Fever, aches from Pfizer, Moderna jabs aren’t dangerous but may be intense for some

A health care worker prepares to give an injection. Shots of some new coronavirus vaccines may cause noticeable but temporary side effects, researchers say.

iStock

Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

This summer, Luke Hutchison, a Massachusetts Institute of Technology–educated computational biologist, volunteered for a trial of Moderna’s COVID-19 vaccine. After he got the second injection, his arm immediately swelled up to the size of a “goose egg,” Hutchison says. He can’t be sure he got the vaccine and not a placebo, but within a few hours, the healthy then-43-year-old was beset by bone and muscle aches and a 38.9°C fever that felt, he says, “unbearable.” “I started shaking. I had cold and hot rushes,” he says. “I was sitting by the phone all night long thinking: ‘Should I call 911?’”

Hutchison’s symptoms resolved after 12 hours. But, he says, “Nobody prepared me for the severity of this.”

He says the public should be better prepared than he was, because a subset of people may face intense, if transient, side effects, called reactogenicity, from Moderna’s vaccine. Some health experts agree.

“Somebody needs to address the elephant: What about vaccine reactogenicity? While it’s safe, [and] it’s not going to cause any long-term issues … how is that perception going to go with the public once they start receiving it?” says Deborah Fuller, a vaccinologist at the University of Washington, Seattle, whose lab is developing second-generation RNA vaccines against COVID-19. She worries the side effects could feed vaccine hesitancy. “I feel like it’s being glossed over.”

Those concerns arise after a week of good news about coronavirus vaccines: Both Moderna and Pfizer, with BioNTech, announced that their messenger RNA (mRNA) vaccines reached 95% efficacy in clinical trials of tens of thousands of people. The trials revealed no serious safety concerns, both companies added.

Both vaccines consist of a snippet of genetic code directing production of the coronavirus’ spike protein, delivered in a tiny fat bubble called a lipid nanoparticle. Some suspect the immune system’s response to that delivery vehicle is causing the short-term side effects.  

Those transient reactions should not dissuade people from getting vaccinated in the face of a pandemic virus that kills at least one in 200 of those it infects, says Florian Krammer, a vaccinologist at the Icahn School of Medicine at Mount Sinai, who participated in Pfizer’s pivotal trial. Sore arms, fevers, and fatigue are “unpleasant but not dangerous. I’m not concerned about [reactogenicity],” he says.

And most people will escape “severe” side effects, defined as those that prevent daily activity. Fewer than 2% of recipients of the Pfizer and Moderna vaccines developed severe fevers of 39°C to 40°C. But if the companies win regulatory approvals, they’re aiming to supply vaccine to 35 million people globally by the end of December. If 2% experienced severe fever, that would be 700,000 people.

Other transient side effects would likely affect even more people. The independent board that conducted the interim analysis of Moderna’s huge trial found that severe side effects included fatigue in 9.7% of participants, muscle pain in 8.9%, joint pain in 5.2%, and headache in 4.5%. For the Pfizer/BioNTech vaccine, the numbers were lower: Severe side effects included fatigue (3.8%) and headache (2%).

That’s a higher rate of severe reactions than people may be accustomed to. “This is higher reactogenicity than is ordinarily seen with most flu vaccines, even the high-dose ones,” says Arnold Monto, an epidemiologist at the University of Michigan School of Public Health.

Front-line public health workers should prepare their messages, says Bernice Hausman, an expert on vaccine controversy at the Pennsylvania State University College of Medicine. “Public health professionals are going to have to have a story that gets out in front of [stories like Hutchison’s]—that responds to the way that people are going to try to make that a story about vaccine injury.”

Transparency is key, Hausman emphasizes. Rather than minimizing the chance of fever, for instance, vaccine administrators could alert people that they may experience a fever that can feel severe but is temporary. “That would go a significant way toward people feeling like they are being told the truth.” Adds Drew Weissman, an immunologist at the University of Pennsylvania whose work contributed to both vaccines: “The companies just have to warn people: ‘This is what you need to expect. Take Tylenol and suck it up for a day.’”

Hausman also sees a need to support people who have serious reactions. “The real question is whether or not there is going to be an apparatus set up to support the experience of people going through [experiences like Hutchison’s]. Like a hotline with a nurse triaging … and figuring out if you need to go to the hospital or not. Will your medical expenses be covered if you do? These are important questions.”

Both Moderna’s and Pfizer/BioNTech’s vaccines require two doses separated by several weeks. Reactogenicity is typically higher after a second dose, Weissman says. The side effects “mean the vaccine is working well. … [It] means you had such a good immune response to the first dose and now you are seeing the effects of that,” he says. (Weissman co-invented the mRNA modifications that both Moderna and BioNTech have licensed to make their vaccines, and he receives royalties from the companies.)

“We suspect the lipid nanoparticle causes the reactogenicity, because lipid nanoparticles without mRNA in them do the same thing in animals,” Weissman says. “We see production, in the muscle, of inflammatory mediators that cause pain, [redness], swelling, fever, flulike symptoms, etc.”

Ian Haydon, who received the highest dose of the Moderna vaccine in its first human trial, knows what that’s like. (He received 250 micrograms, but partly in response to reactions like his, the company chose to take forward a lower dose of 100 micrograms.)

Twelve hours after receiving his second injection in May, Haydon got chills as well as “headache, muscle ache, fatigue, nausea,” and had a fever of 39.6°C. He went to urgent care, and later vomited and fainted before the symptoms receded, roughly 24 hours after they started, he says.

But Haydon says his experience was “a small price to pay” for the possibility of returning to normal life. “For me, this was a rough day. But if you compare it to what COVID can do, I think it really pales in comparison.”

Longer term side effects of mRNA vaccines remain theoretical. They include the possibility that people with lupus, whose disease is driven by antibodies against their own genetic code, could experience flare-ups because of the revved up immune response induced by the vaccines, says Sarfaraz Hasni, director of lupus clinical research at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

But there’s no evidence currently that mRNA vaccines cause autoimmune disease or make it worse, says Betty Diamond, an immunologist and rheumatologist at the Feinstein Institutes for Medical Research of Northwell Health. “At the moment there’s every reason to suggest that people with autoimmune diseases ought to get either of these vaccines when they get rolled out.”

As for more general public acceptance of the vaccines, Weissman notes that the new shingles vaccine, Shingrix, can also cause significant transient reactions. In a large, pivotal trial of people 50 and older, Shingrix caused severe reactions including pain at the injection site and muscle aches, in 17% of vaccine recipients. Yet demand for that vaccine, licensed in 2017, has been huge.

Hausman says the reported 95% efficacy of both mRNA COVID-19 vaccines bodes well for acceptance. “If you know that a vaccine is really effective, like measles, in making sure you don’t get the infection, then you might be willing to accept a more severe initial reaction.”

Hutchison agrees. Although he hopes better vaccines are on the way, “Given that COVID can kill or incapacitate people, everybody should bite the bullet and expect a rough night,” he says. “Get lots of naproxen.”

*Correction, 20 November, 3:45 p.m.: This article has been updated to reflect that severe vaccine side effects are defined as preventing daily activities, and that Pfizer/BioNTech and Moderna hope to provide vaccines for 35 million people worldwide by the end of December.

China set to bring back first rocks from the Moon in more than 40 years

Chang’e-5 is targeting Mons Rümker, a volcanic mound that may contain 1.3-billion-year-old lava.

NASA

On Earth, deep time is an open book. By measuring trace radioactive compounds in rocks that decay with metronomic regularity, dating experts have learned when oceans opened, volcanoes erupted, and mass extinctions struck. But the story is muddled elsewhere in the Solar System because records are sparse. Scientists estimate ages on the Moon and the rocky planets from the number of craters that pock their surfaces. They have fixed dates from just nine places, all on the Moon: the six Apollo and three Soviet Luna sites from which samples were returned to laboratories on Earth.

China’s Chang’e-5 mission, set to launch on 24 November, aims to make it 10, by returning the first Moon rocks since the last Luna mission in 1976. Getting a firm date from another location will improve the shaky crater counting scheme, says Kentaro Terada, a cosmochemist at Osaka University. It will also sharpen the picture of the Moon’s history. A fresh sample date “is the most important and exciting new finding [that will come] from the Chang’e-5 samples,” Terada says. Getting it will require a tour-de-force, round-trip space flight that has not been attempted for more than 40 years.

Chang’e-5’s target is Mons Rümker, a 70-kilometer-wide volcanic mound on the Moon’s near side, which may have erupted as recently as about 1.3 billion years ago. It is “the youngest mare basalt on the Moon,” says Xiao Long, a planetary geoscientist at the China University of Geosciences, referring to the dark lava also seen in the Moon’s maria, or seas. Brett Denevi, a planetary geologist at Johns Hopkins University’s Applied Physics Laboratory and science chair of a NASA lunar analysis group, says China has picked a spot where it can have a big scientific impact. “Understanding the age of those samples and all of the Solar System–wide implications that flow from that result will be a big leap forward for planetary science,” she says.

The crater counting method for determining age relies on the notion that surfaces scarred with fewer craters are younger than those that have accumulated more. Regions dated with Apollo and Luna samples have helped calibrate the method. But except for one young outlier, all of those dates cluster between 3.2 billion and 3.9 billion years, leaving the method unanchored, and highly uncertain, for surfaces younger than 3 billion years old, Terada says. “Chang’e-5 samples will provide another data point,” he says.

Getting a firm date for Mons Rümker will also shed light on how lunar volcanism changed over time. Evidence suggests numerous eruptions in the first billion years of the Moon’s existence blanketed the surface with volcanic basalts, forming the dark maria, before tapering off about 3 billion years ago. If Mons Rümker material proves to be just 1.3 billion years old, it will raise questions about how the interior of a small planetary body remained hot enough to erupt so long after formation, says Romain Tartese, a planetary scientist at the University of Manchester.

Retrieving the samples will require a complex deep-space ballet. After launch from the Wenchang launch center in southern China, Chang’e-5 will arrive at the Moon about 3 days later, where an orbiter will release a lander. Over the course of 14 days, the lander’s robotic arm will scoop up surface samples and a drill will retrieve cores down to 2 meters. Scientists are hoping for 2 kilograms of material. (NASA’s Apollo program brought back more than 380 kilograms; three Soviet robotic Luna missions returned 301 grams.) An ascent vehicle will ferry the samples to the orbiter, where they will be packed into a re-entry capsule for return to Earth and a touchdown in the grasslands of Inner Mongolia. Xiao says international investigators will have access to the samples, but U.S. scientists may not because of limits on cooperation with China set by the U.S. Congress.

Chang’e-5 is the latest in a set of increasingly ambitious Moon missions from the China National Space Administration, all named after Chang’e, a Chinese Moon goddess. A pair of orbiters, launched in 2007 and 2010, focused on mapping and remote observations. The lander-rover Chang’e-3 mission, in 2013, carried the first ground-penetrating radar to the lunar surface. In 2019, Chang’e-4, another lander-rover, was the first spacecraft to soft-land on the far side of the Moon. Three more Chang’e missions and a robotic scientific research station are planned by 2035.

Results from Chang’e-4, still trundling along after having traveled nearly 600 meters, are raising questions for later missions. The craft landed in the South Pole–Aitken basin, the Moon’s largest, deepest, and oldest impact crater, at perhaps 4 billion years. Scientists have calculated that the impacting body likely burrowed 70 kilometers into the Moon and churned material from the mantle up to the surface. In a study published in 2019 in Nature, one group of Chinese scientists said the rover’s instruments had detected mantle minerals, but other groups, including Xiao’s, have challenged that interpretation. Patrick Pinet, a planetary geophysicist at France’s Astrophysics and Planetology Research Institute, says researchers are debating why such an enormous impact apparently did not exhume mantle material—or whether the mantle composition is somehow unexpected.

Zou Yongliao, a geochemist at the Chinese Academy of Sciences’s National Space Science Center, says China is making the South Pole the focus of its near-term lunar plans. And although the target site has not been revealed for Chang’e-6, another sample return mission, planetary scientists are rooting for South Pole–Aitken. A basin sample would provide clues to the mantle puzzle. It would also anchor the older end of the crater-counting curve, says Carolyn van der Bogert, a planetary geologist at the University of Münster, and “illuminate the early history of the Moon.”

Famed Arecibo telescope, on the brink of collapse, will be dismantled

A second cable break on 7 November tore through the Arecibo telescope’s dish panels and brought the suspended instrument platform to the verge of collapse.

Arecibo Observatory/University of Central Florida

The Arecibo telescope’s long and productive life has come to an end. The National Science Foundation (NSF) announced today it will decommission the iconic radio telescope in Puerto Rico following two cable breaks in recent months that have brought the structure to near collapse. The 57-year-old observatory, a survivor of numerous hurricanes and earthquakes, is now in such a fragile state that attempting repairs would put staff and workers in danger. “This decision was not an easy one to make,” Sean Jones, NSF’s assistant director for mathematical and physical sciences, said at a news briefing today. “We understand how much Arecibo means to [the research] community and to Puerto Rico.”

Ralph Gaume, director of NSF’s astronomy division, said at the briefing the agency wants to preserve other instruments at the site, as well as the visitor and outreach center. But they are under threat if the telescope structure collapses. That would bring the 900-ton instrument platform, suspended 137 meters above the 305-meter-wide dish, crashing down. Flailing cables could damage other buildings on the site, as could the three support towers if they fell, too. “There is a serious risk of an unexpected and uncontrolled collapse,” Gaume said. “A controlled decommissioning gives us the opportunity to preserve valuable assets that the observatory has.”

Over the next few weeks, engineering firms will develop a plan for a controlled dismantling. It may involve releasing the platform from its cables explosively and letting it fall.

The Arecibo telescope has been widely used by astrophysicists as well as atmospheric and planetary scientists since the early 1960s. For many years it was the main instrument involved in listening for messages from extraterrestrial civilizations, and its striking looks won it a supporting role in feature films.

The observatory has been battered by the elements over the years, most recently by Hurricane Maria in 2017 and an earthquake and aftershocks in December 2019. It’s unknown whether those stresses contributed to the cable failures, the first of which occurred on 10 August. An auxiliary cable, installed in the 1990s when 300 tons of new instruments were added to the suspended platform, broke away from its socket at one end, damaging some instruments and gashing the surface of the dish below.

On 7 November, a main suspension cable (seen hanging down) broke free from its support tower at the Arecibo Observatory. Engineers had already noticed the cable’s wires were degraded.

Arecibo Observatory/University of Central Florida

Engineers investigating the break ordered a replacement cable and others to lend support. During their studies, they noticed that one of the 12 main suspension cables—one connected to the same tower as the failed auxiliary cable—had a dozen broken wires around its exterior. Because these 9-centimeter-thick cables are made up of 160 wires, they thought it had enough capacity to shoulder the extra load.

But on 7 November, that cable broke. The University of Central Florida (UCF), which leads the consortium managing the facility for NSF, already had three engineering firms on-site assessing the first break. They quickly set about analyzing the safety of the whole structure. NSF sent another firm and the Army Corps of Engineers. Of the five, three said the only way forward was a controlled decommissioning. If one main cable was operating below its design capacity, “now all the cables are suspect,” said Ashley Zauderer, NSF’s program director for the Arecibo Observatory. If one of three remaining main cables connected to the impaired tower also failed, the engineers concluded, the platform would collapse.

NSF has, in recent years, been seeking to reduce its commitment to the Arecibo Observatory and, in taking over its management, UCF has shouldered more of the financial burden. But Gaume stated: “This decision has nothing to do with the scientific merits of Arecibo Observatory. It is all about safety.” The facility still has powerful and unique capabilities that researchers rely on, he said. “I’m confident of the resilience of the astrophysics community,” he added, and NSF is working with some of its other facilities to take up some of the studies that have been halted.

‘Exceptional’ cancer patients yield clues to better drug treatments

A scan of a patient with glioblastoma, a type of brain cancer. In rare cases, patients receiving chemotherapy for this cancer have been tumor-free for years. 

Living Art Enterprises, LLC/Science Source

Although even the best cancer drugs don’t buy much time for most people whose cancer has spread, there are rare exceptions: the patients whose multiple tumors melt away and who remain healthy years later. Researchers have long dismissed these “exceptional responders” as unexplainable outliers. Now, an effort to systematically study them is yielding data that could help improve cancer treatments.

The project, led by the U.S. National Cancer Institute (NCI), examined the DNA of tumors and immune cells found around or within those cancers in 111 exceptional responders. In 26 of the patients, scientists found genomic changes to the tumors or immune clues that may explain why a drug that didn’t work for most people shrank the responders’ tumors for months or years. Some cases suggest combining certain drugs could yield better outcomes. The findings show that examining these fortunate few is worthwhile, says Dale Garsed of the Peter MacCallum Cancer Centre in Australia. The study “opens new avenues for treating comparable cancers in the wider population,” he says.

The former NCI director who launched the initiative in 2014 is equally excited. “It is gratifying to see so much novel information from this initial survey of cancer patients who have done unexpectedly well with existing therapies,” says cancer biologist Harold Varmus of Weill Cornell Medicine, who did not work on the study itself. The results are “complex,” he notes, but they “promote unique hypotheses” and underscore the value of conducting genomic tests of patients’ tumors in order to customize treatments.

Varmus was inspired in part by a bladder cancer patient who responded to a generally lackluster drug because of certain mutations in her tumor. From more than 500 cases submitted by clinical researchers, NCI selected those that fit specific criteria: The patient’s tumors shrank or disappeared in response to a drug that worked for less than 10% of patients overall in a clinical trial. Or the patient had a response that lasted at least three times longer than it had for a typical patient.

A team led by NCI’s Louis Staudt and Percy Ivy pared the patient list further to those who had enough medical data and tumor samples with intact DNA. Their team ran these 111 cases through a battery of genomic analyses and tests for immune cells in and near the tumors.

In 26 cases, the data appeared to explain the patient’s exceptional response. For example, a patient with brain cancer who was still alive after more than 10 years had received a chemotherapy drug called temozolomide that kills tumor cells by damaging their DNA. The patient’s tumor had genomic changes that crippled two DNA repair pathways that cells use to counter the drug’s assault, the NCI team reports today in Cancer Cell.

A colon cancer patient in remission for nearly 4 years after temozolomide treatment had two changes that crippled DNA repair pathways and had received a second experimental drug that blocked a third one. “Every backup system that would have reversed the damage was inactivated” in this person, Staudt says. These results suggest treating some patients with a cocktail of drugs, each blocking different DNA repair pathways, could be useful, Ivy says. 

Two patients who had received chemotherapy for rectal cancer and bile duct cancer had unexpected tumor mutations—they were in the BRCA genes, best known for causing breast cancer. BRCA mutations also weaken DNA repair, which made the tumors vulnerable to chemotherapy.

In other cases, tumors shrank after the patients had received a drug that blocks a protein that drives cell growth. The tumors had DNA changes that spurred high activity of the protein’s gene, which made the tumor cells highly dependent on the growth signal; as a result, the drug worked unusually well.

In other exceptional responders, their tumors were infiltrated with unusually high levels of certain immune cells. This suggests their immune systems were primed to swoop in and destroy tumors once a cancer drug started to kill some cells, Staudt says.

The findings suggest more patients should have their tumors analyzed with genomic tests so doctors can select appropriately matching drugs. But results may still be hard to interpret—many tumors had combinations of mutations and immune cell changes, the NCI authors found.

As for the 85 cases the NCI team could not solve, Staudt says the molecular evidence wasn’t strong enough to draw any conclusions. His team is putting data for all 111 patients online in an NCI database so that other researchers can study it and look for similar cases. “Maybe we missed something,” he says.

Researchers in North America, Europe, and Australia have launched similar exceptional responder projects, and NCI researchers hope some of these efforts can pool their data. Staudt would like to see a study of at least 1000 patients. “These are puzzles to be solved,” he says. “I do think they teach us something.”

Twisted graphene could power a new generation of superconducting electronics

A model of twisted graphene reveals a moiré pattern—key to its striking properties.

© 2018 BY YUAN CAO

In 2018, a group of researchers at the Massachusetts Institute of Technology (MIT) pulled off a dazzling materials science magic trick. They stacked two microscopic cards of graphene—sheets of carbon one atom thick—and twisted one ever so slightly. Applying an electric field transformed the stack from a conductor to an insulator and then, suddenly, into a superconductor: a material that frictionlessly conducts electricity. Dozens of labs leapt into the newly born field of “twistronics,” hoping to conjure up novel electronic devices without the hassles of fusing together chemically different materials.

Two groups—including the pioneering MIT group—are now delivering on that promise by turning twisted graphene into working devices, including superconducting switches like those used in many quantum computers. The studies mark a crucial step for the material, which is already maturing into a basic science tool able to capture and control individual electrons and photons. Now, it’s showing promise as the basis of new electronic devices, says Cory Dean, a condensed matter physicist at Columbia University whose lab was one of the first to confirm the material’s superconducting properties after the 2018 announcement. “The idea that this platform can be used as a universal material is not fantasy,” he says. “It’s becoming fact.”

The secret behind twisted graphene’s chameleonlike nature lies with the so-called “magic angle.” When researchers rotate the sheets by precisely 1.1°, the twist creates a large-scale “moiré” pattern—the atom-scale equivalent of the darker bands seen when two grids are juxtaposed. By bringing thousands of atoms together, the moiré allows them to act in unison, like superatoms. That collective behavior enables a modest number of electrons, shepherded to the right place by an electric field, to radically change the material’s behavior, from insulator to conductor to superconductor. Interactions with the supercells also force electrons to slow down and feel each other’s presence, which makes it easier for them to pair off, a requirement for superconductivity.

Now, researchers have shown they can dial desired properties into small regions of the sheet by slapping on a pattern of metallic “gates” that subject different areas to varying electric fields. Both groups built devices known as Josephson junctions, in which two superconductors flank a thin layer of nonsuperconducting material, creating a valve for controlling the flow of superconductivity. “Once you have demonstrated that then the world is open,” says Klaus Ensslin, a physicist at ETH Zurich, and a co-author on one of the studies, posted to the preprint server arXiv on 30 October. Conventional Josephson junctions serve as the workhorse of superconducting electronics, found in magnetic devices for monitoring electrical activity in the brain, and ultrasensitive magnetometers.

The MIT group went further, electrically transforming their Josephson junctions into other submicroscopic gadgets, “just as proof of concept, to show how versatile this is,” says lab leader Pablo Jarillo-Herrero, whose group posted its results to arXiv on 4 November. By tuning the carbon into a conductor-insulator-superconductor configuration, they were able to measure how tightly the electron pairs were yoked together—an early clue to the nature of its superconductivity and how it compares with other materials. The team also built a transistor that can control the movement of single electrons; researchers have studied such single-electron switches as a way to shrink circuits and diminish their thirst for energy.

Magic angle graphene devices are unlikely to challenge consumer silicon electronics anytime soon. Graphene itself is easy to make: Sheets of it can be stripped off blocks of graphite with nothing more than Scotch tape. But the devices must be chilled nearly to absolute zero before they can superconduct. And maintaining the precise twist is awkward, as the sheets tend to wrinkle, disrupting the magic angle. Reliably creating smoothly twisted sheets even just 1 micron or two across is still a challenge, and researchers don’t yet see a clear path toward mass production. “If you wanted to do a real complex device,” Jarillo-Herrero says, “you’d need to create hundreds of thousands of [graphene substrates] and that technology doesn’t exist.”

Nevertheless, many researchers are excited by the promise of exploring electronic devices without worrying about the constraints of chemistry. Materials scientists typically have to find substances with the right atomic properties and fuse them together. And when the concoction is finished, the different elements may not mesh in the desired way.

In magic angle graphene, in contrast, all the atoms are carbon, eliminating messy boundaries between different materials. And scientists can change the electronic behavior of any given patch at the press of a button. These advantages grant unprecedented control over the material, Ensslin says. “Now, you can play like on a piano.”

That control could simplify quantum computers. Those being developed by Google and IBM rely on Josephson junctions with properties that are fixed during fabrication. To operate the finicky qubits, the junctions must be manipulated jointly in cumbersome ways. With twisted graphene, however, qubits could come from single junctions that are smaller and easier to control.

Kin Chung Fong, a Harvard University physicist and member of Raytheon BBN Technologies’s quantum computing team, is enthusiastic about another potential use for the material. In April, he and his colleagues proposed a twisted graphene device that could detect a single photon of far infrared light. That could be useful for astronomers probing the faint light of the early universe; their current sensors can spot lone photons only in the visible or nearly visible parts of the spectrum.

The field of twistronics remains in its infancy, and the fussy process of twisting microscopic specks of graphene to the magic position still requires sleight of hand, or at least deft lab work. But regardless of whether twisted graphene finds its way into industrial electronics, it’s already profoundly changing the world of materials science, says Eva Andrei, a condensed matter physicist at Rutgers University, New Brunswick, whose lab was one of the earliest to notice twisted graphene’s peculiar properties.

“It’s a really new era,” she says. “It’s a totally new way of making materials without chemistry.”

Fish farming’s future, and how microbes compete for space on our face

Fish with podcast symbol overlay


Erik Christensen/Wikipedia

These days, about half of the protein the world’s population eats is from seafood. Staff Writer Erik Stokstad joins host Sarah Crespi to talk about how brand-new biotech and old-fashioned breeding programs are helping keep up with demand, by expanding where we can farm fish and how fast we can grow them.

Sarah also spoke with Jan Claesen, an assistant professor at the Cleveland Clinic’s Lerner Research Institute, about skin microbes that use their own antibiotic to fight off harmful bacteria. Understanding the microbes native to our skin and the molecules they produce could lead to treatments for skin disorders such as atopic dermatitis and acne.

Finally, in a segment sponsored by MilliporeSigma, Science’s Custom Publishing Director and Senior Editor Sean Sanders talks with Timothy Cernak, an assistant professor of medicinal chemistry and chemistry at the University of Michigan, Ann Arbor, about retrosynthesis—the process of starting with a known chemical final product and figuring out how to make that molecule efficiently from available pieces.

This week’s episode was produced with help from Podigy.

Listen to previous podcasts.

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New genetic tools will deliver improved farmed fish, oysters, and shrimp. Here’s what to expect

At research pens in Chile researchers develop strains of farmed Atlantic salmon with improved traits such as growth and health.

Hendrix Genetics

Two years ago, off the coast of Norway, the blue-hulled Ro Fjell pulled alongside Ocean Farm 1, a steel-netted pen the size of a city block. Attaching a heavy vacuum hose to the pen, the ship’s crew began to pump brawny adult salmon out of the water and into a tank below deck. Later, they offloaded the fish at a shore-based processing facility owned by SalMar, a major salmon aquaculture company.

The 2018 harvest marked the debut of the world’s largest offshore fish pen, 110 meters wide. SalMar’s landmark facility, which dwarfs the typical pens kept in calmer, coastal waters, can hold 1.5 million fish—with 22,000 sensors monitoring their environment and behavior—that are ultimately shipped all over the world. The fish from Ocean Farm 1 were 10% larger than average, thanks to stable, favorable temperatures. And the deep water and strong currents meant they were free of parasitic sea lice.

Just a half-century ago, the trade in Atlantic salmon was a largely regional affair that relied solely on fish caught in the wild. Now, salmon farming has become a global business that generates $18 billion in annual sales. Breeding has been key to the aquaculture boom. Ocean Farm 1’s silvery inhabitants grow roughly twice as fast as their wild ancestors and have been bred for disease resistance and other traits that make them well suited for farm life. Those improvements in salmon are just a start: Advances in genomics are poised to dramatically reshape aquaculture by helping improve a multitude of species and traits.

Genetic engineering has been slow to take hold in aquaculture; only one genetically modified species, a transgenic salmon, has been commercialized. But companies and research institutions are bolstering traditional breeding with genomic insights and tools such as gene chips, which speed the identification of fish and shellfish carrying desired traits. Top targets include increasing growth rates and resistance to disease and parasites. Breeders are also improving the hardiness of some species, which could help farmers adapt to a shifting climate. And many hope to enhance traits that please consumers, by breeding fish for higher quality fillets, eye-catching colors, or increased levels of nutrients. “There is a paradigm shift in taking up new technologies that can more effectively improve complex traits,” says Morten Rye, director of genetics at Benchmark Genetics, an aquaculture breeding company.

After years of breeding, Atlantic salmon grow faster and larger than their wild relatives.

Hendrix Genetics

Aquaculture breeders can tap a rich trove of genetic material; most fish and shellfish have seen little systematic genetic improvement for farming, compared with the selective breeding that chickens, cattle, and other domesticated animals have undergone. “There’s a huge amount of genetic potential out there in aquaculture species that’s yet to be realized,” says geneticist Ross Houston of the Roslin Institute.

Amid the enthusiasm about aquaculture’s future, however, there are concerns. It’s not clear, for example, whether consumers will accept fish and shellfish that have been altered using technologies that rewrite genes or move them between species. And some observers worry genomic breeding efforts are neglecting species important to feeding people in the developing world. Still, expectations are high. “The technology is amazing, it’s advancing very quickly, the costs are coming down,” says Ximing Guo, a geneticist at Rutgers University, New Brunswick. “Everybody in the field is excited.”

Fish farming may not have roots as old as agriculture, but it dates back millennia. By about 3500 years ago, Egyptians were raising gilt-head sea bream in a large lagoon. The Romans cultivated oysters. And carp have been grown and selectively bred in China for thousands of years. Few aquaculture species, however, saw systematic, scientific improvement until the 20th century.

One species that has received ample attention from breeders is Atlantic salmon, which commands relatively high prices. Farming began in the late 1960s, in Norway. Within 10 years, breeding had helped boost growth rates and harvest weight. Each new generation of fish—it takes salmon 3 to 4 years to mature—grows 10% to 15% faster than its forebears. “My colleagues in poultry can only dream of these kinds of percentages,” says Robbert Blonk, director of aquaculture R&D at Hendrix Genetics, an animal breeding firm. During the 1990s, breeders also began to select for improved disease resistance, fillet quality, delayed sexual maturation (which boosts yields), and other traits.

Another success story involves tilapia, a large group of freshwater species that doesn’t typically bring high prices but plays a key role in the developing world. An international research center in Malaysia, now known as WorldFish, began a breeding program in the 1980s that quickly doubled the growth rate of one commonly raised species, Nile tilapia. Breeders also improved its disease resistance, a task that continues because of the emergence of new pathogens, such as tilapia lake virus.

Genetically improved farmed tilapia “was a revolution in terms of tilapia production,” says Alexandre Hilsdorf, a fish geneticist at the University of Mogi das Cruzes in Brazil. China, a global leader in aquaculture production, has capitalized on the strain, building the world’s largest tilapia hatchery. It raises billions of young fish annually.

Now, aquaculture supplies nearly half of the fish and shellfish eaten worldwide (see chart, below), and production has been growing by nearly 4.5% annually over the past decade—faster than most sectors of the farmed food sector. That expansion has come with some collateral damage, including pollution from farm waste, heavy catches of wild fish to feed to penned salmon and other species, and the destruction of coastal wetlands to build shrimp ponds. Nevertheless, aquaculture is now poised for further acceleration, thanks in large part to genomics.

A rising tide

Aquaculture is rivaling catches from wild fisheries and is projected to increase. Much of the growth comes from freshwater fish in Asia, such as grass carp, yet most research has focused on Atlantic salmon and other high-value species. Genomic technology is now spreading to shrimp and tilapia.

0 20 40 60 80 100 120 140 160 180Million tons1950Value ($ billions)Harvest (thousand tons, annually)*First research on breeding19581966197419821990199820062014Capture fisheries (inland)Aquaculture (inland)Capture fisheries (marine)Aquaculture (marine)Grass carp12.6570420107.645251989Nile tilapia16.724361971Atlantic salmon26.749661995Whiteleg shrimp1.26441984Pacific cupped oyster*First scientific report of breeding for a specific trait

(GRAPHIC) N. DESAI/SCIENCE; (DATA, TOP TO BOTTOM) FOOD AND AGRICULTURE ORGANIZATION OF HE UNITED NATIONS; HOUSTON et al., NATURE REVIEWS GENETICS 21, 389 (2020)

Breeders are most excited about a technique called genomic selection. To grasp why, it helps to understand how breeders normally improve aquaculture species. They start by crossing two parents and then, out of hundreds or thousands of their offspring, select individuals to test for traits they want to improve. Advanced programs make hundreds of crosses in each generation and choose from the best performing families for breeding. But some tests mean the animal can’t later be used for breeding; measuring fillet quality is lethal, for instance, and screening for disease resistance means the infected individual must remain quarantined. As a result, when researchers identify a promising animal, they must pick a sibling to use for breeding—and hope that it performs just as well. “You don’t know whether they’re the best of the family or the worst,” says Dean Jerry, an aquaculture geneticist at James Cook University, Townsville, who works with breeders of shrimp, oysters, and fish.

With genomic selection, researchers can identify siblings with high-performance traits based on genetic markers. All they need is a small tissue sample—such a clipping from a fin—that can be pureed and analyzed. DNA arrays, which detect base-pair changes called single nucleotide polymorphisms (SNPs), allow breeders to thoroughly evaluate many siblings for multiple traits. If the pattern of SNPs suggests that an individual carries optimal alleles, it can be selected for further breeding even if it hasn’t been tested. Genomic analyses also allow breeders to minimize inbreeding.

Cattle breeders pioneered genomic selection. Salmon breeders adopted it a few years ago, followed by those working with shrimp and tilapia. “There is a big race from industry to implement this technology,” says geneticist ‪José Yáñez of the University of Chile, who adds that even small-scale producers are now interested in genetic improvement. As a rough average, the technique increases selection accuracy and the amount of genetic improvement by about 25%, Houston says. It and other tools are helping researchers pursue goals such as:

Faster growth

This trait improves the bottom line, allowing growers to produce more frequent and bigger hauls. Growth is highly heritable and easy to measure, so traditional breeding works well. But breeders have other tactics for boosting growth, including providing farmers with fish of a single sex. Male tilapia, for example, can grow significantly faster than females. Another strategy is to hybridize species. The dominant farmed catfish in the United States, a hybrid of a female channel catfish and a male blue catfish, grows faster and is hardier.

Inducing sterility stimulates growth, too, and has helped raise yields in shellfish, particularly oysters. In the 1990s, Guo and Standish Allen, now at the Virginia Institute of Marine Science, figured out a new way to create triploid oysters, which are infertile because they have an extra copy of each chromosome. These oysters don’t devote much energy to reproduction, so they reach harvest size sooner, reducing exposure to disease. (When oysters reproduce, more than half their body consists of sperm or eggs, which no one wants to eat.)

Looking ahead, researchers are exploring gene transfer or gene editing to further enhance gains. And one U.S. company, AquaBounty, is just beginning to sell the world’s first transgenic food animal, an Atlantic salmon, that it claims is 70% more productive than standard farmed salmon. But the fish is controversial and has faced consumer resistance and regulatory hurdles.

Healthier fish

Disease is often the biggest worry and expense for aquaculture operations. In shrimp, outbreaks can slash overall yield by up to 40% annually and can wipe out entire operations. Vaccines can prevent some diseases in fish, but not invertebrates, because their adaptive immune systems are less developed. So, for all species, resistant strains are highly desirable.

To improve disease resistance, researchers need a rigorous way to test animals. Thanks to a collaboration with fish pathologists at the U.S. Department of Agriculture (USDA), Benchmark Genetics was able to screen tilapia for susceptibility to two major bacterial diseases by delivering a precise dose of the pathogen and then measuring the response. They identified genetic markers correlated with infection and used genomic selection to help develop a more resistant strain. USDA scientists have also worked with Hendrix Genetics to increase the survival of trout exposed to a different bacterial pathogen from 30% to 80% in just three generations.

The fecundity of most aquatic species, like this trout (left), helps breeding efforts. Salmon eggs, 0.7 millimeters wide (right), are robust and easy for molecular biologists to work with.

Hendrix Genetics

Perhaps the most celebrated success has been in salmon. After researchers discovered a genetic marker for resistance to infectious pancreatic necrosis, companies quickly bred strains that can survive this deadly disease. Oyster breeders, meanwhile, have had success in developing strains resistant to a strain of herpes that devastated the industry in France, Australia, and New Zealand.

Parasite-resistant salmon

A big problem for Atlantic salmon growers is the sea louse. The tiny parasite clings to the salmon’s skin, inflicting wounds that damage or kill fish and make their flesh worthless. Between fish losses and the expense of controlling the parasites, lice cost growers more than $500 million a year in Norway alone. Lice are attracted to fish pens and can jump to wild salmon that pass by.

For years farmers have relied on pesticides to fight lice, but the parasite has become resistant to many chemicals. Other techniques, such as pumping salmon into heated water, which causes the lice to drop off, can stress the fish.

Researchers have found that some Atlantic salmon are better than others at resisting lice, and breeders have been trying to improve this trait. So far, they’ve had modest success. Better understanding why several species of Pacific salmon are immune to certain lice could lead to progress. Scientists are exploring whether sea lice are attracted to certain chemicals released by Atlantic salmon; if so, it’s possible these could be modified with gene editing.

Sterile stock

No sex on the farm. That’s a goal with many aquaculture species, because reproduction diverts energy from growth. Moreover, fertile fish that escape from aquaculture operations can cause problems for wild relatives. When wild fish breed with their domesticated cousins, for instance, the offspring are often less successful at reproducing.

Salmon can be sterilized by making them triploid, typically by pressurizing newly fertilized embryos in a steel tank when the chromosomes are replicating. But this can have side effects, such as greater susceptibility to disease. Anna Wargelius, a molecular physiologist at Norway’s Institute of Marine Research, and colleagues have instead altered the genes of Atlantic salmon to make them sterile, using the genome editor CRISPR to knock out a gene called deadend. In 2016, they showed that these fish, though healthy, lack germ cells and don’t sexually mature. Now, they’re working on developing fertile broodstock that produce these sterile offspring for hatcheries. Embryos with the knocked-out genes should develop into fertile adults if injected with messenger RNA, according to a paper the group published last month in Scientific Reports. When these fish mature later in December, they will try to breed them. “It looks very promising,” Wargelius says.

Another approach would not involve genetic modifications. Fish reproductive physiologists Yonathan Zohar and Ten-Tsao Wong of the University of Maryland, Baltimore County, are using small molecule drugs to disrupt early reproductive development so that fish mature without sperm or eggs.

Bone-free fillets

Cooks and diners hate bones. Nearly half of the top species in aquaculture are species of carp or their relatives, which are notorious for the small bones that pack their flesh. These bones can’t be easily removed during processing, so “you can’t just get a nice, clean fillet,” says Benjamin Reading, a reproductive physiologist at North Carolina State University.

Researchers are studying the biology of these fillet bones to see whether they might one day be removed through breeding or genetic engineering. A few years ago, Hilsdorf heard that a Brazilian hatchery had discovered mutant brood stock of a giant Amazonian fish, the widely farmed tambaqui, that lacked these fillet bones. After trying and failing to breed a boneless strain, he’s studying tissue samples from the mutants for clues to their genetics.

Geneticist Ze-Xia Gao of Huazhong Agricultural University is focusing on blunt snout bream, a carp that is farmed in China. Guided by five genetic markers, she and colleagues are breeding the bream to have few fillet bones. It could take 8 to 10 years to achieve, she says. They have also had some success with gene editing—they’ve identified and knocked out two genes that control the presence of fillet bones—and they plan to try the approach in other carp species. “I think it will be feasible,” Gao says.

New items for the menu

Aquaculture projects worldwide are hustling to domesticate new species—a kind of gold rush rare in terrestrial farming. In New Zealand, researchers are domesticating native species because they are already adapted to local conditions. The New Zealand Institute for Plant and Food Research began to breed the Australasian snapper in 2004. Early work concentrated on simply getting the fish to survive and reproduce in a tank. One decade later, researchers started to breed for improved growth, and they’ve since increased juvenile growth rates by 20% to 40%.

Genomic techniques have proved critical. Snapper are mass spawners, so it was hard for breeders to identify the parents of promising offspring, which is crucial for optimizing selection and avoiding inbreeding. DNA screening solved that problem, because the markers reveal ancestry. The institute is also breeding another local fish, the silver trevally, aiming for a strain that will reproduce in captivity without hormone implants. “It’s a long-term effort to breed a wild species to make it suitable for aquaculture,” says Maren Wellenreuther, an evolutionary geneticist at the New Zealand institute and the University of Auckland.

These breeding efforts require money. Despite the growth of aquaculture, the field’s research funding lags the amounts invested in livestock, although some governments are boosting investments.

Looking globally, geneticist Dennis Hedgecock of Pacific Hybreed, a small U.S. company that is developing hybrid oysters, sees a “huge disparity” between breeding investment in developed countries—which produce a fraction of total harvests but have the biggest research budgets—and the rest of the world. Simply applying classical breeding techniques could rapidly improve production, especially in the developing world, he says. Yet the hundreds of species now farmed could overwhelm breeding programs, especially those aimed at enhancing disease resistance, Hedgecock adds. “The growth and the production is outstripping the scientific capability of dealing with the diseases,” he says, adding that a focus on fewer species would be beneficial.

For genomics to help, experts say costs must continue to come down. One promising development in SNP arrays, they note, is a technique called imputation, in which cheaper arrays that search for fewer genetic changes are combined with a handful of higher cost chips that probe the genome in more detail. Such developments suggest genomic technology is “at a pivot point where you’re going to see it used broadly in aquaculture,” says John Buchanan, president of the Center for Aquaculture Technologies, a contract research organization.

Many companies are already planning for larger harvests. SalMar will decide next year whether it will order a companion to Ocean Farm 1. It has already drawn up plans for a successor that can operate in the open ocean and would be more than twice the size, big enough to hold 3 million to 5 million salmon at a time.

Fires can kindle biodiversity, sparking new approaches to conservation

Raging fires throughout the United States and Australia over the past year have put vulnerable species at risk. But not all blazes are devastating—in fact, fire can promote biodiversity. In grasslands, fires prevent trees and roots from taking hold. This allows grazing animals the space and vegetation they need to thrive. As the pattern of wildfires changes, a new review in Science outlines effective ways to let natural fires burn, while preventing out-of-control blazes. Watch to learn how a few of these techniques have been applied around the world.

To explain away dark matter, gravity would have to be really weird, cosmologists say

The spatial distribution of more than 4 million galaxies as measured by the Sloan Digital Sky Survey, which can’t be easily explained by modifying gravity

SDSS (CC-BY)

Dark matter, the invisible stuff whose gravity is thought to hold galaxies together, may be the least satisfying concept in physics. But if you want to get rid of it, a new study finds, you’ll need to replace it with something even more bizarre: a force of gravity that, at some distances, pulls massive objects together and, at other distances, pushes them apart. The analysis underscores how hard it is to explain away dark matter.

Concocting such a theory of gravity “is so complicated that it seems very unlikely that anyone could come up with a scenario that would work,” says Scott Dodelson, a theoretical physicist at Carnegie Mellon University, who wasn’t involved in the new work. Still, some theorists say it may be possible to pass the test.

According to cosmologists’ prevailing theory, dark matter pervades pretty much every galaxy, providing the extra gravity that keeps stars from swirling out into space, given the speeds at which astronomers see the galaxies rotating. A vast web of clumps and strands of the stuff served as the scaffolding on which the cosmos developed. Yet, after of decades of trying, physicists haven’t spotted particles of dark matter floating around, and many would happily dismiss the idea—if it didn’t work so well.

Some scientists have tried to kick the dark matter habit. In 1983, Israeli physicist Mordehai Milgrom found he could account for the high speeds of stars swirling around the peripheries of galaxies by modifying Isaac Newton’s famous second law of motion: force equals mass times acceleration. That insight suggested the need for dark matter could be obviated by changing the law of gravity, at least on the scale of individual galaxies. But theorists labored for decades to turn the idea into a coherent theory of gravity akin to Albert Einstein’s general theory of relativity, and to do so, they had to add new fields, cousins of the usual gravitational field.

But to do away with dark matter, theorists would also need explain away its effects on much larger, cosmological scales. And that is much harder, argues Kris Pardo, a cosmologist at NASA’s Jet Propulsion Laboratory, and David Spergel, a cosmologist at Princeton University. To make their case, they compare the distribution of ordinary matter in the early universe as revealed by measurements of the afterglow of the big bang—the cosmic microwave background (CMB)—with the distribution of the galaxies today.

The evolution of the universe is a tale of two fluids: dark matter, which doesn’t interact with light, and ordinary matter, which does. The big bang left ripples in the dark matter, which under its own gravity began to coalesce into the denser spots. Ordinary matter—then, a hot soup of free-flying protons and electrons—also began to fall into the dark matter clumps. However, those charged particles themselves generated radiation that pushed them back out, creating sound waves known as a baryon acoustic oscillations. The waves continued to spread until the universe cooled enough to form neutral atoms, 380,000 years after the big bang, when the CMB was born. The sound wave left its imprint on the CMB and, faintly, in the distribution of the galaxies.

Or could that evolution be explained with only ordinary matter interacting through modified gravity? To explore that possibility, Pardo and Spergel derived a mathematical function that describes how gravity would have had to work to get from the distribution of ordinary matter revealed by the CMB to the current distribution of the galaxies. They found something striking: That function must swing between positive and negative values, meaning gravity would be attractive at some length scales and repulsive at others, Pardo and Spergel report this week in Physical Review Letters. “And that’s superweird,” Pardo says.

The strange behavior is required to explain how the larger baryon acoustic oscillation faded over cosmic time while the smaller galaxies emerged, Pardo says. Just as Milgrom did with individual galaxies, the new work shows how, without dark matter, gravity would have to change to explain the universe’s large-scale structure, Dodelson says. But that change would have to be radical, he says. “They’re demonstrating that to do that you have to jump through these 13 hoops,” he says.

However, theorists already seem prepared to jump through those hoops. In a paper posted in June to the preprint server arXiv, theoretical cosmologists Constantinos Skordis and Tom Złosnik of the Czech Academy of Sciences present a dark matterless theory of modified gravity they say jibes with CMB data. To do that, researchers add to a theory like general relativity an additional, tunable field called a scalar field. It has energy, and through Einstein’s equivalence of mass and energy, it can behave like a form of mass. Set things up just right and at large spatial scales, the scalar field interacts only with itself and acts like dark matter.

The team hasn’t explicitly shown that the theory, which isn’t meant to be a fundamental theory of gravity, passes Pardo’s and Spergel’s particular test. But because it’s designed to mimic dark matter, it ought to, Skordis says. “We engineered it to have that behavior.”

Skordis’s and Złosnik’s paper is “very exciting,” Pardo says. But he notes that in some sense it merely replaces one mysterious thing—dark matter—with another—a carefully tuned scalar field. Given the complications, Pardo says, “dark matter is kind of the easier explanation.”

*Correction, 20 November, 1:30 p.m.: An earlier version of this story misstated Kris Pardo’s affiliation.  

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