — took zookeepers years to figure out.
Over time the zoo adapted, making gradual changes that eventually improved the lives of its inhabitants. It seemed to morph, finally, from mostly “a playground of the privileged,” as Charman calls it, to a reliable place for scientific study, where curious people could learn about the “wild and wonderful” creatures within.
One of those people was Darwin, whose ideas about human origins clicked into place after he spent time with Jenny the orangutan. Her teasing relationship with her keeper, apparent understanding of language and utter likeness to people helped convince Darwin that humankind was just another branch on the tree of life, Charman writes. Darwin’s work on the subject wouldn’t be published for decades, but in the meantime, the zoo’s early improvements seemed to have stuck. Over 30 years after Tommy the chimpanzee died in his keeper’s arms, a hippopotamus gave birth to “the first captive-bred hippo to be reared by its mother,” Charman notes. The baby hippo not only survived — she lived for 36 years.
Readers may wonder how standards for animal treatment have changed over time. But Charman sticks to history, rather than examining contrasts to modern zoos. Still, what she offers is gripping enough on its own: a bold, no-holds-barred look at one zoo’s beginning. It was impressive, no doubt. But it wasn’t pretty.
Researchers have identified new enemies in the war on cancer: ones that are already inside cells and that no one can avoid.
Random mistakes made as stem cells divide are responsible for about two-thirds of the mutations in cancer cells, researchers from Johns Hopkins University report in the March 24 Science. Across all cancer types, environment and lifestyle factors, such as smoking and obesity, contribute 29 percent of cancer mutations, and 5 percent are inherited. That finding challenges the common wisdom that cancer is the product of heredity and the environment. “There’s a third cause and this cause of mutations is a major cause,” says cancer geneticist Bert Vogelstein.
Such random mutations build up over time and help explain why cancer strikes older people more often. Knowing that the enemy will strike from within even when people protect themselves against external threats indicates that early cancer detection and treatment deserve greater attention than they have previously gotten, Vogelstein says.
Vogelstein and biomathematician Cristian Tomasetti proposed in 2015 that random mutations are the reason some organs are more prone to cancer than others. For instance, stem cells are constantly renewing the intestinal lining of the colon, which develops tumors more often than the brain, where cell division is uncommon. That report was controversial because it was interpreted as saying that most cancers are the result of “bad luck.” The analysis didn’t include breast and prostate cancers. Factoring in those common cancers might change the results, some scientists said. And because the researchers looked at only cancer within the United States, critics charged that the finding might not hold up when considering places around the world where different environmental factors, such as infections, affect cancer development.
In the new study, Vogelstein, Tomasetti and Hopkins colleague Lu Li examined data from 69 countries about 17 types of cancer, this time including breast and prostate. Again, the researchers found a strong link between cancer and tissues with lots of dividing stem cells. The team also used DNA data and epidemiological studies to calculate the proportions of mutations in cancer cells caused by heredity or environmental and lifestyle factors. Remaining mutations were attributed to random errors — including typos, insertions or deletions of genes, epigenetic changes (alterations of chemical tags on DNA or proteins that affect gene activity) and gene rearrangements. Such errors unavoidably happen when cells divide. Usually cancer results after a cell accumulates many mutations. Some people will have accumulated a variety of cancer-associated mutations but won’t get cancer until some final insult goads the cell into becoming malignant (SN: 12/26/15, p. 28). For some tumors, all the mutations may be the hit-and-miss result of cell division mistakes. There’s no way to evade those cancers, Vogelstein says. Other malignancies may spring up as a result of different combinations of heritable, environmental and random mutations. Lung cancer and other tumor types that are strongly associated with environmentally caused mutations could be eluded by avoiding the carcinogen, even when most of the mutations that spur cancer growth arise from random mistakes, Tomasetti says.
“They are venturing into new territory,” says Giovanni Parmigiani, a biostatistician at the Harvard T.H. Chan School of Public Health. Tomasetti, Li and Vogelstein are the first to rigorously estimate the contribution of environment, heredity and DNA-copying errors to cancer, he says. “Perhaps the estimates will improve in the future, but theirs seems like a very solid starting point.”
Now that the Hopkins researchers have pointed it out, the relationship between dividing cells and cancer seems obvious, says biological physicist Bartlomiej Waclaw of the University of Edinburgh. “I don’t think that the existence of this correlation is surprising,” he says. “What’s surprising is that it’s not stronger.”
Some tissues develop cancers more or less often than other tissues with a similar number of cell divisions, Waclaw and Martin Nowak of Harvard University pointed out in a commentary on the Hopkins study, published in the same issue of Science. That suggests some organs are better at nipping cancer in the bud. Discovering how those tissues avoid cancer could lead to new ways to prevent tumors elsewhere in the body, Waclaw suggests.
Other researchers say the Hopkins team is guilty of faulty reasoning. “They are assuming that just because tissues which have high stem cell turnover also have high cancer rates, that one is causing the other,” says cancer researcher Anne McTiernan of the Fred Hutchinson Cancer Research Center in Seattle. “In this new paper, they’ve added data from other countries but haven’t gotten away from this biased thinking.”
Tomasetti and colleagues based their calculations on data from Cancer Research UK that suggest that 42 percent of cancers are preventable. Preventable cancers are ones for which people could avoid a risk factor, such as unprotected sun exposure or tanning bed use, or take positive steps to lower cancer risks, such as exercising regularly and eating fruits and vegetables. But those estimates may not be accurate, McTiernan says. “In reality, it’s very difficult to measure environmental exposures, so our estimates of preventability are likely very underestimated.”
To attribute so many cancer mutations to chance seems to negate public health messages, Waclaw says, and some people may find the calculation that 66 percent of cancer-associated mutations are unavoidable disturbing because they spend a lot of time trying to prevent cancer. “It’s important to consider the randomness, or bad luck, that comes with cellular division,” he says.
In fact, Tomasetti and Vogelstein stress that their findings are compatible with cancer-prevention recommendations. Avoiding smoking, tanning beds, obesity and other known carcinogens can prevent the “environmental” mutations that combine with inherited and random mutations to tip cells into cancer. Without those final straws loaded from environmental exposures, tumors may be averted or greatly delayed.
People with cancer may be able to take some comfort from the study, says Elaine Mardis, a cancer genomicist at the Nationwide Children’s Hospital in Columbus, Ohio. “Perhaps the positive message here is that, other than known risk factors, such as smoking, radiation exposure and obesity, there is a component of cancer that is simply a consequence of being human.”
The Martian atmosphere definitely had more gas in the past.
Data from NASA’s MAVEN spacecraft indicate that the Red Planet has lost most of the gas that ever existed in its atmosphere. The results, published in the March 31 Science, are the first to quantify how much gas has been lost with time and offer clues to how Mars went from a warm, wet place to a cold, dry one.
Mars is constantly bombarded by charged particles streaming from the sun. Without a protective magnetic field to deflect this solar wind, the planet loses about 100 grams of its now thin atmosphere every second (SN: 12/12/15, p. 31). To determine how much atmosphere has been lost during the planet’s lifetime, MAVEN principal investigator Bruce Jakosky of the University of Colorado Boulder and colleagues measured and compared the abundances of two isotopes of argon at different altitudes in the Martian atmosphere. Using those measurements and an assumption about the amounts of the isotopes in the planet’s early atmosphere, the team estimates that about two-thirds of all of Mars’ argon gas has been ejected into space. Extrapolating from the argon data, the researchers also determined that the majority of carbon dioxide that the Martian atmosphere ever had also was kicked into space by the solar wind.
A thicker atmosphere filled with carbon dioxide and other greenhouse gases could have insulated early Mars and kept it warm enough for liquid water and possibly life. Losing an extreme amount of gas, as the results suggest, may explain how the planet morphed from lush and wet to barren and icy, the researchers write.
The way babies learn to speak is nothing short of breathtaking. Their brains are learning the differences between sounds, rehearsing mouth movements and mastering vocabulary by putting words into meaningful context. It’s a lot to fit in between naps and diaper changes.
A recent study shows just how durable this early language learning is. Dutch-speaking adults who were adopted from South Korea as preverbal babies held on to latent Korean language skills, researchers report online January 18 in Royal Society Open Science. In the first months of their lives, these people had already laid down the foundation for speaking Korean — a foundation that persisted for decades undetected, only revealing itself later in careful laboratory tests.
Researchers tested how well people could learn to identify and speak tricky Korean sounds. “For Korean listeners, these sounds are easy to distinguish, but for second-language learners they are very difficult to master,” says study coauthor Mirjam Broersma, a psycholinguist of Radboud University in Nijmegen, Netherlands. For instance, a native Dutch speaker would listen to three distinct Korean sounds and hear only the same “t” sound.
Broersma and her colleagues compared the language-absorbing skills of a group of 29 native Dutch speakers to 29 South Korea-born Dutch speakers. Half of the adoptees moved to the Netherlands when they were older than 17 months — ages at which the kids had probably begun talking. The other half were adopted as preverbal babies younger than 6 months. As a group, the South Korea-born adults outperformed the native-born Dutch adults, more easily learning both to recognize and speak the Korean sounds.
This advantage held when the researchers looked at only adults who had been adopted before turning 6 months old. “Even those who were only 3 to 5 months old at the time of adoption already knew a lot about the sounds of their birth language, enough even to help them relearn those sounds decades later,” Broersma says.
Uncovering this latent skill decades after it had been imprinted in babies younger than 6 months was thrilling, Broersma says. Many researchers had assumed that infants start to learn the sounds of their first language later, around 6 to 8 months after birth. “Our results show that that assumption must have been wrong,” she says.
It’s possible that some of these language skills were acquired during pregnancy, as other studies have hinted. Because the current study didn’t include babies who were adopted immediately after birth, the results can’t say whether language heard during gestation would have had an influence on later language skills. Still, the results suggest that babies start picking up language as soon as they possibly can.
Computers don’t have eyes, but they could revolutionize the way scientists visualize cells.
Researchers at the Allen Institute for Cell Science in Seattle have devised 3-D representations of cells, compiled by computers learning where thousands of real cells tuck their component parts.
Most drawings of cells in textbooks come from human interpretations gleaned by looking at just a few dead cells at a time. The new Allen Cell Explorer, which premiered online April 5, presents 3-D images of genetically identical stem cells grown in lab dishes (composite, above), revealing a huge variety of structural differences. Each cell comes from a skin cell that was reprogrammed into a stem cell. Important proteins were tagged with fluorescent molecules so researchers could keep tabs on the cell membrane, DNA-containing nucleus, energy-generating mitochondria, microtubules and other cell parts. Using the 3-D images, computer programs learned where the cellular parts are in relation to each other. From those rules, the programs can generate predictive transparent models of a cell’s structure (below). The new views, which can capture cells at different time points, may offer clues into their inner workings. The project’s tools are available for other researchers to use on various types of cells. Insights gained from the explorations might lead to a better understanding of human development, cancer, health and diseases.
Researchers have already learned from the project that stem cells aren’t the shapeless blobs they might appear to be, says Susanne Rafelski, a quantitative cell biologist at the Allen Institute. Instead, the stem cells have a definite bottom and top, a proposed structure that’s now confirmed by the combined cell data, Rafelski says. A solid foundation of skeleton proteins forms at the bottom. The nucleus is usually found in the cell’s center. Microtubules bundle together into large fibers that tend to radiate from the top of the cell toward the bottom. During cell division, microtubules form structures called bipolar spindles that are necessary to divvy up DNA. One surprise was that the membrane surrounding the nucleus gets ruffled, but never completely disappears, during cell division. Near the top of the cell, above the nucleus, stem cells store tubelike mitochondria much the way plumbing and electrical wires are tucked into ceilings. The tubular mitochondria were notable because some researchers thought that since stem cells don’t require much energy, the organelles might separate into small, individual units.
Old ways of observing cells were like trying to get to know a city by looking at a map, Rafelski says. The cell explorer is more like a documentary of the lives of the citizens.
Every year science offers a diverse menu of anniversaries to celebrate. Births (or deaths) of famous scientists, landmark discoveries or scientific papers — significant events of all sorts qualify for celebratory consideration, as long as the number of years gone by is some worthy number, like 25, 50, 75 or 100. Or simple multiples thereof with polysyllabic names.
2017 has more than enough such anniversaries for a Top 10 list, so some worthwhile events don’t even make the cut, such as the births of Stephen Hawking (1942) and Arthur C. Clarke (1917). The sesquicentennial of Michael Faraday’s death (1867) almost made the list, but was bumped at the last minute by a book. Namely:
On Growth and Form, centennial (1917) A true magnum opus, by the Scottish biologist D’Arcy Wentworth Thompson, On Growth and Form has inspired many biologists with its mathematical analysis of physical and structural forces underlying the diversity of shapes and forms in the biological world. Nobel laureate biologist Sir Peter Medawar praised Thompson’s book as “beyond comparison the finest work of literature in all the annals of science that have been recorded in the English tongue.”
Birth of Abraham de Moivre, semiseptcentennial (1667). Born in France on May 26, 1667, de Moivre moved as a young man to London where he did his best work, earning election to the Royal Society. Despite exceptional mathematical skill, though, he attained no academic position and earned a meager living as a tutor. He is most famous for his book The Doctrine of Chances, which was in essence an 18th century version of Gambling for Dummies. It contained major advances in probability theory and in later editions introduced the concept of the famous bell curve. Isaac Newton was impressed; the legend goes that when anyone asked him about probability, Newton said to go talk to de Moivre.
Exoplanets, quadranscentennial (1992)It seems like exoplanets have been around almost forever (and probably actually were), but the first confirmed by Earthbound astronomers were reported just a quarter century ago. Three planets showed up orbiting not an ordinary star, but a pulsar, a rapidly spinning neutron star left behind by a supernova. Astrophysicists Aleksander Wolszczan and Dale Frail found a sign of the planets, first detected with the Arecibo radio telescope, in irregularities in the radio pulses from the millisecond pulsar PSR1257+12. Some luck was involved. In 1990, the Arecibo telescope was being repaired and couldn’t pivot to point at a specific target; instead it constantly watched just one region of the sky. PSR1257+12 just happened to float by.
Birth of Marie Curie, sesquicentennial (1867) No doubt the most famous Polish-born scientist since Copernicus, Curie was born in Warsaw on November 7, 1867, as Maria Sklodowska. Challenged by poverty, family tragedies and poor health, she nevertheless excelled as a high school student. But she then worked as a governess, while continuing as much science education as possible, until her married sister invited her to Paris. There she completed her physics education with honors and met and married another young physicist, Pierre Curie.
Together they tackled the mystery of the newly discovered radioactivity, winning the physics Nobel in 1903 along with radioactivity’s discoverer, Henri Becquerel. Marie continued the work after her husband’s tragic death in 1906; she became the first person to win a second Nobel, awarded in chemistry in 1911 for her discovery of the new radioactive elements polonium and radium.
Laws of Robotics, semisesquicentennial (1942) One of science fiction’s greatest contributions to modern technological philosophy was Isaac Asimov’s Laws of Robotics, which first appeared in a short story in the March 1942 issue of Astounding Science Fiction. Later, those laws formed the motif of his many robot novels and appeared in his famous Foundation Trilogy (and subsequent sequels and prequels). They were:
A robot may not injure a human being or, through inaction, allow a human being to come to harm. A robot must obey the orders given to it by human beings, except where such orders would conflict with the First Law. A robot must protect its own existence as long as such protection does not conflict with the First or Second Law. Much later Asimov added a “zeroth law,” requiring robots to protect all of humankind even if that meant violating the other three laws. Artificial intelligence researchers all know about Asimov’s laws, but somehow have not managed to enforce them on social media. Incidentally, this year is also the quadranscentennial of Asimov’s death in 1992.
First sustained nuclear fission chain reaction, semisesquicentennial (1942) Enrico Fermi, the Italian Nobel laureate, escaped fascist Italy to come to the United States shortly after nuclear fission’s discovery in Germany. Fermi directed construction of the “atomic pile,” or nuclear reactor, on a squash court under the stands of the University of Chicago’s football stadium. Fermi and his collaborators showed that neutrons emitted from fissioning uranium nuclei could induce more fission, creating a chain reaction capable of releasing enormous amounts of energy. Which it later did.
Discovery of pulsars, semicentennial (1967) Science’s awareness of the existence of pulsars turns 50 this year, thanks to the diligence of Irish astrophysicist Jocelyn Bell Burnell. She spent many late-night hours examining the data recordings from the radio telescope she helped to build that first spotted a signal from a pulsar. She recognized that the signal was something special even though others thought it was just a glitch in the apparatus. But she was a graduate student so her supervisor got the Nobel Prize instead of her.
Einstein’s theory of lasers, centennial (1917) Albert Einstein did not actually invent the laser, but he developed the mathematical understanding that made lasers possible. By 1917, physicists knew that quantum physics played a part in the working of atoms, but the details were fuzzy. Niels Bohr had shown in 1913 that an atom’s electrons occupy different energy levels, and that falling from a high energy level to a lower one emits radiation.
Einstein worked out the math describing this process when many atoms have electrons in high-energy states and emit radiation. His analysis of matter-radiation interaction indicated that it would be possible to prepare many atoms in the same high-energy state and then stimulate them to emit radiation all at once. Properly done, all the atoms would emit radiation of identical wavelength with the waves in phase. A few decades later other physicists figured out how to build such a device for use as a powerful weapon or to read bar codes at grocery stores.
Qubits, quadranscentennial (1992) An even better quantum anniversary than lasers is the presentation to the world of the concept of quantum bits of information. Physicist Ben Schumacher of Kenyon College in Ohio unveiled the idea at a conference in Dallas in 1992 (I was there). A “quantum bit” of information, or qubit, represents the information contained in a quantum particle, which can exist in multiple states at once. A photon, for instance, might simultaneously be in a state of horizontal or vertical polarization. Or an electron’s spin could be up and down at the same time.
Such states differ from classical bits of information in a computer, recorded as either a 0 or 1; a quantum bit is both 0 and 1 at the same time. It becomes one or the other only when observed, much like a flipped coin is nether heads nor tails until somebody catches it, or it lands on the 50 yard line. Schumacher’s idea did not get a lot of attention at first, but it eventually became the foundational idea for quantum information theory, a field now booming with efforts to construct a quantum computer based on the manipulation of qubits.
Birth of modern cosmology, centennial (1917) It might seem unfair that Einstein gets two Top 10 anniversaries in 2017, but 1917 was a good year for him. Before publishing his laser paper, Einstein tweaked the equations of his brand-new general theory of relativity in order to better explain the universe (details in Part 1). Weirdly, Einstein didn’t understand the universe, and he later thought the term he added to his equations was a mistake. But it turns out that today’s understanding of the universe’s behavior — expanding at an accelerating rate — seems to require the term that Einstein thought he had added erroneously. But you can’t expect Einstein to have foreseen everything. He probably had no idea that lasers would revolutionize grocery shopping either.
A lizard’s intricately patterned skin follows rules like those used by a simple type of computer program.
As the ocellated lizard (Timon lepidus) grows, it transforms from a drab, polka-dotted youngster to an emerald-flecked adult. Its scales first morph from white and brown to green and black. Then, as the animal ages, individual scales flip from black to green, or vice versa.
Biophysicist Michel Milinkovitch of the University of Geneva realized that the scales weren’t changing their colors by chance. “You have chains of green and chains of black, and they form this labyrinthine pattern that very clearly is not random,” he says. That intricate ornamentation, he and colleagues report April 13 in Nature, can be explained by a cellular automaton, a concept developed by mathematicians in the 1940s and ’50s to simulate diverse complex systems. A cellular automaton is composed of a grid of colored pixels. Using a set of rules, each pixel has a chance of switching its shade, based on the colors of surrounding pixels. By comparing photos of T. lepidus at different ages, the scientists showed that its scales obey such rules. In the adult lizard, if a black scale is surrounded by other black scales, it is more likely to switch than a black one bounded by green, the researchers found. Eventually, the lizards’ scales settle down into a mostly stable state. Black scales wind up with around three green neighbors, and green scales have around four black ones. The researchers propose that interacting pigment cells could explain the color flips.
Computer scientists use cellular automata to simulate the real world, re-creating the turbulent motions of fluids or nerve cell activity in the brain, for example. But the new study is the first time the process has been seen with the naked eye in a real-life animal. The scales on an ocellated lizard change color as the animal ages (more than three years of growth shown in first clip). Circles highlight four instances of color-flipping scales. Blue circles indicate a scale that switches from green to black, the green circle indicates a black to green transformation, and the light blue circle marks a scale that flip-flops from green to black to green. Researchers used a cellular automaton to simulate the adult lizard’s color-swapping scales (second clip), and re-create the labyrinthine patterns that develop on its skin.
The Zika virus probably arrived in the Western Hemisphere from somewhere in the Pacific more than a year before it was detected, a new genetic analysis of the epidemic shows. Researchers also found that as Zika fanned outward from Brazil, it entered neighboring countries and South Florida multiple times without being noticed.
Although Zika quietly took root in northeastern Brazil in late 2013 or early 2014, many months passed before Brazilian health authorities received reports of unexplained fever and skin rashes. Zika was finally confirmed as the culprit in May 2015. The World Health Organization did not declare the epidemic a public health emergency until February 2016, after babies of Zika-infected mothers began to be born with severe neurological problems. Zika, which is carried by mosquitoes, infected an estimated 1 million people in Brazil alone in 2015, and is now thought to be transmitted in 84 countries, territories and regions.
Although Zika’s path was documented starting in 2015 through records of human cases, less was known about how the virus spread so silently before detection, or how outbreaks in different parts of Central and South America were connected. Now two groups working independently, reporting online May 24 in Nature, have compared samples from different times and locations to read the history recorded in random mutations of the virus’s 10 genes.
One team, led by scientists in the United Kingdom and Brazil, drove more than 1,200 miles across Brazil — “a Top Gear–style road trip,” one scientist quipped — with a portable device that could produce a complete catalog of the virus’s genes in less than a day. A second team, led by researchers at the Broad Institute of MIT and Harvard, analyzed more than 100 Zika genomes from infected patients and mosquitoes in nine countries and Puerto Rico. Based on where the cases originated, and the estimated rate at which genetic changes appear, the scientists re-created Zika’s evolutionary timeline.
Together, the studies revealed an epidemic that was silently churning long before anyone knew. “We found that in each of the regions we could analyze, Zika virus circulated undetected for many months, up to a year or longer, before the first locally transmitted cases were reported,” says Bronwyn MacInnis, an infectious disease geneticist at the Broad Institute, in Cambridge, Mass. “This means the outbreak in these regions was under way much earlier than previously thought.”
Although the epidemic exploded out of Brazil, the scientists also found a remote possibility of early settlement in the Caribbean. “It’s not immediately clear whether Zika stopped off somewhere else in the Americas before it got to northeast Brazil,” said Oliver Pybus, who studies evolution and infectious disease at the University of Oxford in England. In a third study reported in Nature, researchers from more than two dozen institutions followed a trail of genetic clues to determine when and how Zika made its way to Florida. Those researchers concluded that Zika was introduced multiple times into the Miami area, most likely from the Caribbean, before local mosquitoes picked it up. The number of human cases increased in step with the rise in mosquito populations, said Kristian Andersen, an infectious disease researcher at the Scripps Research Institute in La Jolla, Calif. “Focusing on getting rid of mosquitoes is an effective way of preventing human cases,” he says. Stealth spread An analysis of more than 100 Zika genomes revealed that the virus showed up in nine countries 4.5 to 9 months earlier than the first confirmed cases of Zika virus infection. Colors indicate the distribution of groups of closely related strains of the virus.
Hover over/tap map to explore Zika’s spread in the Americas. Previous studies have found traces of the virus’s footprints across the Americas, but none included so many different samples, says Young-Min Lee of Utah State University, who has also studied Zika’s genes. The current studies provide a higher-resolution look at the timing of the epidemic’s spread, he says, but in terms of Zika’s origins and progression from country to country, “overall the big picture is consistent with what we suspected.”
In addition to revealing Zika’s history, genetic studies are also valuable in fighting current and future disease outbreaks. Since diagnostic tests and even vaccine development are based on Zika’s genetics, it’s important to monitor mutations during an outbreak. Researchers developed quick-turnaround genomic analyses for Ebola in recent years, for example, that could aid a faster response during the next outbreak.
In the future, faster analysis of viral threats in the field might improve the odds of stopping the next epidemic, Lee says. It’s possible for a single infected traveler stepping off a plane to spark an epidemic long before doctors notice. “If one introduction [of a virus] can cause an outbreak, you have a very narrow window to try to contain it.”
Last year, Joan Peay slipped on her garage steps and smashed her knee on the welcome mat. Peay, 77, is no stranger to pain. The Tennessee retiree has had 17 surgeries in the last 35 years — knee replacements, hip replacements, back surgery. She even survived a 2012 fungal meningitis outbreak that sickened her and hundreds of others, and killed 64. This knee injury, though, “hurt like the dickens.”
When she asked her longtime doctor for something stronger than ibuprofen to manage the pain, he treated her like a criminal, Peay says. His response was frustrating: “He’s known me for nine years, and I’ve never asked him for pain medicine other than what’s needed after surgery,” she says. She received nothing stronger than over-the-counter remedies. A year after the fall, she still lives in constant pain. Just five years ago, Peay might have been handed a bottle of opioid painkillers for her knee. After all, opioids — including codeine, morphine and oxycodone — are some of the most powerful tools available to stop pain. But an opioid addiction epidemic spreading across the United States has soured some doctors on the drugs. Many are justifiably concerned that patients will get hooked or share their pain pills with friends and family. And even short-term users risk dangerous side effects: The drugs slow breathing and can cause constipation, nausea and vomiting.
A newfound restraint in prescribing opioids is in many cases warranted, but it’s putting people like Peay in a tough spot: Opioids have become harder to get. Even though the drugs are far from perfect, patients have few other options. Many drugs that have been heralded as improvements over existing opioids are just old opioids repackaged in new ways, says Nora Volkow, director of the National Institute on Drug Abuse. Companies will formulate a pill that is harder to crush, for instance, or mix in another drug that prevents an opioid pill from working if it’s crushed up and snorted for a quick high. Addicts, however, can still sidestep these safeguards. And the newly packaged drugs have the same fundamental risks as the old ones.
The need for new pain medicines is “urgent,” says Volkow.
Scientists have been searching for effective alternatives for years without success. But a better understanding of the way the brain sends and receives specific chemical messages may finally boost progress.
Scientists are designing new, more targeted molecules that might kill pain as well as today’s opioids do — with fewer side effects. Others are exploring the potential of tweaking existing opioid molecules to skip the negative effects. And some researchers are steering clear of opioids entirely, testing molecules in marijuana to ease chronic pain.
Opioid action Humans recognized the potential power of opioids long before they understood how to control it. Ancient Sumerians cultivated opium-containing poppy plants more than 5,000 years ago, calling their crop the “joy plant.” Other civilizations followed suit, using the plant to treat aches and pains. But the addictive power of opium-derived morphine wasn’t recognized until the 1800s, and scientists have only recently begun to piece together exactly how opioids get such a stronghold on the brain.
Opioids mimic the body’s natural painkillers — molecules like endorphins. Both endorphins and opioids latch on to proteins called opioid receptors on the surface of nerve cells. When an opioid binds to a receptor in the peripheral nervous system, the nerve cells outside the brain, the receptor changes shape and sets in motion a cellular game of telephone that stops pain messages from reaching the brain.
The danger comes because opioid receptors scattered throughout the body and in crucial parts of the brain can cause far-reaching side effects when drugs latch on. For starters, many opioid receptors are located near the base of the brain — the part that controls breathing and heart rate. When a drug like morphine binds to one of these receptors in the brain stem, breathing and heart rate slow down. At low doses, the drug just makes people feel relaxed. At high doses, though, it can be deadly — most opioid overdose deaths occur when a person stops breathing. And high numbers of opioid receptors in the gut — thanks in part to all the nerve endings there — can trigger constipation and sometimes nausea. Plus, opioids are highly addictive. These drugs mess with the brain’s reward system, triggering release of dopamine at levels higher than what the brain is used to. Gradually, the opioid receptors in the brain become less sensitive to the drugs, so the body demands higher and higher doses to get the same feel-good benefit. Such tolerance can reset the system so the body’s natural opioids no longer have the same effect either. If a person tries to go without the drugs, withdrawal symptoms like intense sweating and muscle cramps kick in — the body is physically dependent on the drugs. Addiction is a more complex phenomenon than dependence, involving physical cravings so strong that a person will go to extreme lengths to get the next dose. Long-term users of prescription opioids might be dependent on the drugs, but not necessarily addicted. But dependence and addiction often go together.
Despite their risks, opioids are still widely used because they work so well, particularly for moderate to severe short-term pain.
“No matter how much I say I want to avoid opioids, half of my patients will get some kind of opioid. It’s just unavoidable,” says Christopher Wu, an anesthesiologist at Johns Hopkins Medicine.
In the late 1990s and early 2000s, more doctors began doling out the drugs for long-term pain, too. Aggressive marketing campaigns from Purdue Pharma, the maker of OxyContin, promised that the drug was safe — and doctors listened. Opioid overdoses nearly quadrupled between 2000 and 2015, with almost half of those deaths coming from opioids prescribed by a doctor, according to data from the U.S. Centers for Disease Control and Prevention. Opioid prescriptions have dipped a bit since 2012, thanks in part to stricter prescription laws and prescription registration databases. U.S. doctors wrote about 30 million fewer opioid prescriptions in 2015 than in 2012, data from IMS Health show. But restricting access doesn’t make pain disappear or curb addiction. Some people have turned to more dangerous street alternatives like heroin. And those drugs are sometimes spiked with more potent opioids such as fentanyl (SN: 9/3/16, p. 14) or even carfentanil, a synthetic opioid that’s used to tranquilize elephants. Overdose deaths from fentanyl and heroin have both spiked since 2012, CDC data reveal.
A sharper target Scientists have been searching for a drug that kills pain as successfully as opioids without the side effects for close to a hundred years, with no luck, says Sam Ananthan, a medicinal chemist at Southern Research in Birmingham, Ala. He is newly optimistic.
“Right now, we have more biological tools, more information regarding the biochemical pathways,” Ananthan says. “Even though prior efforts were not successful, we now have some rational hypotheses.”
Scientists used to think opioid receptors were simple switches: If a molecule latched on, the receptor fired off a specific message. But more recent studies suggest that the same receptor can send multiple missives to different recipients.
The quest for better opioids got a much-needed jolt in 1999, when researchers at Duke University showed that mice lacking a protein called beta-arrestin 2 got more pain relief from morphine than normal mice did. And in a follow-up study, negative effects were less likely. “If we took out beta-arrestin 2, we saw improved pain relief, but less tolerance development,” says Laura Bohn, now a pharmacologist at the Scripps Research Institute in Jupiter, Fla. Bohn and colleagues figured out that mu opioid receptors — the type of opioid receptor targeted by most drugs — send two different streams of messages. One stops pain. The other, which needs beta-arrestin 2, drives many of the negatives of opioids, including the need for more and more drug and the dangerous slowdown of breathing.
Since that work, Bohn’s lab and many others have been trying to create molecules that bind to mu opioid receptors without triggering beta-arrestin 2 activity. The approach, called biased agonism, “has been around some time, but now it’s bearing the fruit,” says Susruta Majumdar, a chemist at Memorial Sloan Kettering Cancer Center in New York City. Scientists have identified dozens of molecules that seem to avoid beta-arrestin 2 in mice. But only a few might make good drugs. One, called PZM21, was described in Nature last year. Another one has shown promise in humans — a much higher bar. The pharmaceutical company Trevena, headquartered in King of Prussia, Pa., has been working its way through the U.S. Food and Drug Administration’s drug approval process with a molecule called oliceridine. In studies reported in April in San Francisco at the Annual Regional Anesthesiology and Acute Pain Medicine Meeting, oliceridine was as effective as morphine in patients recovering from bunion removal and others who had tummy tuck surgeries. Over the short term, people taking a moderate dose of the drug got pain relief comparable to that of morphine, but reported fewer side effects, such as vomiting and breathing problems.
Oliceridine is an intravenous opioid, not an oral one. That means it would be administered in the short term in hospitals, during and after surgeries. It’s not a replacement for the pills people can go home with, says Jonathan Violin, Trevena’s cofounder. And it’s not perfect: More side effects cropped up at higher doses. But it’s the first opioid using this targeted approach to get this far in human studies. The company hopes to submit an application for FDA approval by the end of 2017, Violin says.
Avoiding the beta-arrestin 2 pathway isn’t the only approach to targeted opioids — just one of the best studied. Ananthan’s lab is taking a different tack. His team showed that mice lacking a different opioid receptor, the delta receptor, tended not to show negative effects in response to the drugs. Now, the researchers are trying to find molecules that can activate mu opioid receptors while blocking delta receptors.
There may also be a way to direct pain-killing messages specifically to the parts of a person’s body that are feeling pain. In one recent study, scientists described a molecule that bound to opioid receptors only when the area around the receptors was more acidic than normal. Inflammation from pain and injury raises acidity, so this molecule could quash pain where necessary, but wouldn’t bind to receptors elsewhere in the body, reducing the likelihood of side effects. Rats in the study, published in the March 3 Science, didn’t find the new molecule as rewarding as fentanyl, so it may be less addictive. And they were less likely to have constipation and slowed breathing.
Drugs face a long uphill climb from even the most promising animal studies to FDA approval for use in humans. Very few make it that far. It’s too soon to tell whether PZM21 and other molecules being studied in mice will ever end up as treatments for patients.
Unwilling to wait, some people in pain are turning to substances that are already available — without a doctor’s order. And scientists are trying to catch up.
Kratom crackdown In August 2016, the Drug Enforcement Administration announced that it was cracking down on a supplement called kratom. Officials wanted to put the herb in the same regulatory category as heroin and LSD, labeling it a dangerous substance with no medical value. Members of the public vehemently disagreed. More than 23,000 comments poured in from veterans, cancer survivors, factory workers, lawyers and teachers. Almost all of them said the same thing: Kratom freed them from pain. Made from the leaves of the tropical plant Mitragyna speciosa , kratom is sold in corner convenience stores and through online retailers. Its pain-killing abilities come mainly from two different molecules in the plant’s leaves: mitragynine and the structurally similar 7-hydroxymitragynine. Both have a structure that’s very different from morphine, but they bind to opioid receptors. That technically makes them opioids, even though they don’t look like morphine or oxycodone, Majumdar says. And that’s what concerned the DEA. But just like some of the new opioids that scientists are developing, kratom’s active ingredients appear — anecdotally, at least — to deliver pain relief with fewer problems and less risk of tolerance. Some chronic opioid users switch to kratom to wean themselves off of pain pills and ease withdrawal symptoms, says Oliver Grundmann, a medicinal chemist at the University of Florida in Gainesville. Other users have never habitually used opioids but are seeking relief from chronic pain or mental health problems, according to a survey he published online May 10 in Drug and Alcohol Dependence. Grundmann hopes the survey results will help guide research into the substance’s efficacy for specific medical concerns.
The safety and efficacy of kratom is still up for debate. There’s a lack of controlled clinical studies about the leaf’s impact on the body, Grundmann says. Plus, the way kratom is regulated — as a supplement — means that people buying it have no guarantee of what they’re actually getting.
While kratom has its fans, its active compounds aren’t very potent, says Majumdar. He thinks he could make a better drug by modifying these molecules.
Majumdar, Sloan Kettering collaborator András Váradi and colleagues tested a structural cousin of 7-hydroxymitragynine: mitragynine pseudoindoxyl. It binds to mu opioid receptors about 200 times as effectively as mitragynine in mice, the researchers reported in August in the Journal of Medicinal Chemistry. Just like Trevena’s oliceridine, the new molecule does not activate beta-arrestin 2. The pseudoindoxyl version also blocks the delta opioid receptor, further impeding nonpain-related activities.
Majumdar hopes a DEA ban on kratom won’t happen; it would severely restrict access, making research much harder to do. For now, there is no ban — but scientists are wary, he says.
Mix it up Despite the potential for new, better opioids, other researchers are focused on an altogether different set of pain-killing drugs: the cannabinoids (made famous by marijuana, the dried leaves and other parts of the hemp plant, Cannabis sativa).
The active molecules in marijuana don’t have the same fast-acting pain-quenching abilities that opioids do. “If I go into an emergency room with acute pain, give me morphine,” says Yasmin Hurd, a pharmacologist at Mount Sinai in New York City. But with medical marijuana legal in 29 states plus the District of Columbia, the plant is getting more attention as a potential pain reliever, especially for chronic pain (SN: 6/14/14, p. 16).
Doctors in states where marijuana is legal write fewer prescriptions for opioid painkillers, a 2016 study in Health Affairs showed. Those states also had about a 25 percent lower rate of opioid overdose deaths compared with states that didn’t legalize marijuana, according to a 2014 study in JAMA Internal Medicine. When marijuana becomes legally available, some people might choose it instead of opioids. There might be some merit to that choice. There are plenty of cannabinoid receptors in parts of the brain that process pain messages. But unlike opioid receptors, few exist in the brain stem. That means cannabinoids are far less likely to influence breathing than opioids, says Joseph Cheer, a neurobiologist at the University of Maryland School of Medicine in Baltimore. Fatal overdoses are nearly unheard of.
As with kratom, though, there’s a glut of anecdotal evidence suggesting marijuana’s power to cure everything from pain to anxiety to ulcers — but not many controlled clinical trials to back up the assertions (SN Online: 1/12/17). The knowledge gap is made even wider by the fact that marijuana has wildly different effects depending on how it’s ingested and the relative ratios of certain active molecules in each strain of the plant.There might be some merit to that choice. There are plenty of cannabinoid receptors in parts of the brain that process pain messages. But unlike opioid receptors, few exist in the brain stem. That means cannabinoids are far less likely to influence breathing than opioids, says Joseph Cheer, a neurobiologist at the University of Maryland School of Medicine in Baltimore. Fatal overdoses are nearly unheard of.
“People think they know how marijuana affects the brain,” Hurd says. In reality, “there’s been very little evidence-based structural scientific studies done with marijuana.”
Aron Lichtman, a pharmacologist at Virginia Commonwealth University in Richmond, agrees. “There’s definitely medicine in that plant — that’s been proven,” he says. “The challenge is that it may not work for everybody and every type of pain.”
Scientists who are serious about figuring out marijuana are breaking it down, looking at the plant’s active molecules — cannabinoids — one by one. Cannabidiol, or CBD, has garnered particular attention. Because of the way it indirectly interacts with cannabinoid receptors, it doesn’t give people the high that’s characteristic of tetrahydrocannabinol, or THC, the mind-altering chemical in marijuana. That makes CBD less rewarding and better suited to longer-term use. The molecule can influence signals sent by a number of other receptors in the brain, many involved in pain and inflammation.
But THC might have merit, too. It’s already used in a couple of FDA-approved drugs to treat nausea and vomiting from chemo-therapy. There’s some evidence that those medications might also help relieve pain, though Lichtman calls those studies a “mixed bag.”
Alone, cannabinoids might be fairly weak painkillers. But combined with opioids, he’s shown, they can amplify the pain relief and reduce the opioid dose needed in mice.
Drugs that might amp up the power of the body’s natural cannabinoids are another option. That’s what Ruth Ross of the University of Toronto is studying. A few years ago, her team identified a region on a cannabinoid receptor called CB1 that has an interesting property: Small molecules that bind to it act like volume knobs for the body’s natural cannabinoids, called endocannabinoids. When a molecule of the right shape locks on to CB1, it makes endocannabinoids naturally present in the body more likely to latch on. That boosts pain relief in a targeted way — when endocannabinoids are already being released by the body, such as after injury or stress.
“You magnify the already existing effects of the compound,” Ross says. Her team has identified and patented several of these volume-knob molecules, and is working on improving them.
“For various reasons they wouldn’t be good as drugs,” she says. They have too many effects on the body beyond their intended one. But she’s making slight tweaks to their chemical structures to try to reduce those off-target effects, with the hope that one day the molecules could be studied in patients.
Safer opioids or alternative painkillers would help people deal with their pain without risking addiction or death. Peay has gotten to know people — as a member of social media groups for those living with chronic pain — who are experiencing the crushing results of poorly managed pain. People lose their jobs, she says, or move to Colorado just to get access to legal marijuana. As for her? “I still have my sense of humor, and that helps me get through all the pain.” But she’s holding out for something better.
