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.
Nuclear physicist Evangeline Downie hadn’t planned to study one of the thorniest puzzles of the proton.
But when opportunity knocked, Downie couldn’t say no. “It’s the proton,” she exclaims. The mysteries that still swirl around this jewel of the subatomic realm were too tantalizing to resist. The plentiful particles make up much of the visible matter in the universe. “We’re made of them, and we don’t understand them fully,” she says.
Many physicists delving deep into the heart of matter in recent decades have been lured to the more exotic and unfamiliar subatomic particles: mesons, neutrinos and the famous Higgs boson — not the humble proton. But rather than chasing the rarest of the rare, scientists like Downie are painstakingly scrutinizing the proton itself with ever-higher precision. In the process, some of these proton enthusiasts have stumbled upon problems in areas of physics that scientists thought they had figured out.
Surprisingly, some of the particle’s most basic characteristics are not fully pinned down. The latest measurements of its radius disagree with one another by a wide margin, for example, a fact that captivated Downie. Likewise, scientists can’t yet explain the source of the proton’s spin, a basic quantum property. And some physicists have a deep but unconfirmed suspicion that the seemingly eternal particles don’t live forever — protons may decay. Such a decay is predicted by theories that unite disparate forces of nature under one grand umbrella. But decay has not yet been witnessed.
Like the base of a pyramid, the physics of the proton serves as a foundation for much of what scientists know about the behavior of matter. To understand the intricacies of the universe, says Downie, of George Washington University in Washington, D.C., “we have to start with, in a sense, the simplest system.”
Sizing things up For most of the universe’s history, protons have been VIPs — very important particles. They formed just millionths of a second after the Big Bang, once the cosmos cooled enough for the positively charged particles to take shape. But protons didn’t step into the spotlight until about 100 years ago, when Ernest Rutherford bombarded nitrogen with radioactively produced particles, breaking up the nuclei and releasing protons.
A single proton in concert with a single electron makes up hydrogen — the most plentiful element in the universe. One or more protons are present in the nucleus of every atom. Each element has a unique number of protons, signified by an element’s atomic number. In the core of the sun, fusing protons generate heat and light needed for life to flourish. Lone protons are also found as cosmic rays, whizzing through space at breakneck speeds, colliding with Earth’s atmosphere and producing showers of other particles, such as electrons, muons and neutrinos.
In short, protons are everywhere. Even minor tweaks to scientists’ understanding of the minuscule particle, therefore, could have far-reaching implications. So any nagging questions, however small in scale, can get proton researchers riled up.
A disagreement of a few percent in measurements of the proton’s radius has attracted intense interest, for example. Until several years ago, scientists agreed: The proton’s radius was about 0.88 femtometers, or 0.88 millionths of a billionth of a meter — about a trillionth the width of a poppy seed. But that neat picture was upended in the span of a few hours, in May 2010, at the Precision Physics of Simple Atomic Systems conference in Les Houches, France. Two teams of scientists presented new, more precise measurements, unveiling what they thought would be the definitive size of the proton. Instead the figures disagreed by about 4 percent (SN: 7/31/10, p. 7). “We both expected that we would get the same number, so we were both surprised,” says physicist Jan Bernauer of MIT.
By itself, a slight revision of the proton’s radius wouldn’t upend physics. But despite extensive efforts, the groups can’t explain why they get different numbers. As researchers have eliminated simple explanations for the impasse, they’ve begun wondering if the mismatch could be the first hint of a breakdown that could shatter accepted tenets of physics.
The two groups each used different methods to size up the proton. In an experiment at the MAMI particle accelerator in Mainz, Germany, Bernauer and colleagues estimated the proton’s girth by measuring how much electrons’ trajectories were deflected when fired at protons. That test found the expected radius of about 0.88 femtometers (SN Online: 12/17/10).
But a team led by physicist Randolf Pohl of the Max Planck Institute of Quantum Optics in Garching, Germany, used a new, more precise method. The researchers created muonic hydrogen, a proton that is accompanied not by an electron but by a heftier cousin — a muon.
In an experiment at the Paul Scherrer Institute in Villigen, Switzerland, Pohl and collaborators used lasers to bump the muons to higher energy levels. The amount of energy required depends on the size of the proton. Because the more massive muon hugs closer to the proton than electrons do, the energy levels of muonic hydrogen are more sensitive to the proton’s size than ordinary hydrogen, allowing for measurements 10 times as precise as electron-scattering measurements.
Pohl’s results suggested a smaller proton radius, about 0.841 femtometers, a stark difference from the other measurement. Follow-up measurements of muonic deuterium — which has a proton and a neutron in its nucleus — also revealed a smaller than expected size, he and collaborators reported last year in Science. Physicists have racked their brains to explain why the two measurements don’t agree. Experimental error could be to blame, but no one can pinpoint its source. And the theoretical physics used to calculate the radius from the experimental data seems solid.
Now, more outlandish possibilities are being tossed around. An unexpected new particle that interacts with muons but not electrons could explain the difference (SN: 2/23/13, p. 8). That would be revolutionary: Physicists believe that electrons and muons should behave identically in particle interactions. “It’s a very sacred principle in theoretical physics,” says John Negele, a theoretical particle physicist at MIT. “If there’s unambiguous evidence that it’s been broken, that’s really a fundamental discovery.”
But established physics theories die hard. Shaking the foundations of physics, Pohl says, is “what I dream of, but I think that’s not going to happen.” Instead, he suspects, the discrepancy is more likely to be explained through minor tweaks to the experiments or the theory.
The alluring mystery of the proton radius reeled Downie in. During conversations in the lab with some fellow physicists, she learned of an upcoming experiment that could help settle the issue. The experiment’s founders were looking for collaborators, and Downie leaped on the bandwagon. The Muon Proton Scattering Experiment, or MUSE, to take place at the Paul Scherrer Institute beginning in 2018, will scatter both electrons and muons off of protons and compare the results. It offers a way to test whether the two particles behave differently, says Downie, who is now a spokesperson for MUSE.
A host of other experiments are in progress or planning stages. Scientists with the Proton Radius Experiment, or PRad, located at Jefferson Lab in Newport News, Va., hope to improve on Bernauer and colleagues’ electron-scattering measurements. PRad researchers are analyzing their data and should have a new number for the proton radius soon.
But for now, the proton’s identity crisis, at least regarding its size, remains. That poses problems for ultrasensitive tests of one of physicists’ most essential theories. Quantum electrodynamics, or QED, the theory that unites quantum mechanics and Albert Einstein’s special theory of relativity, describes the physics of electromagnetism on small scales. Using this theory, scientists can calculate the properties of quantum systems, such as hydrogen atoms, in exquisite detail — and so far the predictions match reality. But such calculations require some input — including the proton’s radius. Therefore, to subject the theory to even more stringent tests, gauging the proton’s size is a must-do task. Spin doctors Even if scientists eventually sort out the proton’s size snags, there’s much left to understand. Dig deep into the proton’s guts, and the seemingly simple particle becomes a kaleidoscope of complexity. Rattling around inside each proton is a trio of particles called quarks: one negatively charged “down” quark and two positively charged “up” quarks. Neutrons, on the flip side, comprise two down quarks and one up quark.
Yet even the quark-trio picture is too simplistic. In addition to the three quarks that are always present, a chaotic swarm of transient particles churns within the proton. Evanescent throngs of additional quarks and their antimatter partners, antiquarks, continually swirl into existence, then annihilate each other. Gluons, the particle “glue” that holds the proton together, careen between particles. Gluons are the messengers of the strong nuclear force, an interaction that causes quarks to fervently attract one another. As a result of this chaos, the properties of protons — and neutrons as well — are difficult to get a handle on. One property, spin, has taken decades of careful investigation, and it’s still not sorted out. Quantum particles almost seem to be whirling at blistering speed, like the Earth rotating about its axis. This spin produces angular momentum — a quality of a rotating object that, for example, keeps a top revolving until friction slows it. The spin also makes protons behave like tiny magnets, because a rotating electric charge produces a magnetic field. This property is the key to the medical imaging procedure called magnetic resonance imaging, or MRI.
But, like nearly everything quantum, there’s some weirdness mixed in: There’s no actual spinning going on. Because fundamental particles like quarks don’t have a finite physical size — as far as scientists know — they can’t twirl. Despite the lack of spinning, the particles still behave like they have a spin, which can take on only certain values: integer multiples of 1/2.
Quarks have a spin of 1/2, and gluons a spin of 1. These spins combine to help yield the proton’s total spin. In addition, just as the Earth is both spinning about its own axis and orbiting the sun, quarks and gluons may also circle about the proton’s center, producing additional angular momentum that can contribute to the proton’s total spin.
Somehow, the spin and orbital motion of quarks and gluons within the proton combine to produce its spin of 1/2. Originally, physicists expected that the explanation would be simple. The only particles that mattered, they thought, were the proton’s three main quarks, each with a spin of 1/2. If two of those spins were oriented in opposite directions, they could cancel one another out to produce a total spin of 1/2. But experiments beginning in the 1980s showed that “this picture was very far from true,” says theoretical high-energy physicist Juan Rojo of Vrije University Amsterdam. Surprisingly, only a small fraction of the spin seemed to be coming from the quarks, befuddling scientists with what became known as the “spin crisis” (SN: 9/6/97, p. 158). Neutron spin was likewise enigmatic.
Scientists’ next hunch was that gluons contribute to the proton’s spin. “Verifying this hypothesis was very difficult,” Rojo says. It required experimental studies at the Relativistic Heavy Ion Collider, RHIC, a particle accelerator at Brookhaven National Laboratory in Upton, N.Y.
In these experiments, scientists collided protons that were polarized: The two protons’ spins were either aligned or pointed in opposite directions. Researchers counted the products of those collisions and compared the results for aligned and opposing spins. The results revealed how much of the spin comes from gluons. According to an analysis by Rojo and colleagues, published in Nuclear Physics B in 2014, gluons make up about 35 percent of the proton’s spin. Since the quarks make up about 25 percent, that leaves another 40 percent still unaccounted for.
“We have absolutely no idea how the entire spin is made up,” says nuclear physicist Elke-Caroline Aschenauer of Brookhaven. “We maybe have understood a small fraction of it.” That’s because each quark or gluon carries a certain fraction of the proton’s energy, and the lowest energy quarks and gluons cannot be spotted at RHIC. A proposed collider, called the Electron-Ion Collider (location to be determined), could help scientists investigate the neglected territory.
The Electron-Ion Collider could also allow scientists to map the still-unmeasured orbital motion of quarks and gluons, which may contribute to the proton’s spin as well. An unruly force Experimental physicists get little help from theoretical physics when attempting to unravel the proton’s spin and its other perplexities. “The proton is not something you can calculate from first principles,” Aschenauer says. Quantum chromo-dynamics, or QCD — the theory of the quark-corralling strong force transmitted by gluons — is an unruly beast. It is so complex that scientists can’t directly solve the theory’s equations.
The difficulty lies with the behavior of the strong force. As long as quarks and their companions stick relatively close, they are happy and can mill about the proton at will. But absence makes the heart grow fonder: The farther apart the quarks get, the more insistently the strong force pulls them back together, containing them within the proton. This behavior explains why no one has found a single quark in isolation. It also makes the proton’s properties especially difficult to calculate. Without accurate theoretical calculations, scientists can’t predict what the proton’s radius should be, or how the spin should be divvied up. To simplify the math of the proton, physicists use a technique called lattice QCD, in which they imagine that the world is made of a grid of points in space and time (SN: 8/7/04, p. 90). A quark can sit at one point or another in the grid, but not in the spaces in between. Time, likewise, proceeds in jumps. In such a situation, QCD becomes more manageable, though calculations still require powerful supercomputers.
Lattice QCD calculations of the proton’s spin are making progress, but there’s still plenty of uncertainty. In 2015, theoretical particle and nuclear physicist Keh-Fei Liu and colleagues calculated the spin contributions from the gluons, the quarks and the quarks’ angular momentum, reporting the results in Physical Review D. By their calculation, about half of the spin comes from the quarks’ motion within the proton, about a quarter from the quarks’ spin, with the last quarter or so from the gluons. The numbers don’t exactly match the experimental measurements, but that’s understandable — the lattice QCD numbers are still fuzzy. The calculation relies on various approximations, so it “is not cast in stone,” says Liu, of the University of Kentucky in Lexington.
Death of a proton Although protons seem to live forever, scientists have long questioned that immortality. Some popular theories predict that protons decay, disintegrating into other particles over long timescales. Yet despite extensive searches, no hint of this demise has materialized.
A class of ideas known as grand unified theories predict that protons eventually succumb. These theories unite three of the forces of nature, creating a single framework that could explain electromagnetism, the strong nuclear force and the weak nuclear force, which is responsible for certain types of radioactive decay. (Nature’s fourth force, gravity, is not yet incorporated into these models.) Under such unified theories, the three forces reach equal strengths at extremely high energies. Such energetic conditions were present in the early universe — well before protons formed — just a trillionth of a trillionth of a trillionth of a second after the Big Bang. As the cosmos cooled, those forces would have separated into three different facets that scientists now observe. “We have a lot of circumstantial evidence that something like unification must be happening,” says theoretical high-energy physicist Kaladi Babu of Oklahoma State University in Stillwater. Beyond the appeal of uniting the forces, grand unified theories could explain some curious coincidences of physics, such as the fact that the proton’s electric charge precisely balances the electron’s charge. Another bonus is that the particles in grand unified theories fill out a family tree, with quarks becoming the kin of electrons, for example.
Under these theories, a decaying proton would disintegrate into other particles, such as a positron (the antimatter version of an electron) and a particle called a pion, composed of a quark and an antiquark, which itself eventually decays. If such a grand unified theory is correct and protons do decay, the process must be extremely rare — protons must live a very long time, on average, before they break down. If most protons decayed rapidly, atoms wouldn’t stick around long either, and the matter that makes up stars, planets — even human bodies — would be falling apart left and right.
Protons have existed for 13.8 billion years, since just after the Big Bang. So they must live exceedingly long lives, on average. But the particles could perish at even longer timescales. If they do, scientists should be able to monitor many particles at once to see a few protons bite the dust ahead of the curve (SN: 12/15/79, p. 405). But searches for decaying protons have so far come up empty.
Still, the search continues. To hunt for decaying protons, scientists go deep underground, for example, to a mine in Hida, Japan. There, at the Super-Kamiokande experiment (SN: 2/18/17, p. 24), they monitor a giant tank of water — 50,000 metric tons’ worth — waiting for a single proton to wink out of existence. After watching that water tank for nearly two decades, the scientists reported in the Jan. 1 Physical Review D that protons must live longer than 1.6 × 1034 years on average, assuming they decay predominantly into a positron and a pion.
Experimental limits on the proton lifetime “are sort of painting the theorists into a corner,” says Ed Kearns of Boston University, who searches for proton decay with Super-K. If a new theory predicts a proton lifetime shorter than what Super-K has measured, it’s wrong. Physicists must go back to the drawing board until they come up with a theory that agrees with Super-K’s proton-decay drought.
Many grand unified theories that remain standing in the wake of Super-K’s measurements incorporate supersymmetry, the idea that each known particle has another, more massive partner. In such theories, those new particles are additional pieces in the puzzle, fitting into an even larger family tree of interconnected particles. But theories that rely on supersymmetry may be in trouble. “We would have preferred to see supersymmetry at the Large Hadron Collider by now,” Babu says, referring to the particle accelerator located at the European particle physics lab, CERN, in Geneva, which has consistently come up empty in supersymmetry searches since it turned on in 2009 (SN: 10/1/16, p. 12).
But supersymmetric particles could simply be too massive for the LHC to find. And some grand unified theories that don’t require supersymmetry still remain viable. Versions of these theories predict proton lifetimes within reach of an upcoming generation of experiments. Scientists plan to follow up Super-K with Hyper-K, with an even bigger tank of water. And DUNE, the Deep Underground Neutrino Experiment, planned for installation in a former gold mine in Lead, S.D., will use liquid argon to detect protons decaying into particles that the water detectors might miss. If protons do decay, the universe will become frail in its old age. According to Super-K, sometime well after its 1034 birthday, the cosmos will become a barren sea of light. Stars, planets and life will disappear. If seemingly dependable protons give in, it could spell the death of the universe as we know it.
Although protons may eventually become extinct, proton research isn’t going out of style anytime soon. Even if scientists resolve the dilemmas of radius, spin and lifetime, more questions will pile up — it’s part of the labyrinthine task of studying quantum particles that multiply in complexity the closer scientists look. These deeper studies are worthwhile, says Downie. The inscrutable proton is “the most fundamental building block of everything, and until we understand that, we can’t say we understand anything else.”
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.
Dad bod is a big deal for albatrosses. Bigger male wandering albatrosses live longer and are more likely to breed successfully compared with lighter birds, while mass has no observable effect on female breeding or survival, researchers report May 3 in Proceedings of the Royal Society B.
Climate change could shift the degree to which some seabirds pack on the pounds. It’s unclear how those shifts will play out in species like wandering albatrosses (Diomedea exulans), in which males are much bigger than females.
To investigate, Tina Cornioley of the University of Zurich and her colleagues examined how body mass affects certain aspects of an albatross’s life — survival, odds of mating, having chicks, chick size and chick survival. From 1988 to 2013, the team tracked 662 adult albatrosses on Possession Island in the southern Indian Ocean. Albatross parents take turns sitting on their eggs, but dads actually invest more energy in rearing chicks after they hatch.
In addition to the survival and breeding advantages, the team also found that heavier dads were more likely to have heavier sons, but not daughters, and those sons had better survival odds. Although the team can’t rule out the possibility of a genetic element, the fact that body mass fluctuates throughout a bird’s life and the absence of the trend in mothers and daughters makes genetics a less likely explanation, says Cornioley. Instead, the researchers think that heftier dads invest more in sons than daughters.
A strain of wild Hawaiian worms has helped unmask long-studied genes as just plain selfish. The scammers beat the usual odds of inheritance and spread extra fast by making mother worms poison some of their offspring.
Biologists have for decades discussed how two genes in the familiar lab nematode Caenorhabditis elegans might help embryos build their organs. Working with a little-studied wild strain, however, caused a rethink of the genes’ supposedly beneficial role “that flipped it on its head,” says UCLA geneticist Leonid Kruglyak. Instead of doing some body sculpting, the gene sup-35 doses the eggs with a toxin that will kill them after fertilization, two postdocs in the Kruglyak lab discovered. The toxin gene doesn’t poison itself out of the gene pool because it’s linked to a partner, pha-1, that lets embryos manufacture an antidote. Embryos die unless they inherit a copy of the antidote gene in either egg or sperm, and so the poison-antidote duo can spread unusually fast through populations.
Making a mom on occasion poison some of her offspring doesn’t benefit her but certainly helps the genes. Thus the long-known sup-35 and pha-1 form what’s called a selfish genetic element, Kruglyak’s team proposes May 11 in Science.
That analysis is “very clearly accurate,” says evolutionary geneticist Jack Werren of the University of Rochester in New York. The idea that a gene could behave selfishly, promoting its own spread regardless of its host’s interests, was once controversial (SN: 3/19/16, p. 12). But as molecular biology techniques have improved, researchers have found more and more examples. Many of the most dramatic forms of selfishness, the murderous cheats, come from bacteria, so Werren welcomes the C. elegans scam as a rare case discovered in animals. Kruglyak’s lab has described an earlier example in C. elegans: a gene that doses sperm with a toxin that kills embryos unless an antidote gene rescues them. Finding a second selfish element in the nematode, he says, suggests that these may not be as rare in animals as people have thought. The big community of researchers regularly studying C. elegans had missed discovering the selfish role for a simple reason: The main lab strain of nematodes carries the selfish element, explains study coauthor Eyal Ben-David. Whenever the standard strain mates or self-fertilizes (the species has both males and hermaphrodites), all the offspring inherit sup-35 and pha-1. Researchers see no weird die-offs.
In the Kruglyak lab, however, Ben-David and fellow postdoc Alejandro Burga were doing a project that required crossing the usual lab nematodes with the DL238 strain from Hawaii. In its natural state, this strain has somehow escaped invasion by the selfish sup-35/pha-1 pair.
A series of oddities in interbreeding the disparate strains pushed the researchers to reconsider the two genes. For instance, much higher percentages of offspring died in mixed-parent crosses than the routine few percent in same-strain pairings. And when Ben-David and Burga looked at the genes in the Hawaiian strain isolated from the wild, sup-35 and pha-1 just weren’t there.
That was a shock. Earlier experiments in the lab strain had shown that disabling pha-1 caused death in offspring — which it certainly does. The feeding tube of the dying embryos was not forming properly, so researchers at first speculated that the gene controlled tube development. Later work suggested a more nuanced role for it, Ben-David says, but the overall hypothesis remained that the genes helped regulate embryo development. The Hawaiian strain changed that thinking: “How is this wild isolate alive and happy without a gene that’s supposed to be essential for development?” Kruglyak wanted to know.
A better way of interpreting the old experiments, he and his colleagues suggest, is that the embryos died because pha-1 wasn’t providing the antidote to the sup-35 toxin. “No one had previously considered the possibility,” says David S. Fay of the University of Wyoming in Laramie, who has done much of the work exploring the role of these genes. “All the data, including a lot of our previous published and unpublished findings, seem to fit the [selfish gene] model perfectly,” he says. And perhaps the highest praise: “I wish we had somehow come up with the solution ourselves.”
Dogged genetic detective work has led scientists to a hybrid red blood cell protein that offers some protection against malaria.
Reporting online May 18 in Science, researchers describe a genetic variant that apparently is responsible for the fusion of two proteins that protrude from the membranes of red blood cells. In its hybrid form, the protein somehow makes it more difficult for the malaria parasite to invade the blood cells.
Successful invasion by the parasite can cause flulike illness, and in severe cases, death. In 2015, 212 million cases of malaria occurred worldwide, according to the World Health Organization, and 429,000 people died, mostly young children. People carrying the protective genetic variant are 30 to 50 percent less likely to develop severe malaria than those without, the researchers report. The genetic change was found largely in people from Kenya, Malawi and Tanzania, suggesting that it occurred relatively recently in East Africa.
Discovering any genetic changes that protect against malaria is of great interest, says hematologist and malaria specialist Dave Roberts of the University of Oxford, who was not involved with the study. Understanding such changes, he says, “may help us understand the pathological pathways by which the parasite causes so much disease.”
Previous research had hinted that genetic changes to a particular stretch of DNA on chromosome 4 offered some protection against malaria. But the research team, an international collaboration that included researchers and clinicians from across Africa, had to do substantial legwork spanning 10 years to unmask the changes. Databases that gather the genetic instruction books, or genomes, of individuals are biased toward European populations, while African samples are underrepresented. And human genetic diversity is particularly high in sub-Saharan Africa, so genomes with rare genetic changes can be easily missed.
To overcome these hurdles, the researchers analyzed the genomes of more than 12,000 people, sampling widely in Africa. They surveyed 765 individuals from 10 ethnic groups in Gambia, Burkina Faso, Cameroon and Tanzania, as well as more than 2,000 genomes from the 1000 Genomes Project, a public catalog of genetic data. The team also examined genomes of nearly 10,000 people from Gambia, Kenya and Malawi, about half of whom had been hospitalized with severe malaria.
The team discovered that the stretch of DNA in question has undergone major changes; chunks of genes have been deleted, other chunks duplicated or even triplicated. One result stood out in the DNA of the people who were less at risk for malaria: Two genes that provide instructions for two proteins called glycophorin A and glycophorin B were snipped, fused together and duplicated. These proteins are known red blood cell proteins that the malaria parasite Plasmodium falciparum can use to gain access to the cells. This genetic mash-up seems to lead to a protein mash-up: The arm sticking inside the red blood cell is made up of protein A, while the arm sticking out of the cell is made up of protein B. This hybrid protein turns out to have been first described in 1984. Called the Dantu antigen, it’s found on red blood cells of only a small percentage of people outside of Africa and is part of a rare blood group called MNS. It isn’t clear why the hybrid protein makes it harder for the malaria parasite to breach a blood cell. “It might just make the cell more squishy so it feels different to the parasite,” says study coauthor Chris Spencer, a statistical geneticist at Oxford.
The new research suggests that there may be other stretches of DNA in the human genome that may reveal the diversity of responses to the parasite. Those spots are worth looking for, even if the search is difficult, says Spencer.
Typically, genome analysis studies primarily look for single changes — one altered unit of DNA — not wholesale copying or halving of genes. And because researchers break apart and then reassemble the 3-billion-letter-long genetic instruction book in order to analyze it, sections that have duplicated genes are harder to put in the right order and thus harder to study, which was the case with the region containing the red blood cell protein DNA.
“The genome is a big place and it’s natural to look at the things that are easiest,” Spencer says. “But it could be that the most interesting parts of the genome we just haven’t looked at yet.”
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.
