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SOCIETY | VIEW ON WEBSITE

Q&A — Environmental scientist and physicist Diana Ürge-Vorsatz

The great green building makeover

Getting our homes and workplaces to be energy efficient has major benefits — but not when it is done one window at a time. Here’s why deep retrofits and biomaterials are key to more sustainable living.

By Kaja Šeruga    12.04.2024

Eat less meat, fly less, don’t use plastic: The changes we need to make to lower global emissions can often be tough sells. But one effective strategy is a win-win. Retrofitting buildings to be more energy efficient could drastically reduce emissions, while also making residents healthier, more comfortable and more financially secure.

“It’s a case where we can have our cake and eat it,” says Diana Ürge-Vorsatz, an environmental scientist and climate expert at Central European University in Vienna and vice-chair of the Intergovernmental Panel on Climate Change.

CREDIT: JAMES PROVOST (CC BY-ND)

Environmental scientist and physicist Diana Ürge-Vorsatz

Central European University in Vienna

This is no marginal issue: Buildings and construction account for at least 37 percent of global carbon emissions. Partly, these are operational emissions — keeping the lights on and keeping buildings warm or, increasingly, cool enough for people living and working in them. But as buildings become more energy efficient and their energy sources increasingly renewable, the carbon produced by the materials and construction of the buildings — known as embodied carbon — can make up more than half of their environmental impact.

In 2024, the United States published its first comprehensive federal strategy to reduce emissions from buildings by 90 percent by 2050, while the EU’s goal is to eliminate them entirely by then. It’s doable, says Ürge-Vorsatz, but would require a profound shift in how we approach our built environment.

It’s a delicate balancing act. We need to make our existing buildings as energy efficient as possible, while at the same time minimizing the emissions caused by renovations or new construction. Areas ripe for innovation include insulation materials, which are crucial for energy-efficient buildings but make up more than a quarter of a building’s embodied carbon. Biobased insulation materials derived from renewable, natural sources are one of the possible solutions that scientists, including Ürge-Vorsatz, are looking into.

Knowable Magazine spoke with Ürge-Vorsatz about making buildings more sustainable, and about how biobased materials can support the effort. This conversation has been edited for length and clarity.

Why do you focus on buildings and construction? What is their importance in the context of climate change?

As a physicist, I have been focusing on energy efficiency my entire career. But around 2004, I was leading the chapter on buildings for the fourth assessment report of the Intergovernmental Panel on Climate Change, and one of the lead authors kept saying that buildings can reduce energy use by 90 percent. I thought, “Sure, that’s just a bit of advocacy, show us the literature.” But when he pulled out some examples of passive houses — highly energy-efficient houses that use 90 percent less energy for heating and cooling than typical buildings — I was quite shocked.

I visited an example of such a retrofit in Hungary, where they took this very average panel building [the large Soviet-era apartment buildings made of prefabricated concrete panels], which are all over Eastern Europe, and reduced its energy use by 85 percent. Without any rocket science, and the retrofit costs were really not prohibitive.

I talked to one of the residents who said her quality of life completely changed for the better. Yes, it was nice to have lower energy costs. But what touched me most was her saying that she can now clean five times less than she used to. The engineering literature will never consider this an achievement, but this is an industrial area, with lots of dust, which was gone with the filtered ventilation system. It saved so much of her time and effort.

Her allergy was also gone. I started looking into this and the literature is loud and clear. The energy benefits of deep retrofits can be 80 to 90 percent, but the co-benefits are even more impressive — the improvement in air quality through ventilation and air filtration alone impacts things like cardiovascular disease and the spread of respiratory illnesses. People don’t want to believe it because it sounds too good to be true. But it really is that good.

What share of our greenhouse gas emissions and energy use currently comes from buildings?

Buildings, including their construction, are responsible for over a third of greenhouse gas emissions. But even more importantly, in the European Union half of all gross final energy [the energy sent out to consumers] is used for heating and cooling — not powering cars or keeping the lights on. And high-efficiency buildings can eliminate the vast majority of this. So we have not only enormous emissions and energy use from buildings, but also enormous potential to eliminate these without us noticing it — in fact, with us living much better.

The Roomley sports hall (pictured) in the Netherlands is one of many old buildings that have been retrofitted to the highest energy efficiency standards. Originally built in the 1970s, the sports hall is now insulated with straw and, thanks to lower energy needs combined with solar panels, produces more energy that it consumes.

CREDIT: © EUROPEAN UNION

Both the EU and the US have ambitious plans for drastically reducing greenhouse gas emissions related to buildings and construction. What, realistically, would need to happen for them to hit these targets?

First, we need to accept that we have enough buildings in the developed world. There are exceptions, of course, but by and large the population is not increasing, and we already have enough per-capita floor space. For any new construction we should have to justify why an existing building cannot be repurposed and retrofitted instead. We also need a way to disincentivize more floor space, to discourage third homes and huge mansions.

Secondly, we have to significantly reform the financing for deep retrofits. We’ll never reach these ambitious climate targets relying on building owners. While these are very profitable investments, it usually takes 20 to 30 years for them to pay back, just based on energy cost. But from a societal perspective, it’s among the most attractive carbon mitigation strategies — because we are killing so many birds with one stone. We are improving energy security. We are making ourselves independent of Russian natural gas. We are helping the social welfare of our residents by reducing their energy costs. It’s really win-win, from a government perspective.

We need serious public financing for it, and the money is there. Currently, over 7 percent of the world’s GDP is used to subsidize fossil fuels. If we just divert part of that to building retrofits, we are achieving so many goals at once.

What exactly do you mean by “deep retrofit”?

There are many different definitions of a deep retrofit. In our paper in the Annual Review of Environment and Resources, we use the term to refer to buildings that save 80-90 percent of the heating- and cooling-related energy. Deep retrofits take a holistic view of the building, increasing its efficiency by improving the building envelope through measures like enhanced insulation and new windows. Special attention is given to remedying thermal bridges and ensuring air tightness. This, combined with a heat recovery ventilation system, can ideally result in a building that does not need additional heating or cooling at all, though this depends on climate and what the building is used for.

Europe and North America have already recognized the importance of energy saving in retrofits, but what we have been doing is incremental: Let’s change a window here, put a little bit of insulation there. My research has shown that this is actually worse than not doing anything, because it prevents the opportunity for a deep retrofit down the line, which would require different windows and insulation.

Realistically, it makes no economic sense to change a window you just changed. That’s why it’s better to either wait until you can do a deep retrofit, or do it step by step but always with the aim of a deep retrofit. You can only reach the big emission and energy savings if you consider the building as a system, and do it holistically.

Your Annual Review paper looks at maximizing energy efficiency in the construction sector, and highlights insulation as a factor that can hugely impact the emissions and energy costs of a building. Why is insulation so important?

Insulation materials don’t have a huge carbon footprint, but the total can run high because we are using a lot of them. And some forms of insulation are associated with not only carbon dioxide but also much more potent greenhouse gases, like the HCFCs used in the production of some polystyrene foams. Of course, it’s still better to insulate than not to. But another important aspect is plastic, which is increasing exponentially year by year, and we are just beginning to understand its enormous negative impact on our health and the environment. Insulation materials represent a huge volume of plastics and other artificial materials.

You’re involved in a European project, BIO4EEB, developing biobased insulation materials. What are biobased insulation materials and what benefits do they provide?

Biobased insulation materials are made entirely or partially from renewable biological sources like plants, and while they aren’t necessarily always 100 percent renewable, they aim to minimize the reliance on nonrenewable raw materials like fossil fuels in their production. For example, biobased polyurethane foams are made using bio-polyols derived from vegetable oils, instead of fossil fuels. This way, we eliminate the emissions caused by these quite energy-intensive insulation materials.

Beyond that, they could contribute to capturing and storing carbon dioxide. Biological materials, like trees and plants, capture carbon dioxide as they grow and release it when they rot. If we keep them from this rotting phase for as long as possible, we are keeping that carbon dioxide out of the atmosphere.

The third benefit is less toxicity, such as the impact of mineral-based insulation materials like glass wool on the respiratory system, or the toxic effects of microplastics from petrochemical materials.

Are there any downsides to biobased materials?

The question is whether we have enough. Today there is already a huge demand for biomass, and a big pressure on land. In the case of forestry or agriculture residues, it’s also not sustainable to take all the organic material, because that depletes the carbon stock and humus content of soil.

These are all difficult questions. How much biobased material is available in a sustainable way that could be used for this purpose? All of these more sustainable solutions are smaller-scale, which also makes them a bit more expensive.

Can you share examples of biobased insulators that you find particularly promising or exciting?

One thing we’re looking at is Posidonia, which is a seagrass that washes up on the shore in the Mediterranean. We’re creating different insulation materials from that, like prefabricated insulation panels. I find that very exciting. But again, we have to look at the scale of it, how much we can use without having to produce it, or if we have to produce it, how can we do that in a safe way?

Posidonia oceanica, a seaweed endemic to the Mediterranean, washes ashore in fibrous balls and large “banquettes” that can reach up to two metres in height. Scientists are exploring ways to turn this seaweed into insulation, which would not only have lower carbon emissions than traditional insulation materials, but also lock in the carbon that is stored in the biomass.

CREDIT: CHARLOTTE NADADORA / FLICKR

I also think that hemp and straw could be important, because they have traditionally been used in the construction industry. Another one is biobased foams, because the insulation industry uses a lot of foams, which are traditionally petrochemical, nondegradable and toxic.

You and your team at the Central European University in Vienna assess these materials using life cycle assessments. How does this work?

Life cycle assessment means that we are looking at all the environmental impacts, all the way from the mining of the materials to it becoming waste, and every part of the story in between. It’s a very nice concept, but it’s difficult and enormously expensive to run it properly.

We need a streamlined version that focuses on the big items. We know that we’ll be better off if we replace concrete, steel, cement, Styrofoam with biomaterials that are less energy-intensive. Yes, they are very variable in their impact, but I’m not sure it’s always worth spending the time to do very detailed assessments, because we don't have the time or the money. I hope that as a result of this project we can develop some simplified methods to assess where the big issues are.

What would you want to see happen in the next decade to reduce the impact that housing and construction have on the environment? And do you think we can get there?

First, we have to constrain the enormous hunger for construction and allow the construction industry a good, just transition to a lower level. Second, as I said, it’s pivotal to strongly disincentivize luxury construction.

Finally, we should strongly encourage deep retrofits over incremental ones. This needs a lot of public financing, which will be good for so many areas — energy security, the social welfare of our families and businesses, health benefits, productivity.

Will we manage it or not? No, that’s not the question. We have to. The future is always in our hands.

10.1146/knowable-120424-1

Kaja Šeruga is a freelance journalist based in Vienna. You can learn more about her work on her website.

FOOD & ENVIRONMENT | VIEW ON WEBSITE

Can desalination quench agriculture’s thirst?

Miles away from the ocean, projects are afoot to clean up salty groundwater and use it to grow crops. Some say it’s a costly pipe dream, others say it’s part of the future.

By Lela Nargi    11.21.2024

Ralph Loya was pretty sure he was going to lose the corn. His farm had been scorched by El Paso’s hottest-ever June and second-hottest August; the West Texas county saw 53 days soar over 100 degrees Fahrenheit in the summer of 2024. The region was also experiencing an ongoing drought, which meant that crops on Loya’s eight-plus acres of melons, okra, cucumbers and other produce had to be watered more often than normal.

Loya had been irrigating his corn with somewhat salty, or brackish, water pumped from his well, as much as the salt-sensitive crop could tolerate. It wasn’t enough, and the municipal water was expensive; he was using it in moderation and the corn ears were desiccating where they stood.

Ensuring the survival of agriculture under an increasingly erratic climate is approaching a crisis in the sere and sweltering Western and Southwestern United States, an area that supplies much of our beef and dairy, alfalfa, tree nuts and produce. Contending with too little water to support their plants and animals, farmers have tilled under crops, pulled out trees, fallowed fields and sold off herds. They’ve also used drip irrigation to inject smaller doses of water closer to a plant’s roots, and installed sensors in soil that tell more precisely when and how much to water.

In the last five years, researchers have begun to puzzle out how brackish water, pulled from underground aquifers, might be de-salted cheaply enough to offer farmers another water resilience tool. Loya’s property, which draws its slightly salty water from the Hueco Bolson aquifer, is about to become a pilot site to test how efficiently desalinated groundwater can be used to grow crops in otherwise water-scarce places.

Desalination renders salty water less so. It’s usually applied to water sucked from the ocean, generally in arid lands with few options; some Gulf, African and island countries rely heavily or entirely on desalinated seawater. Inland desalination happens away from coasts, with aquifer waters that are brackish — containing between 1,000 and 10,000 milligrams of salt per liter, versus around 35,000 milligrams per liter for seawater. Texas has more than three dozen centralized brackish groundwater desalination plants, California more than 20.

Such technology has long been considered too costly for farming. Some experts still think it’s a pipe dream. “We see it as a nice solution that’s appropriate in some contexts, but for agriculture it’s hard to justify, frankly,” says Brad Franklin, an agricultural and environmental economist at the Public Policy Institute of California. Desalting an acre-foot (almost 326,000 gallons) of brackish groundwater for crops now costs about $800, while farmers can pay a lot less — as little as $3 an acre-foot for some senior rights holders in some places — for fresh municipal water. As a result, desalination has largely been reserved to make liquid that’s fit for people to drink. In some instances, too, inland desalination can be environmentally risky, endangering nearby plants and animals and reducing stream flows.

But the US Bureau of Reclamation, along with a research operation called the National Alliance for Water Innovation (NAWI) that’s been granted $185 million from the Department of Energy, have recently invested in projects that could turn that paradigm on its head. Recognizing the urgent need for fresh water for farms — which in the US are mostly inland — combined with the ample if salty water beneath our feet, these entities have funded projects that could help advance small, decentralized desalination systems that can be placed right on farms where they’re needed. Loya’s is one of them.

US farms consume over 83 million acre-feet (more than 27 trillion gallons) of irrigation water every year — the second most water-intensive industry in the country, after thermoelectric power. Not all aquifers are brackish, but most that are exist in the country’s West, and they’re usually more saline the deeper you dig. With fresh water everywhere in the world becoming saltier due to human activity, “we have to solve inland desal for ag … in order to grow as much food as we need,” says Susan Amrose, a research scientist at MIT who studies inland desalination in the Middle East and North Africa.

Brackish (slightly salty) groundwater is found mostly in the Western United States.

CREDIT: J.S. STANTON ET AL / BRACKISH GROUNDWATER IN THE UNITED STATES: USGS PROFESSIONAL PAPER 1833. 2017

That means lowering energy and other operational costs; making systems simple for farmers to run; and figuring out how to slash residual brine, which requires disposal and is considered the process’s “Achilles’ heel,” according to one researcher.

The last half-decade of scientific tinkering is now yielding tangible results, says Peter Fiske, NAWI’s executive director. “We think we have a clear line of sight for agricultural-quality water.”

Swallowing the high cost

Fiske believes farm-based mini-plants can be cost-effective for producing high-value crops like broccoli, berries and nuts, some of which need a lot of irrigation. That $800 per acre-foot has been achieved by cutting energy use, reducing brine and revolutionizing certain parts and materials. It’s still expensive but arguably worth it for a farmer growing almonds or pistachios in California — as opposed to farmers growing lesser-value commodity crops like wheat and soybeans, for whom desalination will likely never prove affordable. As a nut farmer, “I would sign up to 800 bucks per acre-foot of water till the cows come home,” Fiske says.

Loya’s pilot is being built with Bureau of Reclamation funding and will use a common process called reverse osmosis. Pressure pushes salty water through a semi-permeable membrane; fresh water comes out the other side, leaving salts behind as concentrated brine. Loya figures he can make good money using desalinated water to grow not just fussy corn, but even fussier grapes he might be able to sell at a premium to local wineries.

Such a tiny system shares some of the problems of its large-scale cousins — chiefly, brine disposal. El Paso, for example, boasts the biggest inland desalination plant in the world, which makes 27.5 million gallons of fresh drinking water a day. There, every gallon of brackish water gets split into two streams: fresh water and residual brine, at a ratio of 83 percent to 17 percent. Since there’s no ocean to dump brine into, as with seawater desalination, this plant injects it into deep, porous rock formations — a process too pricey and complicated for farmers.

Rows of reverse osmosis membranes at the Kay Bailey Hutchison Desalination Plant in El Paso.

CREDIT: PHOTO BY ADA COWAN

But what if desalination could create 90 or 95 percent fresh water and 5 to 10 percent brine? What if you could get 100 percent fresh water, with just a bag of dry salts leftover? Handling those solids is a lot safer and easier, “because super-salty water brine is really corrosive … so you have to truck it around in stainless steel trucks,” Fiske says.

Finally, what if those salts could be broken into components — lithium, essential for batteries; magnesium, used to create alloys; gypsum, turned into drywall; as well as gold, platinum and other rare-earth elements that can be sold to manufacturers? Already, the El Paso plant participates in “mining” gypsum and hydrochloric acid for industrial customers.

Loya’s brine will be piped into an evaporation pond. Eventually, he’ll have to pay to landfill the dried-out solids, says Quantum Wei, founder and CEO of Harmony Desalting, which is building Loya’s plant. There are other expenses: drilling a well (Loya, fortuitously, already has one to serve the project); building the physical plant; and supplying the electricity to pump water up day after day. These are bitter financial pills for a farmer. “We’re not getting rich; by no means,” Loya says.

More cost comes from the desalination itself. The energy needed for reverse osmosis is a lot, and the saltier the water, the higher the need. Additionally, the membranes that catch salt are gossamer-thin, and all that pressure destroys them; they also get gunked up and need to be treated with chemicals.

Reverse osmosis presents another problem for farmers. It doesn’t just remove salt ions from water but the ions of beneficial minerals, too, such as calcium, magnesium and sulfate. According to Amrose, this means farmers have to add fertilizer or mix in pretreated water to replace essential ions that the process took out.

To circumvent such challenges, one NAWI-funded team is experimenting with ultra-high-pressure membranes, fashioned out of stiffer plastic, that can withstand a much harder push. The results so far look “quite encouraging,” Fiske says. Another is looking into a system in which a chemical solvent dropped into water isolates the salt without a membrane, like the polymer inside a diaper absorbs urine. The solvent, in this case the common food-processing compound dimethyl ether, would be used over and over to avoid potentially toxic waste. It has proved cheap enough to be considered for agricultural use.

Amrose is testing a system that uses electrodialysis instead of reverse osmosis. This sends a steady surge of voltage across water to pull salt ions through an alternating stack of positively charged and negatively charged membranes. Explains Amrose, “You get the negative ions going toward their respective electrode until they can’t pass through the membranes and get stuck,” and the same happens with the positive ions. The process gets much higher fresh water recovery in small systems than reverse osmosis, and is twice as energy efficient at lower salinities. The membranes last longer, too — 10 years versus three to five years, Amrose says — and can allow essential minerals to pass through.

Data-based design

At Loya’s farm, Wei paces the property on a sweltering summer morning with a local engineering company he’s tapped to design the brine storage pond. Loya is anxious that the pond be as small as possible to keep arable land in production; Wei is more concerned that it be big and deep enough. To factor this, he’ll look at average weather conditions since 1954 as well as worst-case data from the last 25 years pertaining to monthly evaporation and rainfall rates. He’ll also divide the space into two sections so one can be cleaned while the other is in use. Loya’s pond will likely be one-tenth of an acre, dug three to six feet deep.

From left, West Texas farmer Ralph Loya, Quantum Wei of Harmony Desalting and engineer Johanes Makahaube discuss where a desalination plant and brine pond might be placed on Loya’s farm.

CREDIT: PHOTO BY ADA COWAN

The desalination plant will pair reverse osmosis membranes with a “batch” process, pushing water through multiple times instead of once and gradually amping up the pressure. Regular reverse osmosis is energy-intensive because it constantly applies the highest pressures, Wei says, but Harmony’s process saves energy by using lower pressures to start with. A backwash between cycles prevents scaling by dissolving mineral crystals and washing them away. “You really get the benefit of the farmer not having to deal with dosing chemicals or replacing membranes,” Wei says. “Our goal is to make it as painless as possible.”

Another Harmony innovation concentrates leftover brine by running it through a nanofiltration membrane in their batch system; such membranes are usually used to pretreat water to cut back on scaling or to recover minerals, but Wei believes his system is the first to combine them with batch reverse osmosis. “That’s what’s really going to slash brine volumes,” he says. The whole system will be hooked up to solar panels, keeping Loya’s energy off-grid and essentially free. If all goes to plan, the system will be operational by early 2025 and produce seven gallons of fresh water a minute during the strongest sun of the day, with a goal of 90 to 95 percent fresh water recovery. Any water not immediately used for irrigation will be stored in a tank.

Spreading out the research

Ninety-eight miles north of Loya’s farm, along a dead flat and endlessly beige expanse of road that skirts the White Sands Missile Range, more desalination projects burble away at the Brackish Groundwater National Desalination Research Facility in Alamogordo, New Mexico. The facility, run by the Bureau of Reclamation, offers scientists a lab and four wells of differing salinities to fiddle with.

On some parched acreage at the foot of the Sacramento Mountains, a longstanding farming pilot project bakes in relentless sunlight. After some preemptive words about the three brine ponds on the property — “They have an interesting smell, in between zoo and ocean” — facility manager Malynda Cappelle drives a golf cart full of visitors past solar arrays and water tanks to a fenced-in parcel of dust and plants. Here, since 2019, a team from the University of North Texas, New Mexico State University and Colorado State University has tested sunflowers, fava beans and, currently, 16 plots of pinto beans. Some plots are bare dirt; others are topped with compost that boosts nutrients, keeps soil moist and provides a salt barrier. Some plots are drip-irrigated with brackish water straight from a well; some get a desalinated/brackish water mix.

A brine pond at the Brackish Groundwater National Desalination Research Facility in Alamogordo, New Mexico.

CREDIT: PHOTO BY ADA COWAN

Eyeballing the plots even from a distance, the plants in the freshest-water plots look large and healthy. But those with compost are almost as vigorous, even when irrigated with brackish water. This could have significant implications for cash-conscious farmers. “Maybe we do a lesser level of desalination, more blending, and this will reduce the cost,” says Cappelle.

Pei Xu, has been co-investigator on this project since its start. She’s also the progenitor of a NAWI-funded pilot at the El Paso desalination plant. Later in the day, in a high-ceilinged space next to the plant’s treatment room, she shows off its consequential bits. Like Amrose’s system, hers uses electrodialysis. In this instance, though, Xu is aiming to squeeze a bit of additional fresh — at least freshish — water from the plant’s leftover brine. With suitably low levels of salinity, the plant could pipe it to farmers through the county’s existing canal system, turning a waste product into a valuable resource.

Xu’s pinto bean and El Paso work, and Amrose’s in the Middle East, are all relevant to Harmony’s pilot and future projects. “Ideally we can improve desalination to the point where it’s an option which is seriously considered,” Wei says. “But more importantly, I think our role now and in the future is as water stewards — to work with each farm to understand their situation and then to recommend their best path forward … whether or not desalting is involved.”

Sixteen plots of pinto beans at the Brackish Groundwater National Desalination Research Facility are being irrigated with water of differing salinities, as part of an experiment.

CREDIT: PHOTO BY ADA COWAN

Indeed, as water scarcity becomes ever more acute, desalination advances will help agriculture only so much; even researchers who’ve devoted years to solving its challenges say it’s no panacea. “What we're trying to do is deliver as much water as cheaply as possible, but that doesn't really encourage smart water use,” says NAWI’s Fiske. “In some cases, it encourages even the reverse. Why are we growing alfalfa in the middle of the desert?”

Franklin, of the California policy institute, highlights another extreme: Twenty-one of the state’s groundwater basins are already critically depleted, some due to agricultural overdrafting. Pumping brackish aquifers for desalination could aggravate environmental risks.

There are an array of measures, say researchers, that farmers themselves must take in order to survive, with rainwater capture and the fixing of leaky infrastructure at the top of the list. “Desalination is not the best, only or first solution,” Wei says. But he believes that when used wisely in tandem with other smart partial fixes, it could prevent some of the worst water-related catastrophes for our food system.

10.1146/knowable-112124-3

Lela Nargi is a journalist covering food and agriculture systems, climate science and social justice issues. She is also a 2023-24 Nova Institute for Health media fellow. Find her at lelanargi.com.

PHYSICAL WORLD | VIEW ON WEBSITE

In Review

String theory is not dead

Out of the limelight, theoretical physicists seek the math that can explain the universe’s particles and forces

By Tom Siegfried    11.21.2024

Scientists seeking the secrets of the universe would like to make a model that shows how all of nature’s forces and particles fit together. It would be nice to do it with Legos. But perhaps a better bet would be connecting everything with strings.

Not literal strings, of course — but tiny loops or snippets of vibrating energy. And the “fit together” needs to be mathematical, not via properly shaped pieces of plastic. For decades now, many physicists have pursued the hope that equations involving an especially tiny “string” could provide the theory that solves nature’s ultimate subatomic mysteries.

String theory, as it’s called, has acquired a sort of fuzzy cultural acclaim, showing up in popular TV shows like The Big Bang Theory  and NCIS. Among physicists, reaction to the theory has been mixed. After several promising bursts of discovery in the 1980s and ’90s, strings fell somewhat out of favor for not delivering on their promises. Among those was providing the proper way to include gravity in the quantum theory of subatomic particles. Another was revealing the math that would show nature’s multiple fundamental forces to be just different offspring of one unified force. Still promises unkept.

Yet during the time since string theory’s retreat from the limelight, a considerable cadre of string devotees have labored to tie all the loose ends together. Success remains elusive, but real progress has been made. Questions plaguing physicists about not only the smallest bits of matter but also the properties of the entire universe may yet yield to string theorists’ efforts.

“Many of the unsolved problems in particle physics and cosmology are deeply intertwined,” write physicists Fernando Marchesano, Gary Shiu and Timo Weigand in the 2024 Annual Review of Nuclear and Particle Science. String theory may provide the path to solving those problems.

Reality’s equations

One major approach in this quest is figuring out whether string theory can explain what is known as the Standard Model of particle physics. Developed in the last part of the 20th century, the Standard Model provides a sort of roster listing all of nature’s basic particles. Some provide the building blocks of matter; others transmit forces between the matter particles, governing how they behave.

The Standard Model of particle physics describes nature’s known forces and subatomic particles. They include quarks, leptons and bosons. Protons and neutrons are composed of up and down quarks. Leptons include electrons and neutrinos. Photons transmit the electromagnetic force; gluons hold particles together in the atomic nucleus; and W and Z particles transmit the weak nuclear force, important for some forms of radioactivity. The Higgs boson is involved in conferring some particles with mass.

It’s pretty simple to draw a chart displaying those particles. You need 12 spots for matter particles — six quarks and six leptons. You need four spots for force particles (collectively known as bosons) plus a spot for the Higgs boson, a particle needed to explain why some particles have mass. But the mathematics underlying the chart is unfathomably complex, a combination of equations that make hieroglyphics seem self-explanatory.

Those equations work superbly for explaining the results of virtually all particle physics behavior. But the Standard Model cannot be the whole story of the universe. “Despite the incredible success of the Standard Model in describing the observed particle physics up to the currently accessible energy scales, there are compelling arguments for why it is incomplete,” Marchesano and collaborators write.

For one thing, its equations do not encompass gravity, which has no spot on the Standard Model chart. And Standard Model math leaves many questions unanswered, such as why some of the particles have the precise masses that they do. Standard Model math also does not include the mysterious dark matter that lurks within and between galaxies, nor does it explain why empty space is infused with a form of energy that causes the universe to expand at an accelerating rate.

Some physicists investigating these problems believe that string theory can help, since a string version of the Standard Model will contain additional math that could account for its shortcomings. In other words, if string theory is correct, the Standard Model would be just one segment of string theory’s full mathematical description of reality. The problem is that string theory describes many different versions of reality. That’s because the strings exist in a realm with multiple dimensions of space beyond the ordinary three. Kind of like the Twilight Zone on steroids.

String theorists concede that daily life proceeds just fine in a three-dimensional world. Therefore, the extra dimensions of the string world must be too small to notice: They have to shrink, or “compactify,” into submicroscopic size. It’s like the way an ant living on a vast sheet of paper would perceive a two-dimensional surface without ever realizing the paper had a third, very small dimension.

Not only must string theory’s extra dimensions shrink, but they also can shrink into innumerable different configurations, or geometries, of the vacuum of space. One of those possible geometries might be the right shape of the shrunk dimensions to explain the properties of the Standard Model.

“Standard Model … features, questions, and puzzles can be reformulated in terms of the geometry of extra dimensions,” Marchesano and collaborators write.

Because string theory math can be expressed in several different forms, theorists have to explore multiple possible avenues to find the most fruitful formulation. So far, string approaches have been found that describe many features of the Standard Model. But different compactification geometries of the vacuum are needed to explain each feature. The challenge, Marchesano and colleagues point out, is to find one geometry for the vacuum that combines all those features at once, while also incorporating features that describe the known universe.

A successful compactification of the extra dimensions, for instance, would produce a vacuum in space that contained the right amount of “dark energy,” the source of the universe’s accelerating expansion. And candidates for the cosmic dark matter should appear in the string math as well. In fact, a whole additional set of force and matter particles emerges from string equations involving a mathematical property called supersymmetry. “Almost all string theory models that resemble the Standard Model display supersymmetry at the compactification scale,” write Marchesano and his coauthors.

Versions of string theory containing supersymmetric particles go by the moniker “superstring theory.” Such “superparticles” have long been suspected of comprising the universe’s dark matter. But attempts to detect them in space or create them in particle accelerators have so far been unsuccessful.

As for gravity, particles conveying the gravitational force appear naturally in string theory math — one of the theory’s big attractions to begin with. But the fact that many formulations of string theory include gravity does not tell you which formulation provides the correct description of the real world.

Tests are possible

If string theory is correct, fundamental particles of nature would not be the zero-dimensional pointlike objects of standard theory. Instead, different particles would result from different modes of vibration of a one-dimensional string, either a loop or a snippet with ends attached to multidimensional spatial objects called branes. Such strings would roughly be smaller than an atom to the extent that an atom is smaller than the solar system. Very small, with no feasible way of detecting them directly. The amount of energy needed to probe scales so tiny is far beyond the reach of any practical technology.

But if string theory can account for the Standard Model, it would also contain other features of reality that would be accessible to experiments, such as types of particles not included on the Standard Model chart. “String constructions that realize the Standard Model always contain additional sectors … at an energy scale that could be tested in the near future,” Marchesano and colleagues write.

Ultimately, string theory remains a hopeful candidate for putting all the pieces of the cosmic puzzle together. If it works out, scientists could finally unravel the mysteries about how quantum physics’ relation to gravity, and the properties of nature’s particles and forces, are all deeply linked. “String theory,” write Marchesano and colleagues, “has all the ingredients to help us understand this profound connection.”

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Tom Siegfried is a science journalist in Avon, Ohio. His book The Number of the Heavens, about the history of the multiverse, was published in 2019 by Harvard University Press.

TECHNOLOGY | VIEW ON WEBSITE

Cracking the recipe for perfect plant-based eggs

Hint: It involves finding just the right proteins. With new ingredients and processes, the next generation of substitutes will be not just more egg-like, but potentially more nutritious.

By Bob Holmes    11.19.2024

An egg is an amazing thing, culinarily speaking: delicious, nutritious and versatile. Americans eat nearly 100 billion of them every year, almost 300 per person. But eggs, while greener than other animal food sources, have a bigger environmental footprint than almost any plant food — and industrial egg production raises significant animal welfare issues.

So food scientists, and a few companies, are trying hard to come up with ever-better plant-based egg substitutes. “We’re trying to reverse-engineer an egg,” says David Julian McClements, a food scientist at the University of Massachusetts Amherst.

That’s not easy, because real eggs play so many roles in the kitchen. You can use beaten eggs to bind breadcrumbs in a coating, or to hold together meatballs; you can use them to emulsify oil and water into mayonnaise, scramble them into an omelet or whip them to loft a meringue or angel food cake. An all-purpose egg substitute must do all those things acceptably well, while also yielding the familiar texture and — perhaps — flavor of real eggs.

Today’s plant-based eggs still fall short of that one-size-fits-all goal, but researchers in industry and academia are trying to improve them. New ingredients and processes are leading toward egg substitutes that are not just more egg-like, but potentially more nutritious and better tasting than the original.

In practice, making a convincing plant-based egg is largely a matter of mimicking the way the ovalbumin and other proteins in real eggs behave during cooking. When egg proteins are heated beyond a critical point, they unfold and grab onto one another, forming what food scientists call a gel. That causes the white and then the yolk to set up when cooked.

Eggs aren’t just for frying or scrambling. Cooks use them to bind other ingredients together and to emulsify oil and water to make mayonnaise. The proteins in egg whites can also be whipped into a foam that’s essential in meringues and angel food cake. Finding a plant-based egg substitute that does all of these things has proven challenging.

CREDIT: NEW AFRICA / SHUTTERSTOCK

That’s not easy to replicate with some plant proteins, which tend to have more sulfur-containing amino acids than egg proteins do. These sulfur groups bind to each other, so the proteins unfold at higher temperatures. As a result, they must usually be cooked longer and hotter than ones in real eggs.

To make a plant-based egg, food scientists typically start by extracting a mix of proteins from a plant source such as soybean, mung bean or other crops. “You want to start with what is a sustainable, affordable and consistent source of plant proteins,” says McClements, who wrote about the design of plant-based foods in the 2024 Annual Review of Food Science and Technology. “So you’re going to narrow your search to that group of proteins that are economically feasible to use.”

Fortunately, some extracts are dominated by one or a few proteins that set at low-enough temperatures to behave pretty much like real egg proteins. Current plant-based eggs rely on these proteins: Just Egg uses the plant albumins and globulin found in mung bean extract, Simply Eggless uses proteins from lupin beans, and McClements and others are experimenting with the photosynthetic enzyme rubisco that is abundant in duckweed and other leafy tissues.

One reason that plant-based eggs don’t behave like real ones when cooked is that most plant proteins set, or denature, at higher temperatures. Choosing plant proteins that set at lower temperatures is an important first step in making a convincing egg substitute.

These days, food technologists can produce a wide range of proteins in large quantities by inserting the gene for a selected protein into hosts like bacteria or yeast, then growing the hosts in a tank, a process called precision fermentation. That opens a huge new window for exploration of other plant-based protein sources that may more precisely match the properties of actual eggs.

A few companies are already searching. Shiru, a California-based biotech company, for example, uses a sophisticated artificial intelligence platform to identify proteins with specific properties from its database of more than 450 million natural protein sequences. To find a more egglike plant protein, the company first picked the criteria it needed to match. “For eggs, that is the thermal gel onset — that is, when it goes from liquid to solid when you heat it,” says Jasmin Hume, a protein engineer who is the company’s founder and CEO. “And it must result in the right texture — not too hard, not too gummy, not too soft.” Those properties depend on details such as which amino acids a protein contains, in what order, and precisely how it folds into a 3D structure — a hugely complex process that was the subject of the 2024 Nobel Prize in chemistry.

The company then scoured its database, winnowing it down to a short list that it predicted would fit the bill. Technicians produced those proteins and tested their properties, pinpointing a handful of potential egglike proteins. A few were good enough to start the company working to commercialize their production, though Hume declined to provide further details.

Cracking the flavor code

With the main protein in hand, the next step for food technologists is to add other molecules that help make the product more egglike. Adding vegetable oils, for example, can change the texture. “If I don’t put any oil in the product, it’s going to scramble more like an egg white,” says Chris Jones, a chef who is vice president of product development at Eat Just, which produces the egg substitute Just Egg. “If I put 8 to 15 percent, it’s going to scramble like a whole egg. If I add more, it’s going to behave like a batter.”

Developers can also add gums to prevent the protein in the mixture from settling during storage, or add molecules that are translucent at room temperature but turn opaque when cooked, providing the same visual cue to doneness that real eggs provide.

And then there’s the taste: Current plant-based eggs often suffer from off flavors. “Our first version tasted like what you imagine the bottom of a lawn mower deck would taste like — really grassy,” says Jones. The company’s current product, version 5, still has some beany notes, he says.

These plant-based eggs scramble almost like the real thing. Once food scientists get the texture right, they can begin to refine the flavor and nutritional content of the product.

CREDIT: EAT JUST, INC.

Those beany flavors aren’t caused by a single molecule, says Devin Peterson, a flavor chemist at Ohio State University: “It’s a combination that creates beany.” Protein extracts from legumes contain enzymes that create some of these off-flavor volatile molecules — and it’s a painstaking process to single out the offending volatiles and avoid or remove them, he says. (Presumably, cooking up single proteins in a vat could reduce this problem.) Many plant proteins also have molecules called polyphenols bound to their surfaces that contribute to beany flavors. “It’s very challenging to remove these polyphenols, because they’re tightly stuck,” says McClements.

Experts agree that eliminating beany and other off flavors is a good thing. But there’s less agreement on whether developers need to actively make a plant-based egg taste more like a real egg. “That’s actually a polarizing question,” says Jones.

Much of an egg’s flavor comes from sulfur compounds that aren’t necessarily pleasing to consumers. “An egg tastes a certain way because it’s releasing sulfur as it decays,” says Jones. When tasters were asked to compare Eat Just’s egg-free mayonnaise against the traditional, real-egg version, he notes, “at least 50 percent didn’t like the sulfur flavor of a true-egg mayo.”

That poses a quandary for developers. “Should it have a sulfur flavor, or should it have its own point of view, a flavor that our chefs develop? We don’t have an answer yet,” Jones says. Even for something like an omelet, he says, developers could aim for “a neutral spot where whatever seasoning you add is what you’re going to taste.”

As food technologists work to overcome these challenges, plant-based eggs are likely to get better and better. But the ultimate goal might be to surpass, not merely match, the performance of real eggs. Already, McClements and his colleagues have experimented with adding lutein, a nutrient important for eye health, to oil droplets in plant-based egg yolks.

In the future, scientists could adjust the amino acid composition of proteins or boost the calcium or iron content in plant-based eggs to match nutritional needs. “We ultimately could engineer something that’s way healthier than what’s available now,” says Bianca Datta, a food scientist at the Good Food Institute, an international nonprofit focused on advancing alternative proteins. “We’re just at the beginning of seeing what’s possible.”

Editor’s note: This article was updated November 20, 2024, to clarify the scope of activities supported by the Good Food Institute. Rather than solely promoting plant-based foods, as the article initially implied, it is more broadly interested in facilitating the development of alternative protein sources.

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Bob Holmes is a science writer based in Edmonton, Canada. He’s still underwhelmed by plant-based eggs but is willing to be convinced.

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The secrets of butterfly migration, written in pollen

Trillions of insects move around the globe each year. Scientists are working on new ways to map those long-distance journeys.

By Saugat Bolakhe    11.18.2024

On a warm summer morning in Ieper, Belgium, 66-year-old Sylvain Cuvelier steps into his blooming garden with his 14-year-old granddaughter, hoping to identify and count all the fluttering butterflies. Other days, he helps scientists by netting butterfly samples. Then he records each sighting’s location using GPS, logs them in his Excel database, and sometimes sends the samples to his academic colleagues, who will analyze pollen grains clinging to the insects’ bodies.

Those tiny pollen grains, gathered by citizen scientists like Cuvelier, are helping researchers study a process that until now has been largely inscrutable: the migratory patterns of insects as they move around the globe over the course of multiple generations.

Using pollen, scientists have been able to identify where individual butterflies began their journeys, and even infer the events that likely triggered their migration. The knowledge may help conservationists better understand some of the effects of climate change — not only on the insects themselves, but on their migrations and the ecosystems they inhabit.

Unusual rainfall in 2019 spurred vegetation growth, creating ideal breeding conditions for the painted lady butterfly, shown feeding here, and fueling a massive population surge across the Middle East, Europe and Africa. The phenomenon was so remarkable that the year became known as The Painted Lady Year.

CREDIT: REBECCA COLE / ALAMY STOCK PHOTO

A lot of insects spend their whole lives in one place. Many others migrate, like many birds do, to avoid harsh weather, to find food or to breed. Some estimates suggest that trillions of insects migrate across the globe each year, yet scientists know little about where they go or how they get there.

Tracking insect migration is not as straightforward as tracking birds or mammals. With birds, “you can attach a ring to the leg or use radio tracking, and it’s easy to prove that they move from point A to B,” says Tomasz Suchan, a molecular ecologist at the Polish Academy of Sciences in Krakow. But most insects are too small for these techniques to be successful.

In North America, researchers have had some success tracking monarch butterflies, known for their remarkable migration from southern Canada and the northern United States to central Mexico. In the early 1990s, the Monarch Watch citizen science initiative began tagging butterflies around the Rocky Mountains. Over 2 million monarchs have been tagged, with more than 19,000 recoveries reported in Mexico where monarchs congregate to roost for the winter. This has helped biologists to track their migration routes.

Butterflies without such well-defined aggregations are more difficult to track, however. For example, painted lady butterflies often appear in Europe in the fall, sometimes in great abundance. “Then they disappear, and we don’t really know where they go,” says Gerard Talavera, an entomologist at the Institut Botànic de Barcelona.

Some years back, Talavera and his team realized they might be able to track the butterflies indirectly, by studying the pollen that accumulates on their bodies. Every time a butterfly visits a flower for a sip of nectar, it also picks up grains of pollen. If the researchers could identify plants from their pollen, confirm where and when the plants were blooming, and keep tracing them as the butterflies reached different geographic regions, perhaps they could trace the butterflies’ overall journey. “The method is like we put a GPS on them,” Talavera says. “Because we cannot do that, this is the closest we can go.”

This monarch butterfly has many small, white pollen grains clinging to its body from earlier visits to flowers. Scientists study such pollen grains to identify the plant species they came from and where butterflies likely acquired them.

CREDIT: ROBERT / STOCK.ADOBE.COM

Pollen migratory maps

The scientists were able to test the idea in 2019, when painted ladies experienced one of their sporadic population booms. In March of that year, as swarms of the butterflies appeared in the Middle East and the Mediterranean, the citizen scientists netted butterfly samples, then preserved them in an alcohol mixture and shipped them to Talavera’s lab.

There, researchers isolated the pollen grains attached to the butterflies’ bodies and sequenced a particular stretch of the pollen DNA that offers a unique signature for each plant species, a process known as metabarcoding. All the while, citizen scientists kept netting butterfly samples as the population surge gradually spread through eastern, northern and western Europe over the following months, reaching southern Morocco in early November.

Analyzing pollen collected from 264 butterflies from 10 different countries in seven months, the researchers identified 398 different plants they could use to track the butterflies’ movements backward through the year. From this, they found that swarms of butterflies observed in Russia, Scandinavia and the Baltic countries were likely the offspring of butterflies originating from the surge in Arabia and the Middle East. This appears to have spread to eastern Europe, then Scandinavia and then to western Europe, resulting in a noticeable population boom in the United Kingdom, France and Spain. From there, the butterflies may have migrated to southern Morocco, likely continuing on to tropical Africa to complete their annual cycle.

The 2019 population surge of painted lady butterflies began in the Middle East. That triggered a massive, multigenerational migration that spread across Europe and Africa in the following months. Solid arrows represent migratory movements confirmed by pollen grains; dashed arrows represent movements inferred by observations of butterflies but not confirmed by pollen. The different colors on the map represent different generations of butterflies.

The pollen record even suggested a reason why painted ladies suddenly became so abundant in 2019. Butterflies collected from the eastern Mediterranean, right in the beginning of the population spike, were carrying pollen from plant species found primarily in semi-arid shrublands, grasslands and salt marshes of northern Arabia and the Middle East. Examining satellite images, the researchers noticed that from December 2018 to April 2019, those plants experienced big boosts in growth following a period of unusually heavy rainfall. That burst of growth, the researchers speculate, may have provided ideal conditions for the butterflies to feed and breed, kicking off the population explosion and leaving a ripple effect that affected many generations.

Talavera and his team have used pollen signatures to track other butterfly movements as well. In 2013, for example, painted lady butterflies had been found resting on the coast of South America, in French Guiana. Painted ladies don’t normally live in South America, and it was a mystery where they had come from. A decade later, Talavera’s team sampled pollen from the still-preserved butterfly bodies and found that Guiera senegalensis, a common plant found only in sub-Saharan Africa, was by far the most common type of pollen attached to these butterflies.

By analyzing coastal surveys, wind patterns, pollen and environmental conditions, they confirmed that the butterflies probably crossed the Atlantic in up to eight days’ worth of continuous flight from Africa. This finding marked the first verified instance of an insect crossing the Atlantic.

“The use of pollen metabarcoding to track where each generation of butterflies comes from and how they progress through the cycle is super novel,” says Christine Merlin, a biologist at Texas A&M University and coauthor of an article on the neurobiology of butterfly migration in the Annual Review of Entomology. Because it identifies individual plant species, she notes, this method promises greater precision than the standard method, isotope signature analysis, which tracks regional variations in the insects’ chemical makeup.

While painted ladies serve as a model system for understanding insect migration, researchers say they are confident that this method could be suited for tracking other migrating pollinators that actively visit flowers to collect nectar, including other butterflies, syrphid flies, wasps, beetles and moths.

Tracking migration routes of insects could be of growing importance in the face of changing climate, because such insects can carry fungal diseases in addition to pollen. In fact, Suchan detected many species of fungi in some butterflies. Approximately 1,000 fungi are known to affect insects and over 19,000 can affect crops. Thus, migrating insects could potentially spread these fungal diseases across continents, posing risks to ecosystems and economies. Talavera, Suchan and colleagues hope that using pollen signatures to map changing migration patterns could help to predict where fungal disease outbreaks might occur.

Cuvelier, meanwhile, hopes to continue counting butterflies with his granddaughter. Ecologists will increasingly need more “big data” to understand large-scale phenomena, he says. Without citizen scientists, he says, “it is impossible for researchers to gather such databases.”

Besides, he adds, young people have more to learn from citizen science than just how to catch a butterfly. “They learn about nature,” he says, “and this fosters curiosity in the world.”

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Saugat Bolakhe is a freelance science journalist. He studied zoology as an undergraduate in Nepal and received a master’s degree from the Craig Newmark Graduate School of Journalism at the City University of New York. His work has appeared in Scientific American, Nature, New Scientist, Quanta, Eos, Discover, Knowable Magazine and other publications.

LIVING WORLD | VIEW ON WEBSITE

She ain’t scary, she’s my mother

Elaborate courtship, devoted parenthood, gregarious nature (and occasional cannibalism) — earwigs have a lot going for them

By Tim Vernimmen    11.13.2024

Few people are fond of earwigs, with their menacing abdominal pincers — whether they’re skittering across your floor, getting comfy in the folds of your camping tent or minding their own business.

Scientists, too, have given them short shrift, compared with the seemingly endless attention they have lavished on social insects like ants and bees.

Yet there are a handful of exceptions. Some researchers have made conscious career decisions to dig into the hidden, underground world where earwigs reside, and have found the creatures to be surprisingly interesting and social, if still not exactly endearing.

Work in the 1990s and early 2000s focused on earwig courtship. These often-intricate performances of attraction and repulsion — in which pincers and antennae play prominent roles — can last hours, and the mating itself as long as 20 hours, at least in one Papua New Guinea species, Tagalina papua. The females usually decide when they’ve had enough, though males of some species use their pincers to restrain the object of their desire.

InTagalina papua, an earwig species from Papua New Guinea, mating can last up to 20 hours. That is the longest documented in any earwig species, but few have been studied in detail.

CREDIT: PHILIPP HOENLE / iNATURALIST

Males of the bone-house earwig Marava arachidis (often found in bone meal plants and slaughterhouses) are particularly coercive, says entomologist Yoshitaka Kamimura of Keio University in Japan, who has studied earwig mating for 25 years. “They bite the female’s antennae and use a little hook on their genitalia to lock them inside her reproductive tract.”

Size matters

Female earwigs collect sperm in one or more internal pouches and can use it to fertilize multiple broods, so they don’t need to mate again. The only thing most males can do is add their own sperm, but Kamimura has seen males of the pale-legged earwig Euborellia pallipes remove the sperm of other males using an elongated part of their peculiar penis.

It’s better if females can prevent this from happening, because they can be particular about the males they mate with. This may explain why, in some species, male and  female genitalia have increased in size as part of a kind of evolutionary arms race in which males benefit from access to the pouch and females benefit from keeping them out. In the bristly earwig Echinosoma horridum, the male’s genitalia are nearly as long as the rest of his body, and the female’s genitalia almost four times as long as the rest of hers.

Fascinating though they are, the amorous adventures of earwigs weren’t what first caught Kamimura’s attention. Rather, he was intrigued by the female’s dedication to her offspring. “When I was a student, I accidentally disturbed an earwig caring for her eggs in our backyard,” he recalls. “She ran away but returned the next day. I was very interested, and I started to rear them.”

Two European earwigs. When, after lengthy courtship, a female is persuaded to mate, she will lift and twist the tip of her abdomen to allow the male to insert his sperm.

CREDIT: JAN VAN DUINEN / NATURE IN STOCK

Grow your own earwigs

The care that female earwigs provide to their eggs has also become the focus of study in Europe, where a surge of lab research on European earwigs — Forficula auricularia — was kick-started almost 20 years ago by entomologist Mathias Kölliker at the University of Basel, Switzerland. “Getting them to breed continuously over multiple generations was a big challenge,” he recalls. “The females did lay eggs, but they didn’t develop, and never hatched.”

It turned out that the eggs, which are laid in late fall and hatch in January, need the winter cold to start their development. So the scientists figured out a lab regimen that would chill but not kill the eggs. “That took us about two years,” says Kölliker.

In 2009, Kölliker hired entomologist Joël Meunier, who continues to study earwigs at the University of Tours in France and wrote an overview of the biology and social life of earwigs for the Annual Review of Entomology. Earwigs are high maintenance, he says. “If you work with fruit flies, you can breed 10 generations in a few months, but earwigs take much longer.… And they’re all kept in separate petri dishes — thousands of them — that we have to open twice a week to replace the food.

“I think this is one of the reasons few people work on them. But they’re very fascinating.”

In the lab, earwigs are kept in thousands of petri dishes that have to be opened twice a week to replace the food. The complicated lab care may be one reason few scientists work with them.

CREDIT: COURTESY OF JOËL MEUNIER

Fending off males

The female’s careful egg-grooming has at least two important functions. First, she uses a small brush on her mouthparts to remove the spores of fungi that can kill the eggs. Secondly, as Kölliker, Meunier and colleagues found, she applies water-repellent hydrocarbons to keep them from drying out.

Males that attempt to approach the nest are aggressively chased away, and with good reason, says Meunier. “Once, when we were in the field in Italy to collect earwigs, we found a male and a female together with a clutch of eggs. We were quite excited: Wow, biparental care, cool! So we brought them to the lab. But what we actually observed was that the female was very stressed out, showing a lot of aggression towards the male, while the clutch size was continuously decreasing.”

Males, it turns out, love to snack on eggs, even ones that they fathered. To chase them off, females raise their abdomens to show off their pincers. If that’s not enough, they can use the pincers to hurt the male — even to cut him in half. (Scary as they look, the pincers can’t harm people at all, Meunier says.)

Earwigs can also spray each other with defensive secretions that may have antimicrobial properties too. “They often use those secretions when meeting others,” says Meunier. “Maybe it also prevents the spread of disease.”

As far as scientists know, these secretions are harmless to humans. But because they contain quinone derivatives, which are also found in substances like henna, they have some quirky side effects. “When you get a lot of it on your hands,” Meunier says, “they’ll turn blue, like a bruise, and these marks can last all week.”

The secretions smell quite pleasant, says Kölliker. “When I had a visitor in the lab, I would sometimes pick up an earwig and hold it under their nose. It’s a very nice odor, actually, kind of an earthy smell.” Kölliker’s cat was less appreciative when he tried it on her: “She immediately backed off,” he says.

Overbearing moms

Surprisingly, Meunier’s recent work suggests that earwig offspring may pay a price for their mom’s protectiveness. In European earwigs and several other species, although the nymphs that emerge from eggs can feed on their own after a couple of days, mothers usually stay with them for a few weeks after they hatch. Yet, at least in the lab, that does not seem to enhance the nymphs’ chances of survival.

“In the best case, the mother’s presence doesn’t change a thing,” says Meunier. “At worst, nymphs that grow up with their mother are less likely to reach adulthood and will become smaller adults.” It’s unclear why. But things may be different in the wild, where male earwigs or predators like spiders pose threats, making it safer to stay with mom.

The nymphs that emerge from earwig eggs can feed on their own after a couple of days, but their mother will often stay with them for longer.

CREDIT: JAN VAN DUINEN / NATURE IN STOCK

The mother herself seems to benefit. Meunier has observed that as soon as the nymphs emerge, they eat the parasitic mites that often bother breeding females. And once they start foraging on their own, the feces they leave all over the nest may be food for their mother and help her to produce a second brood. The nymphs also feast on each other’s feces, sometimes straight from the source.

The voracious nymphs don’t stop there: They regularly eat each other, and nymphs of the hump earwig Anechura harmandi will almost always eat their mother. “It occurs in every family,” Meunier says, “and it helps the nymphs grow.”

Let’s get together

With all this aggression and cannibalism, you’d expect adult earwigs not actively seeking mates to avoid each other, and in many species, they do. Yet European earwigs regularly group together by the hundreds, sometimes mixing things up with other earwig species.

Recent work from Meunier’s lab showed that European earwigs that grew up in groups are more likely to look for company as adults than those reared in isolation, and females removed from these groups can get so stressed they are more likely to succumb to fungal infections.

“We have no idea why,” says Meunier. “Maybe it’s healthier to live together. Or maybe, they just like company.”

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Tim Vernimmen is a freelance science journalist based near Antwerp, Belgium. He can’t seem to recall seeing any earwigs since summer camp. Perhaps they’re avoiding him.

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Frogs kick back against lethal fungus

Scientists are seeing signs of resistance to the infections that have been wiping out the world’s amphibian populations — and developing strategies to aid in the fight Down Under

By Martin J. Kernan    11.06.2024

Lea en español

More than three decades ago, amphibian researchers from around the globe converged on Canterbury, England, for the first World Congress of Herpetology — and, over drinks, shared the same frightening tale.

Frogs were disappearing in the wild, and no one could explain why.

It was “a scary time,” recalls Australian veterinary scientist Lee Berger, who in the 1990s was one of the first to identify the culprit: a water-borne chytrid fungus known as Batrachochytrium dendrobatidis, or Bd.

Scientists know now that the stealthy menace originated in east Asia and was probably spread inadvertently by people to every continent except Antarctica.

The parasitic fungus can be as transmissible as it is lethal, wiping out entire populations of some frogs in a matter of weeks. And until recently it has proved largely unstoppable. Despite more than 25 years of intense study, conservationists haven’t devised a panacea that can prevent Bd infections or save populations of frogs after they contract the Bd-caused skin disease chytridiomycosis.

Bd has been implicated in the decline and possible extinction of around 200 frog species.

Yet today, Berger and other researchers see grounds for optimism. There’s evidence that some frogs are naturally evolving resistance. Scientists are also trying to exploit the fungus’s sensitivity to temperature by building Bd-free habitats or moving frogs to locales where the fungus can’t survive. Still others are investigating viruses that attack Bd and eventually might be used to reduce its virulence. These innovative strategies are emerging like slimy glimmers of hope on an otherwise gloomy landscape.

Chytridiomycosis kills because skin is an integral part of a frog’s cardiovascular system. When chytrid fungus colonizes the skin, electrolytes can’t get absorbed. This disrupts the heart’s electrical rhythms, and the animals die of heart failure.

But though ruthlessly efficient at killing off some frog species, the fungus is highly vulnerable to heat: Temperatures above 30 degrees Celsius (about 85 degrees Fahrenheit) slow disease progression.

The armoured mist frog in the Wet Tropics of Queensland, Australia, appears to have shifted habitats, allowing it to take advantage of this fungal Achilles’ heel. The frog — thought extinct for almost 20 years — no longer dwells in shaded areas near the forest’s mountain waterfalls. But a population persists in warmer, sun-drenched areas. Perhaps that’s because the frogs can rest on sunbaked rocks through the night, which elevates their body temperatures enough to stave off Bd, says biologist Conrad Hoskin of James Cook University in Queensland.

An armoured mist frog warms itself on a wet rock. Once thought extinct, this species was rediscovered in locales where it has access to the Sun’s warmth, which can help frogs fight the often-deadly fungal infections.

CREDIT: CONRAD HOSKIN

Since 2013, Hoskin has been transplanting armoured mist frogs from the surviving population into new, similarly sunny habitats and closely monitoring the health of these new colonies.

In a larger effort, Hoskin and colleagues recently assessed the habitat ranges of 55 eastern Australian frog species, including 25 affected by Bd. They found that even though the fungus has curtailed the ranges of afflicted species, they are persisting in warmer lower elevations with more rain.

Other researchers have also tried moving groups of Bd-infected frogs, either to salvage dying populations or to spread recovering ones. Of 15 relocations attempted in Australia over the last 20-odd years, seven populations are holding on and three are thriving.

Providing frogs with amenities has also helped. Conservation biologist Anthony Waddle of Macquarie University in Sydney built heat shelters from large bricks prefabricated with holes that just happen to be the perfect size for green and golden bell frogs. Sick frogs that hung out in these “frog saunas” had lower infection loads than those that convalesced in the shade, Waddle and colleagues reported in 2024 in Nature.

Green and golden bell frogs take refuge in the warm confines of sun-soaked bricks. The higher temperatures help the frogs fight chytrid infections, and “frogs really like hanging out in little holes,” says University of Arkansas biologist Erin Sauer, a coauthor of the study on these frog saunas.

CREDIT: ANTHONY WADDLE

As this incremental progress continues, scientists are racing to figure out why some frog species are more susceptible to Bd than others. Conservation biologist Tiffany Kosch, who works with Berger at the One Health Research Group at the University of Melbourne veterinary school, is taking a genetic approach. Kosch recently sequenced the genome of the southern corroboree — a black and brilliantly yellow frog of which 50 or fewer survive in the wild. If the scientists can learn which particular versions of genes are associated with Bd resistance, they could breed and release resistant frogs, or even engineer Bd resistance into the southern corroborees.

Researchers also have discovered a virus of fungi that appears to infect weaker strains of Bd — pathogens for the pathogen, in other words. While harnessing such viruses to help fight Bd is a long way off, it might one day be another weapon. “In the science fiction version, you spray the virus in the field and the frogs all survive — that’s the hope,” says University of California, Riverside, mycologist Jason Stajich, coauthor of a recent report on the virus in Current Biology.

Berger, who coauthored an update on Australian frogs and Bd in the 2024 Annual Review of Animal Biosciences, says that that despite the losses, optimism is key to working in conservation. “You have to make a choice to focus on the positives.”

Indeed, there’s a lot more work to be done to avoid further declines and extinctions, says ecologist Andrea Adams of the University of California, Santa Barbara. “We can’t afford to take a hands-off approach.”

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Martin J. Kernan is a science writer from central New York who attributes his interest in slimy critters to spending many unsupervised hours as a kid elbow-deep in pond muck.

PHYSICAL WORLD | VIEW ON WEBSITE

Comic

Bustling through the physics of crowds

COMIC: Using tools from fields like fluid dynamics to better understand how groups of people move around can improve flow and make large gatherings safer

By Matthew R. Francis   Illustrated by Maki Naro    11.05.2024

10.1146/knowable-110424-1

Matthew R. Francis is a science journalist, physicist and wearer of jaunty hats. In today’s chaotic social media landscape, he is most reliably tracked using his website.

Maki Naro is a feral cartoonist and science communicator. You can find his work at makinaro.com.

HEALTH & DISEASE | VIEW ON WEBSITE

Severe irritability in children and teens: A new understanding

Kids with disruptive mood dysregulation disorder have explosive outbursts well past toddler age. Scientists are trying to work out the causes and what treatments help.

By Katarina Zimmer    10.30.2024

It wasn’t until her daughter entered preschool that Holly Provan, a nurse in Los Angeles, began to worry. Compared to other kids, including her younger sister, Anna had a harder time coping when something wasn’t going her way. When told to stop coloring or to leave the playground, she’d respond with explosive tantrums.

Between ages 5 and 9, Anna (her name has been changed) would have meltdowns several times a week, screaming, raging and crying for an hour at a time. A few times in elementary school, she ended up hitting other kids. The outbursts weren’t premeditated; Anna just couldn’t control her temper. “Seeing how bad your kid feels after they’ve come back to themselves — it’s heartbreaking,” Provan says.

At age 7, after several doctors’ visits, Anna was diagnosed with disruptive mood dysregulation disorder (DMDD), a condition in children and adolescents, typically diagnosed between ages 6 and 10, that is characterized by chronic irritability and temper outbursts. But Provan couldn’t find much information on how to help Anna. “My husband and I at the time were just like, ‘I don’t know if she’ll ever be able to live away from home or to function normally,’” Provan recalls.

Irritability — a proneness to frustration or anger — is familiar to many of us. But in children with severe irritability, a hair-trigger temper can get in the way of making friends, getting along with siblings and doing well at school. Parents often express the feeling of walking on eggshells and often refrain from asking their children to do things they don’t like in order to avoid an outburst. In the 11,000-strong Facebook support group for parents of DMDD kids that Provan helps to administrate, some parents are physically afraid of their kids.

There are few specific treatments, says clinical psychologist Melissa Brotman of the National Institute of Mental Health, who coauthored a review on the topic in the Annual Review of Clinical Psychology. But now, after years of severe irritability in children being mistaken for other mental health conditions, scientists are studying it as a condition in its own right. “We’re starting to try and understand the problem from a brain-based mechanistic perspective,” Brotman says.

Inside the irritable mind

Starting in the 1990s, many experts saw severe irritability in children — often accompanied by energetic behavior and an inability to focus — as an early manifestation of the mania experienced by adults with bipolar disorder. Bipolar diagnoses, as well as prescriptions for mood-stabilizing and antipsychotic medications, skyrocketed among adolescents and children.

But by tracking children with severe irritability over many years, Brotman found that they didn’t transition to bipolar disorder as adults; instead, they tended to develop depression and anxiety. Perhaps, then, Brotman hypothesizes, severe childhood irritability is an early manifestation of depression and anxiety-like disorders in adulthood.

Antipsychotic prescriptions among youth in the United States rose steeply in the late 1990s/early 2000s, as shown here in an analysis of prescriptions made during medical office visits by children and adolescents up to 20 years of age. This trend might reflect what some experts suspect was a common overdiagnosis of bipolar disorder, possibly driven by a widespread, now-outdated belief that irritability in children was an early sign of that condition, which in adults is often treated with antipsychotics. Many experts have expressed concern about the increase in these medications due to their risk of side effects, especially in children.

As scientists furthered their understanding of irritability in children, the Diagnostic and Statistical Manual (DSM) for Mental Health Disorders created a new diagnostic category, DMDD, in its fifth iteration, in 2013. Children with DMDD often also have other conditions like attention-deficit hyperactivity disorder (ADHD) or anxiety, or have experienced bouts of depression. Severely irritable children may have more difficulty than usual coping with negative emotions like frustration, or managing when things don’t go as they expect. They may have a harder time dealing with uncertainty and changes to their routines, says clinical child psychologist Spencer Evans, who directs the University of Miami’s Child Affect and Behavior Lab.

Functional magnetic resonance imaging (fMRI) studies, which use scans to observe brain activity, have affirmed the notion that children with severe irritability respond differently to frustration. One 2019 study compared 134 children between 8 and 18 who had irritability and a diagnosis of DMDD, anxiety disorder or ADHD, with 61 non-irritable volunteers. As they lay in the MRI scanner, the children played a game, earning up to 50 cents for every target they hit — until the researchers intentionally frustrated them by deducting winnings, explains coauthor Wan-Ling Tseng, a developmental neuroscientist at Yale School of Medicine.

Though irritable and non-irritable kids reported similar levels of frustration, the brains of irritable children responded differently: They showed heightened activity in the striatum, a brain region important for processing rewards, as well as in the prefrontal cortex, key to regulating emotions and executing tasks. Some other studies have also hinted at unusual activity in the emotion-processing amygdala in frustrated kids, though Tseng’s study didn’t observe this.

Functional magnetic resonance imaging (fMRI) studies, which monitor brain activity while people undergo certain tasks, have found that the brains of irritable kids have an unusual response to frustration. In one study, the brains of irritable kids (compared with non-irritable kids) showed heightened activity in the striatum (right), which is key to processing reward, as well as the prefrontal cortex (left), which is important for executing tasks. The latter suggests that irritable kids need to exert more effort in order to concentrate.

CREDIT: WAN-LING TSENG

To Tseng, the prefrontal cortex findings suggest that in irritable kids, prefrontal cortices need to work harder to focus. “It’s more effortful for them,” she says. (After the game, the children were given $25 to take home, in addition to their compensation for participating, so that they left with a positive experience.)

It’s unclear how children’s brains end up this way. Research suggests that many kids are genetically predisposed to developing severe irritability, says neuroscientist and child and adolescent psychiatrist Argyris Stringaris of University College London. Adverse environments that involve family conflict or violence are associated with irritability, as are patterns of acquiescence by parents when their child has tantrums, which might reinforce the behaviors. But “we don’t know whether the cause is the parent, the child that elicits the parental response, or both, or some genetic component,” Stringaris says.

New clues for therapies and treatments

DMDD diagnoses are rising, but there’s little concrete treatment guidance. A 2022 analysis of health records found that in the United States, DMDD patients between 10 and 18 were prescribed antipsychotics more often than people with bipolar disorder, and were more likely to get multiple medications. “These drugs have not been FDA-approved specifically for treating irritability or aggression among children in general,” Evans says. Antipsychotics in particular should be used cautiously in children due to their side effects (though there are two antipsychotics approved for irritability in autistic children.)

“We’re starting to try and understand the problem from a brain-based mechanistic perspective.”

— MELISSA BROTMAN

Yet the increasingly evident links between irritability, depressive episodes, anxiety and ADHD point to different kinds of medications. Stimulants like methylphenidate (Ritalin) can help to reduce irritability and anger in youth with ADHD, while the anxiety and depression medication citalopram (Celexa) in combination with Ritalin can reduce irritability in youth where stimulants alone aren’t effective.

For Anna, Ritalin had little effect, and an antidepressant caused her to hallucinate. A popular yet untested DMDD treatment protocol includes anticonvulsants, and one variety, the mood stabilizer divalproex sodium, seemed to give Anna an extra split second to think through the possible consequences before exploding into a tantrum, her mother says.

As researchers learn more about the underlying brain processes, they hope to develop better and more effective treatments. Some, meanwhile, are looking into non-pharmaceutical therapies.

Recently, Brotman adapted an established treatment for anxiety disorders that progressively exposes patients to things they fear, within the safety of a therapist’s office. Adjusting the therapy for kids with DMDD, clinicians identified the triggers of 40 children ages 8 to 17 with DMDD-type symptoms. Then they simulated anger-provoking situations — such as asking the kids to stop a video game or to do their homework, and talked the children through how to constructively cope with their frustrations.

“I was very tentative at first, because it had never been done before, and we didn’t know if it would make them more angry,” Brotman says.

The clinicians also trained parents to ignore tantrums at home and reward constructive coping behaviors — an approach called “parent management training” that tackles reinforcing cycles within families. Remarkably, irritability symptoms decreased significantly in 65 percent of the children over the 12 weeks of the study.

Most parents, including Provan, eventually settle on a combination of talk therapy and medications. While no parent wants to drug their child, Provan says medications can help make them more receptive to therapy, in Anna’s case with a psychologist. And whether it was the treatment or Anna’s growing maturity, the tantrums disappeared. Now 13, Anna is no more irritable than a regular teenager, though she is still managing anxiety and depression. Indeed, studies tracking DMDD kids suggest that irritability symptoms can taper off by late adolescence or young adulthood, while depression and anxiety can continue.

Provan says that kids with DMDD need better medical treatment options and better mental health services — as well as more awareness in general. Because Anna was judged so much for her hair-trigger temper, Provan wrote a short book — Poppy and the Overactive Amygdala — to build understanding and empathy.

Before she had Anna, she recalls, “I was that parent that was, ‘Oh, screaming toddler — can’t they control their child on an airplane?’

“So, I guess, just be nice to your fellow humans.”

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Katarina Zimmer is a science and environment journalist currently based in Germany. A special contributor to Knowable Magazine, she has also written for National Geographic, Scientific American, BBC Future, the Atlantic and elsewhere. Check out more of her work at www.katarinazimmer.com.

LIVING WORLD | VIEW ON WEBSITE

Night of the zombie insects

A parasitic fungus takes over the brains of flies and controls them for its own sinister ends. Here’s the science behind the horror.

By Rohini Subrahmanyam    10.28.2024

Lea en español

A fly is going about its day, buzzing here, buzzing there — but then, it starts behaving weirdly. Its movements become sluggish, its abdomen swells. Its body sprouts white fuzz.

Around sunset, there’s a sudden a burst of movement as the fly climbs — or “summits” — to an elevated location, like the top of a small plant or a stick, and extends its mouthparts. It spews out a sticky ooze that attaches it firmly to its perch — then it lifts up its wings and dies.

Down below, other unsuspecting flies are hit by a shower of white spores shooting out of the dead fly’s corpse. And the cycle starts all over.

The white stuff that engulfs these flies is a fungus called Entomophthora muscae, which translates to “destroyer of insects.” It’s an obligate pathogen — entirely dependent on its host — that infects flies and turns them into “zombies” that execute its will.

Discovered more than 160 years ago, the fungus’s actions are as mind-boggling as they are macabre. Scientists have long wondered: How does the fungus manage to control the fly’s brain? How does it “know” to do it at a specific time of day? What genes within its genome help it to become a master manipulator?

Today, a flurry of experiments is starting to unravel the science behind this eerie mind control.

Fatal necrophilia

Henrik H. De Fine Licht, an evolutionary biologist at the University of Copenhagen, is one of the few people in the world working with “zombie” house flies, Musca domestica. Though initially drawn to the fungus E. muscae because he wanted to study obligate pathogens, “I was, of course, also fascinated by the behavioral manipulation aspects and how that works,” he says.

Those details are like fodder for a horror movie. After the fungus infects the fly, it doesn’t go straight to the vital organs but starts consuming fats and other nutrients first, gradually starving the fly but keeping it alive. Only when it runs out of non-vital organs to chomp on does it start to control the fly’s behavior, thus ensuring its continuity: By forcing the fly to seek some height and get stuck there, it ensures wide distribution of its spores.

Life cycle of the fungus Entomophthora muscae.

De Fine Licht was especially intrigued by reports describing how the fungus manipulates flies by making female fly carcasses attractive to healthy males. The males fly in and try to mate with the infected cadavers — and promptly get infected themselves. To delve into the nature of this fatal attraction, De Fine Licht and his team mashed up infected and uninfected fly carcasses to extract and analyze chemicals, and analyzed the air surrounding the cadavers. They reported in 2022 that the fungus releases volatile chemicals that lure the males in.

It isn’t fully clear, though, whether the volatiles are attracting male flies with the promise of sex or of nutrition, De Fine Licht says. A working hypothesis is that they might just be attracted because they think it is food. “But when they come in close proximity, they start to smell some less-volatile compounds of the cadavers — and that is eliciting the sexual behavior.”

Annette Jensen, an organismal biologist at the University of Copenhagen, also noticed something intriguing about how other insects reacted to the dead flies’ odor. She and one of her students found that the earwig — an insect that feeds on other insects — is drawn to the sporulating fly cadavers infected by E. muscae and prefers to feed on them over uninfected cadavers or cadavers infected with other kinds of fungi. The scientists reached their conclusions after conducting experiments in which earwigs were placed between two types of cadavers and could select which one to move toward.

“There might be something with the volatiles from Entomophthora muscae  that also attracts predators,” says Jensen, who cowrote an overview on fungi that are pathogenic to insects in the Annual Review of Entomology. “It’s probably super nutritious!”

E. muscae-infected female cadavers emit volatile chemicals that lure unsuspecting male flies. The males try to mate with the female corpses, becoming infected in the process. In this image, two male flies were attracted to the scent.

CREDIT: FILIPPO CASTELLUCCI

Fruit flies join the victims list

Most zombie fly work has focused on house flies, but Harvard molecular biologist and zombiologist Carolyn Elya set her research sights on fruit flies after serendipitously discovering some zombified ones in her backyard when she was a PhD student at UC Berkeley. She had put out rotten fruit as bait for capturing wild fruit flies for experiments and was surprised to see some dead ones with their wings up in that telltale pose, with white fuzzy spores on their abdomens. She quickly sequenced some DNA from the spores and confirmed her hunch: These fruit flies were victims of E. muscae.

Elya went on to infect Drosophila melanogaster, a well-established lab model that researchers around the world have studied for over a century. With this E. muscae-D. melanogaster system, she is keen to leverage the powerful Drosophila genetic toolkit and study the fly brain to understand how the fungus carries out its manipulation.

In a 2023 report, Elya and her coworkers showed that the fungus could be secreting something into the fly’s “blood” — its hemolymph — that helps to manipulate fly neurons. When she injected the hemolymph from infected flies into uninfected ones, the latter started behaving as though they had been zombified.

Elya also discovered that the fly’s circadian neurons — the ones that help it keep track of daily rhythms — may be involved in the time-sensitive height-seeking behavior. Silencing specific sets of these neurons in the brain inhibited summiting activity in the infected flies.

E. muscae-infected “zombie” Drosophila fruit flies behave similarly to house flies. This photo shows them climbing to the top of a stick and adhering themselves onto it with their mouthparts. They also lift their wings up before dying, ensuring that the spores will be well-distributed.

CREDIT: CAROLYN ELYA

Elya also wants to understand this mind control from the fungus’s perspective — and to that end, she, De Fine Licht and others recently sequenced the huge E. muscae genome. Focusing on the strain that infects fruit flies, the scientists reported finding genes similar to one called white-collar 1, which carries instructions for making a blue-light sensor in a mold called Neurospora crassa. In N. crassa, white-collar 1 plays a role in circadian rhythms — and so the scientists hypothesize that this gene might be involved in driving the precise timing of infected flies’ summiting behavior around sunset, followed by their death.

The scientists also discovered a lot of genes that could help the fungus make full use of the fly’s tissues and nutrients. These included specialized genes that code for trehalase enzymes, which digest trehalose, the primary sugar in hemolymph; for proteins like chitinases that break down chitin in the fly’s exoskeleton; and for lipases, which break down fats.

“That makes sense, right? Because these fungi are very specialized in the way that they utilize their hosts — not by killing them first and then eating them later, which is a strategy that’s used by a lot of generalist pathogens — but instead they grow inside of the insects,” Elya says. “Being able to specifically target every last tissue in their host is important.”

And the quest for more clues continues, with researchers moving beyond the static genome to study the RNA copies of genes that are made when specific genes are active. In a research paper that has yet to be peer-reviewed, Sam Edwards, a postdoctoral researcher at Wageningen University in the Netherlands, De Fine Licht and colleagues reported their analysis of the RNA in house fly heads at different time points after an E. muscae infection. By figuring out which fly and fungus genes were active inside the fly’s head, they hoped to get a glimpse at how the fungus manipulates the fly’s behavior.

The team detected activity of a fungal gene that is similar to one called egt that is present in certain zombifying viruses. These viruses, like E. muscae, force their infected victims — in this case, caterpillars — to move to high locations, and in a move more gruesome than that of their fungal counterparts, cause the caterpillars to melt and release the viral particles below. The egt gene plays a role in this virus-induced caterpillar summitting behavior, so the researchers now want to know whether the gene in E. muscae is key to inducing summitting in infected flies.

In a further twist, both De Fine Licht’s preprint and a recent UC Berkeley study that Elya coauthored find that E. muscae may not be operating alone. The fungus appears to be infected by a virus at the same time that it’s parasitizing house flies and fruit flies. Whether this virus helps the fungus control the fly, though, remains to be seen.

Elya, De Fine Licht, and others all still want to know how the fungus begins its manipulation. One hypothesis is that E. muscae directly releases a chemical that activates the neurons involved in the fly’s summitting behavior. But another hypothesis is that the fungus’s all-consuming presence, and the consequent physiological changes in the fly, trigger the fly’s own neurons to release chemicals to kickstart the process.

De Fine Licht is keen for the zombie fly-fungus system to be taught in schools, to draw in younger science enthusiasts. He and Edwards recently published instructions on how to observe the zombifying fungus in the lab. “It could encourage high school teachers and others to try this out, if they wanted to,” De Fine Licht says.

Some of this involves collecting fly cadavers from the field and isolating the fungus from them.

“Or you could try to infect some healthy flies in the laboratory by putting them together with the cadaver,” De Fine Licht says. “That might be the most fun, right? Trying to observe the zombie behavior in a tiny little box.”

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Rohini Subrahmanyam is a PhD biologist turned science journalist who loves writing about interesting creatures on our planet. Follow her on X @rohsubb and LinkedIn and see her portfolio here.

LIVING WORLD | VIEW ON WEBSITE

When ribosomes go rogue

Unusual variations in the cellular protein factory can skew development, help cancer spread and more. But ribosome variety may also play biological roles, scientists say.

By Tim Vernimmen    10.23.2024

In the 1940s, scientists at the recently established National Cancer Institute were trying to breed mice that could inform our understanding of cancer, either because they predictably developed certain cancers or were surprisingly resistant.

The team spotted a peculiar litter in which some baby mice had short, kinked tails and misplaced ribs growing out of their neck bones. The strain of mice, nicknamed “tail short,” has been faithfully bred ever since, in the hope that one day, research might reveal what was the matter with them.

After more than 60 years, researchers finally got their answer, when Maria Barna, a developmental biologist then at the University of California San Francisco, found that the mice had a genetic mutation that caused a protein to disappear from their ribosomes — the places in cells where proteins are made.

This came as a complete surprise, says Barna: Everyone had expected the cause to be a mutation in a gene that orchestrated development, not one involved in ribosome structure. Ribosomes, which under the microscope look like millions of specks scattered across the cell, or — closer up — like a bread roll torn into unequal halves, appear similar in all life forms. They exist in every cell and were thought to do the same thing everywhere: translate instructions contained in DNA into the proteins that do most of the work in cells.

How could a defect in this dependable, ubiquitous little workhorse reshuffle the body plan of a mouse in such a curiously specific way?

Today, based on findings like these, a growing number of scientists have come to believe there’s more going on with ribosomes than they once thought — and that ribosome variety may sometimes have biological functions.

Barna, now at Stanford University, reported her finding in the journal Cell in 2011. Since then, researchers have uncovered several other genes that, like the one in “tail short” mutants, code for proteins in ribosomes and appear to distort development in a specific way when mutated.

In the unfortunate mouse that first intrigued Barna, a protein known as RPL38 was not being made correctly. In another mouse, a faulty version of a protein called RPL10A led to even more drastic (and deadly) deformities. “These embryos looked as if a guillotine had cut off their posterior end right after the hindlimb,” Barna recalls.

Mouse embryos with faulty versions of the ribosomal protein gene Rpl10a don’t develop a tail. On the left is a normal embryo; on the right is the mutant embryo.

CREDIT: MARIA BARNA

Picky ribosomes

There are other reasons researchers were surprised that unusual ribosomes lay behind the unusual development of these mutant mice. First, quality control on ribosomes is tight: Since faulty ones may churn out ill-conceived proteins that can do a lot of damage, they tend to be quickly eliminated. Second, embryos that have mutations in genes coding for ribosomal proteins generally don’t make it all the way through a pregnancy.

Yet there are exceptions, including in people. Children with isolated congenital asplenia, for example, are born without spleens, often due to a mutation in a single ribosomal protein, while the rest of the body is completely normal. Again — how could one missing or unusual protein in the ribosomes cause such a thing?

Barna believes that affinity is key. To make a protein, ribosomes don’t receive instructions directly from the unwieldy DNA, but from more succinct messenger RNA (mRNA) molecules that carry instructions about single genes. RNA is made up of a long string of four different building blocks, and every three blocks code for an amino acid. The ribosome reads these instructions and correctly joins the amino acids together to form a protein.

This colorized electron microscope image shows protein production in a cell of the midge salivary gland. The messenger RNA, in red, is read by the ribosomes, in blue. Other RNA molecules bring in the corresponding amino acids, which are then joined together into proteins, shown in green.

CREDIT: DR. ELENA KISELEVA / SCIENCE SOURCE

As far as scientists know, mRNA molecules just float around until they encounter a ribosome, at which point they get translated into protein. But Barna believes — and has evidence to suggest — that different ribosomes have different affinities and may be more apt to translate some mRNA types than others.

For example, the cells of mouse embryos with an Rpl38 mutation produce just as much protein as other embryos do. But they make substantially less of some proteins that are crucial during development. Known as homeobox proteins, they are essential for the embryo to sort out its back end. Barna discovered that ribosomes without RPL38 are less likely to bind to and translate homeobox mRNA. This results in a deficiency of these organizing proteins and perturbed development of vertebrae, ribs and tails.

Similarly, ribosomes without the ribosomal protein RPL10A are less likely to bind to mRNA that codes for another crucial set of embryonic development proteins — ones involved in what’s called the Wnt signaling pathway. Reduced numbers of these crucial proteins cause development to abruptly end after the hindlimb, creating the impression that the back end was cut off.

While some genetic disorders involving ribosomal proteins seem rooted in activities of unusual ribosomes, others may be due to ribosome shortages that result from the cell’s strict quality control, Barna says. Treacher Collins syndrome, which causes abnormalities of the face, and Shwachman-Diamond syndrome, which causes abnormal development of the skeleton, are likely examples.

Those are defects. But sometimes, Barna argues, differences in ribosome structure and composition may be functional. “We are discovering that certain ribosomal proteins occur more often in some cell types than others, say in neurons versus gut cells,” she says. Recent results from her lab suggest that there may even be different types of ribosomes within the same cell that specialize in making certain proteins over others.

In ribosomes, she says, “there appears to be a core that is invariable, and then in the outer shell, proteins that can vary within and between cells and tissues.” She believes this provides our body with yet another way of regulating which proteins get made, and where.

When ribosomal proteins are abnormal or missing, anomalies may arise.

Salty yeast

In November 2023, a two-day conference in London that Barna co-organized brought together many scientists who are intrigued by the variation they have found in the ribosomes they’ve looked at, and what, if anything, its functions may be.

Some aren’t quite so convinced that unusual ribosomes do anything beyond causing trouble. Katrin Karbstein, a biochemist at Vanderbilt University who coauthored a 2024 article about ribosome quality control in the Annual Review of Cell and Developmental Biology, notes that most of the known examples of ribosome variation cause disorders or disease. “Few if any have been demonstrated to be helpful to the organism,” she says.

Karbstein thinks that most genetic disorders associated with ribosome genes are probably just caused by the ribosome shortages that result when faulty ones are eliminated, rather than any special property of the divergent ribosomes themselves. If humans or mice end up with specific defects, she says, that may just be because low ribosome levels are a bigger problem in some cell types than others.

Yet in her own talk at the meeting, Karbstein revisited a discovery she herself made in the yeast cells she studies that, much to her surprise, did reveal a useful ribosome variant. When growing in very high salt concentrations, yeast cells lose a ribosomal protein, Rps26, from about half of their ribosomes. Ribosomes without the protein are different, Karbstein found. They seem more inclined to translate mRNA molecules that are produced in reaction to that stressor.

And when Karbstein and her team went on to deliberately remove Rps26 proteins from yeast cells, they found the cells became resistant to high salt. “In fact,” she says, “they now grow better under high salt.”

Karbstein also found that yeast responds nimbly to salt stress, quickly removing Rps26 proteins from ribosomes when needed and popping them right back in when the stressful situation subsides.

When growing in very high salt concentrations, yeast cells lose a ribosomal protein, Rps26, from about half of their ribosomes, with the assistance of what’s known as a chaperone protein. Yeast cells without Rps26 are better adapted to high salt.

Resistant ribosomes

Ribosomes aren’t made just from proteins: About half their structure consists of RNA. And in eukaryotes (life forms with complex cells like ours) there is plenty of extra RNA sticking out of the ribosomes, like the tentacles of a sea anemone. “We think this may provide a mechanism for trapping messenger RNA,” says Barna.

Ribosomal RNA also performs the most crucial and ancient function inside ribosomes: the fascinatingly efficient translation of mRNA into protein. The very first proteins must have been made by ribosomal RNA, argues structural biologist Ada Yonath of the Weizmann Institute of Science in Israel, who shared a Nobel Prize in 2009 for her work figuring out the structure of the ribosome.

Yonath notes that the pocket in ribosomal RNA where amino acids are joined together to form proteins looks very similar in all species, and she does not consider this to be a coincidence. “We think this is the proto-ribosome from which full ribosomes have evolved,” she says.

Ribosome researchers have long focused most of their attention on this neat, central area where mRNA is read and amino acids are joined together; they’ve spent less time studying the ribosomes’ outskirts. In addition, the ways in which ribosome structure has been studied created a strong impression that all ribosomes were the same. But new methods have uncovered more variation.

Yonath says she wants to see more evidence that differences between ribosomes can be helpful. Her lab is now collaborating with Barna and others to find out whether ribosomes that lack certain proteins or contain unusual ones have different three-dimensional structures that might explain why they work differently.

Yonath has long been interested in the differences between ribosomes of different species. These, she says, might be useful in developing antibiotics that target only the ribosomes of pathogens while avoiding significant damage to the beneficial microbes that live in our body, or to our own cells. “Over 40 percent of the clinically useful antibiotics target protein synthesis, mostly by paralyzing the ribosome,” she notes.

But her interactions with pharmaceutical companies about new possible targets she has identified have been disappointing, she adds: “They say the bacteria will become resistant.” Indeed, in a clear example of ribosomal variation that is helpful — not to us, but to the pathogen — antibiotics targeting bacterial ribosomes may favor the survival of bacteria with slightly different ribosomes that the antibiotic can no longer block.

Powering proliferation

Another area of medicine where variation in ribosomes may turn out to be good news is in cancer treatment and diagnosis. Around 25 percent of cancers are associated with genetic changes in ribosomal proteins, says Yonath, whose lab is working in this area too.

Molecular biologist Davide Ruggero of the University of California San Francisco is a pioneer in research to understand and leverage those differences. “Cancer cells hijack things that evolved for other reasons and use them for their own benefit,” he says — and that includes firing up the activity of ribosomes. Rapidly dividing cancer cells need plenty of protein to keep going.

Studies also show that certain proteins can be made in large amounts during tumor growth or when cancer cells spread through the body, when they have to survive in blood and other places they’ve never been before.

These overproduced proteins include growth factors and other proteins that are known to increase cancer risk, and Ruggero’s lab has found that the mRNAs that code for them are translated in higher amounts in the cancer cells. “Normal cells need to be extremely careful to regulate these,” he says. “Cancer cells do the opposite.”

Ruggero and Barna have found evidence that a ribosomal protein called RPL24 is involved: When it goes missing from the ribosomes of mice, the increase in protein production that is required for cancer cell proliferation doesn’t occur. “I do believe that the more we understand this dynamic, the more we can improve cancer therapy,” Ruggero says.

Cancer treatments that specifically target ribosome variants are nowhere near implementation today, but some products already used in the clinic hint at their potential importance. Some of these target polymerase I, an enzyme involved in the production of ribosomal RNA that is often hyperactive in cancer cells. And Ruggero’s own work has inspired experimental drugs that block proteins called translation initiation factors that affect how likely mRNA is to be transcribed at the ribosomes. They are used by all cells, but many cancer cells strongly depend on them.

One of these drugs is currently being evaluated in three phase 2 clinical studies to test its effectiveness and safety in the treatment of breast, endometrial and ovarian cancer.

There is not yet evidence that differences in ribosomes themselves might be leveraged to enhance treatments. But researchers like Barna and Ruggero see it as yet another strand of research suggesting that exploring ribosome variation is worthwhile, even in the face of skepticism. “I’ve been in the ribosome story for almost 50 years, and I’ve heard almost everything,” says Yonath, whose early work also met disbelief. “Yet I do expect great medical progress can come from a better understanding of translation.”

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Tim Vernimmen is a freelance science journalist based near Antwerp, Belgium. He has no idea what his ribosomes were up to while he wrote this, but they sure made plenty of protein.

SOCIETY | VIEW ON WEBSITE

Q&A — Developmental psychologist and language scientist Adriana Weisleder

How a child becomes bilingual — and what can be done to help them get there

Kids from immigrant backgrounds in the US often struggle to develop fluency in two languages. Many factors — parental misconceptions, the lack of support in schools and social attitudes — play a role.

By Katarina Zimmer    10.22.2024

Lea en español

Adriana Weisleder knows well the benefits of being bilingual: being able to communicate with one’s community, cultivating connection with one’s heritage culture, contributing to the richness and diversity of society, and opening up professional opportunities. Research also suggests some cognitive benefits of bilingualism — such as improved multitasking — although those are more debated, says Weisleder, a developmental psychologist and language scientist of Costa Rican heritage who directs the Child Language Lab at Northwestern University near Chicago.

Nearly 22 percent of Americans speak a language other than English at home; many of them are English and Spanish speakers from immigrant families. Yet many children from immigrant families in the United States struggle to develop or maintain proficiency in two languages. Some may lose their heritage language in favor of English; others may fall behind in schools where their progress is evaluated only in English.

CREDIT: JAMES PROVOST (CC BY-ND)

Developmental psychologist and language scientist Adriana Weisleder

Northwestern University

In a 2020 article in the Annual Review of Developmental Psychology, Weisleder and educational psychologist Meredith Rowe explain how a person’s environment — at a family, community and societal level — affects language acquisition. In the US, for instance, language development in children from immigrant families is influenced by parental misconceptions about raising children bilingually, a general scarcity of support for bilinguals in schools, and anti-immigrant sentiment in society more broadly.

In her research, Weisleder leads in-depth studies of bilingual toddlers in different social contexts to better understand how they comprehend and learn multiple languages. She hopes her insights will help to dispel misconceptions and fears around bilingualism and improve support for children learning multiple languages.

“It’s interesting theoretically, but also just really important for our society to have more information that can guide caregivers, education practitioners and clinicians on how bilingual children develop, and how to support them,” she says.

Knowable Magazine spoke with Weisleder about how children learn two languages, particular challenges faced by immigrant children in the US, ways to better support multilingualism, and her own experience with raising a 1½-year-old daughter bilingually. This interview has been edited for length and clarity.

What do we know about how infants exposed to two languages learn to speak? How does their language development differ from children only exposed to one language?

Bilingual children go through the same milestones of language development as monolingual children. Both start speaking their first words around one year of age, start combining words around six months or a year later, and eventually reach native proficiency. But we know that under all that, bilinguals are doing a more complex task of figuring out two linguistic systems. So we see a slightly more protracted development of some aspects of language.

The project Leyendo Juntos (reading together) at Northwestern University’s Child Language Lab encourages early reading activities in children and studies how this affects language interactions within Latino families.

CREDIT: COURTESY OF CHILD LANGUAGE LAB / NORTHWESTERN UNIVERSITY

One example is how bilingual children learn to differentiate sounds in their languages. For instance, in English, bile versus vile are different words, but in many varieties of Spanish, there isn’t a meaningful contrast between those sounds because b and v  are interchangeable. Through lots of exposure to sounds, infants learn sound differences that are meaningful and lose the ability to identify differences that are not meaningful in their language. In bilingual children, it takes them a little bit longer to develop that discrimination and specialize in their languages.

For vocabulary, the rate of learning is also linked to the amount of language exposure. So what you’d expect is that for a young child that has 50 percent exposure to English and 50 percent to Spanish, their vocabulary in English will be about half of that of an English monolingual, and in Spanish it will also be about half. The really important thing, though, is that if you add their vocabulary in both languages together, then their rate of vocabulary development is the same as that of monolinguals.

For most aspects of language, bilingual children do eventually end up at the same place as monolinguals, even in a single language. In general, when 60 percent of a child’s total exposure to language has been in one particular language, they score about the same as a monolingual on most tests of that language. By the time they’re 3 or 4 years old — and certainly by school age — they’re looking very similar to monolinguals. That’s amazing, when you think about it — that you have two or maybe three languages, and you’re functionally the same as someone who speaks only one.

What’s really fascinating is that a lot of these characteristics also seem to be true of bilinguals who speak sign languages. So this learning process really is specific to language and not just speech.

What about “sequential bilingual” children, who learn one language after the other? Does their ability to do that depend on their age?

It depends a lot on age. If we’re talking about children who are learning two languages before, let’s say, seven years of age, they can become completely native speakers of those two languages, even if they’re learning them sequentially, although the process is a little bit different than for simultaneous bilinguals. Individuals who learn a language after this age — the exact age is hotly debated — usually don’t attain the same level of proficiency; that can mean speaking with an accent, or making some grammatical mistakes that are unusual for native speakers, for example.

Although there are also some adults that are able to learn languages very, very well, there’s no question that it’s easier to learn a language before adolescence than as an adult, but we don’t completely understand why.

Does someone’s knowledge and experience in one language affect how they understand and learn a second one?

Many things are specific to particular languages and don’t transfer. Learning the past tense in Spanish isn’t going to help me much to learn how to do it in English. But on the meaning side of language, for instance, what you learn in your first language helps. Let’s say I learned the Spanish words for cow, horse, pig and chicken. Those words are very specific to Spanish, but I also learned that all those are farm animals. Those kinds of connections between words are going to transfer to another language, so you’re not learning a whole new semantic system.

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What about learning to read? Is that different from learning to speak?

Most scientists would agree that humans as a species are prepared to learn to speak a language, without having to be taught it explicitly. But our brains aren’t born prepared to learn to read; it’s something we have to teach ourselves. So things that apply to spoken language don’t necessarily apply to reading.

But what is true is that having a stronger foundation in oral language helps children learn to read better. We also know that when children are learning to read in a second language, the number of words they know in their first language is a predictor of their reading skills in the second language.

Tell me about your current research. What questions are you hoping to answer and how are you going about studying it?

We’re looking at how children understand and process language before they begin to speak. Studying comprehension is hard, though, because it happens in the mind.

We use eye-tracking to do this. There’s a special type of camera that tracks children’s eye movements as they’re looking at pictures or videos on a screen. If all of a sudden I say, “Oh look, a dog!” their eyes will immediately go searching for the dog. We can do different manipulations: Do they understand the difference between dog  and cat, for example? What if I say dog  and doll, which have similar sounds? Does that make it harder?

By doing these eye-tracking tasks in both the languages bilingual children are learning, we can ask questions like: How does their language processing ability in one language relate to their language processing in the other? And how does this change over time as they get more exposure to one language or the other?

Adriana Weisleder’s lab uses eye-tracking to study early language development in bilingual children; by monitoring their eye movements as children watch images on a screen, researchers can track how quickly they process sounds and words that relate to particular images.

CREDIT: COURTESY OF CHILD LANGUAGE LAB / NORTHWESTERN UNIVERSITY

Another reason we’re doing this is to find early measurements of language processing that can help identify children with language impairments, so we can give them speech and language therapies at a time when we think they’re going to benefit most from it.

One thing we’ve learned so far is that bilingual children seem to show some of the same signatures of language processing that monolingual children do. One concrete example is that they’re doing what we call “incremental processing” of speech. You actually don’t wait until the very end of a word or sentence to interpret it; you’re kind of doing it as the speech unfolds. If I show you a picture of a dog and a baby, the minute you hear the sound of a d — “duh” — if you’re looking at the baby, you’re going to shift over to look at the dog.

Incremental processing of language is a sign of maturity in language processing, and can help predict later language and cognitive development. We know that monolingual toddlers or infants do this incremental processing early on. And our studies are showing that bilingual children do it too, at least in their more dominant language. It may take them longer for the language that they have less exposure to.

It seems that children are generally very capable of learning to speak multiple languages they’re exposed to. Is this widely appreciated among parents, especially those from immigrant families? Are there any concerns you’ve encountered around raising children bilingually?

Unfortunately, there are a lot of misconceptions about bilingualism. What we hear from parents — especially Latino immigrant parents in the US — is that, on the one hand, there’s a desire for children to speak their home languages and to be bilingual. But at the same time, the parents have some fears that this will confuse their child or cause them to not learn English as well, and that that might hold their child back in key, important ways.

What actually plays the biggest role in discouraging parents from teaching their home languages is that in schools their children will be evaluated only in English.

During the Annual Hispanic Heritage Day Parade in 2019, marchers hold a banner with the statement “We speak Spanish” across Fifth Avenue in Manhattan.

CREDIT: PHOTO BY IRA L. BLACK / CORBIS VIA GETTY IMAGES

There are also some fears and experiences of discrimination against children when they speak their home languages. Especially during times where there’s lot of anti-Hispanic sentiment in the US, for instance, parents may hold back on efforts to teach their children Spanish, like enrolling in bilingual schools.

Misconceptions also exist among some professionals. We’ve found in surveys and interviews with pediatricians that while they often agree that bilingualism can be beneficial for children, they’ll express some hesitancy when asked, for instance, whether speaking another language could make it harder for a child to learn English. I think when pediatricians observe that bilingual children seem not to be acquiring English at the same rate as monolingual children, that makes them fearful about whether they should recommend that parents speak their home language.

We also see pediatricians get nervous when it comes to children with developmental disabilities or communication difficulties. But the research suggests that children with disabilities are also able to learn two languages; bilingualism doesn’t exacerbate their difficulties.

I imagine that this could contribute to the loss of heritage languages among immigrant families in the US. A Pew Research Center survey from 2023 found that one of every four Latinos in the US say they can only carry on a conversation in Spanish a little or not at all, and the numbers grow significantly when you are focusing on only third- or later-generation Latinos. What other factors contribute to that?

In the US, languages other than English are rarely supported in schools or by society in general. Those languages are treated as lower status, and this is particularly true for languages associated with immigrant communities such as Hispanics. So it ends up being up to parents or families to do all the work of supporting both languages. But the way that’s most natural for children to learn language is by actively communicating with peers and friends, not just family.

So sometimes children simply don’t use their heritage language as much, and they lose it over time. Other times they prefer English because it’s the language that helps them the most to communicate in the world — and sometimes they even actively reject their heritage languages. Children don’t want to be labeled as “different,” and language is just one other way in which other children can exclude them.

A survey of US Latinos found that most of them (75 percent) say they can hold a conversation in Spanish. But among third- or later-generation Latinos, a much larger share are not fluent: Close to two-thirds (65 percent) report not being able to converse well in Spanish.

I read in your review that bilingual children from Hispanic households in the US often report relatively lower academic outcomes relative to monolinguals, which contrasts with places like Quebec, Canada, where most children become linguistically and academically competent in both English and French. Why is that?

There are many possible reasons for the lower academic outcomes observed in bilingual children from Hispanic households compared to monolinguals. Some are likely not related to bilingualism at all, as there are often differences between these groups in terms of socioeconomic status, parental education, access to high-quality early childhood education and other factors.

But to the extent that we think bilingualism plays a role, I think that when bilingual children are evaluated only in English — as they are in US schools — these tests can underestimate their knowledge and capacities. Another data point that supports this is that children from bilingual homes who go to dual-language schools — where children are truly immersed in multiple languages rather than just having a class on them — do not underperform their monolingual peers. To me, this suggests that bilingual kids can perform just as well academically as monolingual children but are perceived to be underperforming when assessments are done only in English.

In Quebec or other places where bilingualism is fully supported by families, schools and society more generally, children can become academically competent in both languages. But the US does not have that kind of context.

What can be done at the societal and educational level in the US to help children become or stay fluent in multiple languages?

In 2023, we published an article about this in Policy Insights from the Behavioral and Brain Sciences. One point we make is that we should really internalize that it’s a right for all children to have access to their own languages. Language diversity is something we should be committed to supporting because it will make our society richer.

More concretely, we need to support community-led programs — like some that I work with here in Chicago — that incorporate language, culture, art, music, and provide natural, fruitful contexts to support home languages. Having meaningful communication partners — not just your parents, but your friends, peers, teachers, other people — is a really important signal for children, providing motivation to speak the heritage language.

Son Chiquitos, a program of 18th Street Casa de Cultura in Chicago, offers Spanish immersion sessions for family and children. Community-led programs like this one that incorporate language, culture, art and music can provide children with the motivation to speak their heritage language.

CREDIT: PHOTO BY GINA GAMBOA

Dual-language schools are also an excellent way to support multilingualism. But unfortunately, what has seemed to happen in the US is that these schools tend to cater to higher socioeconomic status families who want their children to learn another language. So they’re not quite as much serving the needs of immigrant communities that could most benefit from them.

For schools more generally, we should also shift away from English-only standards for testing and focus on supporting and assessing children’s academic progress in ways that allow them to make use of multilingual skills.

Can you tell me a bit about your own experience in trying to raise a child bilingually, and any challenges you’ve experienced?

Although Spanish is my native language, I use English almost dominantly now and my husband and I mostly communicate in English. I try to speak to my daughter — who is 1½-years-old — exclusively in Spanish. But that’s just not always practical — like sometimes when we’re all together.

Although she does have some words in Spanish and she understands almost everything I say to her in Spanish, her vocabulary has advanced much faster in English. I try to acknowledge what she says in English and repeat it in English, but I also try to introduce some Spanish words so that hopefully she picks them up.

Another thing that we’ll try to do is to spend more time with my family and in Costa Rica, where I’m from; if she has more people around her speaking in Spanish, I think that that will help solidify some language in her.

Do you have any tips for other parents trying to raise their children in more than one language?

One important thing is finding ways of having deep, immersive, meaningful conversations with your child. I’ve tried to motivate my toddler to speak Spanish when playing with me and during high-quality bonding moments. What I try to avoid is to, for example, only use Spanish when I’m trying to discipline her.

I would really encourage parents to try to find bilingual books or books in their home languages. Books provide complex and diverse language to use, and stories to talk about. A recent study from my lab shows that Latino parents use more Spanish when reading bilingual books with their children. And once kids are a little bit older, using media to find fun and authentic content in your home language can also be helpful.

I hope what parents take away from this is that bilingualism is fascinating and cool and complex, and not something to be fearful of. It’s a wonderful asset for kids that, oftentimes, children themselves will only appreciate later on. But it can be really hard when you’re doing it on your own. I would encourage parents to find community that supports them in doing it.

This story is part of the  Knowable Magazine/Knowable en español series on science that affects or is conducted by Latinos in the United States, supported by HHMI’s Science and Educational Media Group.

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Katarina Zimmer is a science and environment journalist currently based in Germany. A special contributor to Knowable Magazine, she has also written for National Geographic, Scientific American, BBC Future, the Atlantic and elsewhere. Check out more of her work at www.katarinazimmer.com.

TECHNOLOGY | VIEW ON WEBSITE

The Cybathlon: Bionic athletes compete for the gold — and push assistive technologies forward

In the international competition, people with physical disabilities put state-of-the-art devices to the test as they race to complete the tasks of everyday life

By Dana Mackenzie    10.16.2024

Next week, several intrepid cyber-athletes will race to carry out routine household tasks via a computer avatar: They’ll have to open a locked door, for example, and hold a cup under an ice dispenser to collect a precise number of cubes. Those tasks may sound easy, but there’s a catch: The athletes, who are all paralyzed from the neck down, will attempt to complete them using only the power of their thoughts.

This is the brain-computer interface race, one of several challenges in the upcoming 2024 Cybathlon taking place in Switzerland (and remotely) October 25 to 27. The competition, held every four years, pushes the limits of what human bodies and machines can do together, showcasing proficiency at the basic tasks of daily life.

The Cybathlon has no affiliation with the Paralympics and there are big differences between them, says Robert Riener of ETH Zurich, an expert on robotics and rehabilitation who launched the Cybathlon a decade ago. “The Paralympics are more athletic, and more about rewarding the strongest and fastest — but that excludes many people,” Riener says. In the Paralympics, people can use a prosthesis, but all devices must be passive: no motor, no display, no sensors.

By contrast, the Cybathlon is unabashedly “technotopian,” says Riener. It is about the fullest possible collaboration of technology and human effort. For that reason, the competitors are not called athletes: They are “pilots.” The device they are piloting might be a prosthetic arm, for example, or an exoskeleton or a robot assistant.

“I have worked with people with disabilities for more than 30 years and realize the deficits of assistive devices,” Riener says. “They are expensive, and their capabilities are nothing compared to our bodies.” The competition’s aim, he adds, “is to promote the development of better assistive technologies.”

Using a mouthpiece, pilot Samuel Kunz (right) transmits commands to the four-legged robot (foreground) during a February warm-up event for the new Assistance Robot competition. The robot is starting to open the door of a mailbox; to complete the task successfully Kunz had to extract the brown package from inside. Kunz won the warm-up event.

CREDIT: ETH / CYBATHLON / ALESSANDRO DELLA BELLA

Among this year’s technologies are systems that electrically stimulate paralyzed muscles, robots that can be controlled with a mouthpiece, and interfaces that enable direct communication between a pilot’s brain and a computer. As engineers and pilots make their final tweaks, here’s a look at the Cybathlon’s origins, and a preview of the 2024 competition.

‘Pilots’ are the top guns

Riener conceived the idea for the Cybathlon in 2013, inspired by a newspaper article about a man with a prosthetic leg who competed in a race to the top of the Willis Tower in Chicago. Riener imagined a competition where many people with disabilities could show off their abilities in public.

So he made the rounds, attending about 30 conferences in two years, he says, talking about his idea and, most important, recruiting pilots. “The pilots are the crucial thing,” Riener says. Without the pilots, you don’t have an event.

This emphasis on pilots underscores a critical aspect of Riener’s vision. When assistive devices are being developed, users of those devices are often involved late in the game, or not at all. It might seem obvious that engineers and pilots should learn from each other, but in the field of prosthetics that is not always the case. Researchers tend to push the frontiers of technology, when a less sophisticated but more user-friendly device might actually be more useful.

The Cybathlon, in contrast, is about full collaboration between technology developers and users of the technology. The most successful teams usually are the ones in which the pilot has input into the development of the assistive device.

The inaugural Cybathlon was held in Switzerland in 2016. With 66 teams and a packed house of 4,600 fans, the event surpassed expectations. “The biggest surprise was the emotions in the stadium,” Riener says. In 2020, as the pandemic forced teams to compete remotely and with no cheering crowds, it felt quite different. This year, the Cybathlon is back in-person in Switzerland, although some teams are competing remotely.

The 2024 Cybathlon consists of eight events. New ones include the assistance robot race, in which pilots control a robot assistant from their wheelchairs. Returning competitions include the brain-computer interface (BCI) race, wherein pilots with quadriplegia will guide an animated avatar through an obstacle course using their thoughts alone, with no voice commands or physical movements allowed. Another is the functional electrical stimulation (FES) bike race, in which competitors with paraplegia ride a bicycle, with their leg muscles activated by an electronic controller.

Athletic exhaustion

The FES bike race, in which pilots had to cycle 750 meters around a track, was the climax to the inaugural Cybathlon, highlighting both the grit of the competitors and the challenges of integrating machines with humans. The event was conducted in two-person heats, and often one or both riders would come to a complete stop because their muscles were too fatigued, before starting again.

At the 2016 Cybathlon, the difficulty of the Functional Electrical Stimulation bike race is written on the competitors’ faces, but so is their joy.

CREDIT: ETH ZÜRICH, CYBATHLON

This odd denouement is a textbook example of why it’s so tricky to augment human capabilities with machines. When muscles are triggered by external electrical signals, the muscles that respond first are the fast-twitch muscles — but they are also the muscles that get tired fastest. This is exactly the opposite of what you want in a distance race, which is to use mostly your slow-twitch muscles and save the fast-twitch ones for short bursts.

The winning pilot that year, Mark Muhn of Team Cleveland, was the only one who had surgically implanted electrodes inside his legs. These implanted electrodes did not really solve the problem of muscles being recruited in the wrong order, but they did give him better control over the fast-twitch muscles — and a rigorous training program did the rest.

This event also showcased how assistive devices can transform people’s lives. “All of our pilots had exercised before,” says biomechanical engineer Ronald Triolo of Case Western Reserve University and the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, who was the technical lead for Team Cleveland that year. But the exercises were on stationary bikes — “boring,” he says. “It wasn’t until we put them on a bike and they were moving over ground that we saw a palpable effect on their well-being. Every one of them tells us that they appreciate the feeling of freedom that they get when riding over the ground. They can ride on bike trails and people don’t know they’re paralyzed. They just say, ‘Nice wheels.’

“The competition is a means to an end,” Triolo adds. “It’s more about enabling pilots than winning the gold medal.”

To the disappointment of the Cleveland team, this year’s FES race will use stationary bikes. This allows remote participants to compete, and was needed because the Cybathlon is starting to outgrow its stadium: In order to fit 80 teams competing in eight events, the organizers had to sacrifice the track. Without the incentive of a moving bike, Team Cleveland has chosen not to defend its 2016 gold medal.

Another competition also promises an exciting high-tech versus low(er)-tech showdown. For the first time, the brain-computer interface race will allow pilots to have surgically implanted electrodes inside their brains. Previously, pilots were equipped with an EEG device, traditionally a skullcap with electrodes touching the scalp and wires leading to the computer. The PittCrew, a team from the University of Pittsburgh, will be the first team to compete using implanted electrodes.

Pilot Phillip McKenzie of the PittCrew practices for the Brain-Computer Interface challenge. Implanted electrodes record the activity of motor neurons in his brain, and the computer uses those signals to move McKenzie’s avatar on the computer screen at left.

CREDIT: UPMC / UNIVERSITY OF PITTSBURGH HEALTH SCIENCES

Both implanted and EEG devices work the same way. When a person imagines moving a limb, some of the neurons in the motor cortex will fire as if he or she were actually performing that motion. (This is true even if the person is paralyzed.) The computer can, in theory, read the pilot’s intentions from the electrical impulses in their brain, as recorded by the headset or implants. In the BCI race, those signals will be used to guide a virtual avatar through an obstacle course or a series of tasks.

Compared to the EEG, implants can offer much greater control, speed and accuracy. An EEG headset receives the brain’s signal only after it has propagated through up to 4 millimeters of brain tissue and a skull that is an electrical insulator. The signal is not only weakened but also obscured by the chatter of millions of other neurons, reacting to whatever else the pilot happens to be thinking about or sensing. If he is hungry, the “turn” signal from his motor neurons might be drowned out by the din of the “I’m hungry” signal. It takes time and practice for a pilot to learn how to suppress such unwanted thoughts.

By contrast, implanted electrodes can be placed right next to the motor cortex and can eavesdrop on the activity of only those neurons. It’s like giving a microphone to a singer instead of trying to hear her unamplified voice over the babble of the audience.

There are disadvantages to the implant approach — the first and foremost being brain surgery. Pitt’s pilot, Phillip McKenzie, has two motor arrays implanted in his brain, each the size of a pencil eraser, with 100 electrode tips that go a millimeter and a half into the brain. McKenzie did not get the implants specifically for the Cybathlon; he and two other people with quadriplegia at the Rehab Neural Engineering Lab received them one, three and nine years ago.

“These are long-term projects,” says Cecile Verbaarschot, the manager of PittCrew, who started working on brain-computer interfaces as a student assistant with a team from the Netherlands in the 2016 Cybathlon. “The participants come to the lab two or three days a week, and you really get to know them.”

The other teams at the Cybathlon will continue using the lower-tech approach of EEGs. PittCrew will most likely have stiff competition from Team NeuroCONCISE, led by Damien Coyle of the University of Bath in England and piloted by Owen Collumb. The duo have been to every Cybathlon event, competing with external electrodes, and have steadily improved over the years. Collumb won a warmup BCI competition in February.

The BCI race will include several obstacles, including navigating through a furnished room and the aforementioned ice dispenser challenge. “The tasks they come up with are really well thought-out,” says Verbaarschot. In previous years, the BCI competition typically involved tasks like grasping and turning, but not holding an object still. “The challenge is that for a BCI, it’s very difficult to do nothing,” Verbaarschot says.

Both technical leaders are hedging their bets about the outcome. Says Verbaarschot of the Pittsburgh team, “I find it difficult to assess how we will do.” Coyle of NeuroCONCISE gives the nod to his opponents: “If [Pittsburgh’s] system works reliably on the day, then they have an extreme advantage.”

Collumb, the pilot for NeuroCONCISE, is not so reticent. “I go there expecting to win, not to come second,” he says. “I’m not just there to participate.”

Pilot Owen Collumb (left) and technical leader Damien Coyle (center) of NeuroCONCISE practice for the BCI race. Collumb is using an EEG headset — rather than implanted electrodes — to detect his brain activity, which will control various commands on a computer.

CREDIT: ETH ZÜRICH / MAXIMILIAN WÜHRER

Ready, set – robots!

One of the new races this year, the assistance robot race, will feature pilots who use wheelchairs and have a severe impairment of both upper limbs. They will control a robot that will perform real (not virtual) tasks such as taking a package out of a mailbox, brushing the pilot’s teeth and hanging up a scarf. Devices like these are just becoming commercially available, and usually involve attaching a robotic arm to the wheelchair. But this solution has limitations: The arm physically weighs down the chair and steals power from its motor.

A team led by Carmen Scheidemann and Andrei Cramariuc of the Robotic Systems Lab (RSL) at ETH Zurich is trying an exciting new approach. “To the best of our knowledge, our system is the first walking robotic personal care assistant proposed for people with limited mobility,” Scheidemann, Cramariuc and Marco Hutter, the head of the RSL, wrote earlier this year. The assistant, called ANYmal, walks on four legs and it was originally developed by Hutter. It is now manufactured by ANYbotics for industrial applications — for example, to perform inspections on oil platforms.

The team has also developed a specially designed arm for the robot to perform manual tasks. The robot can be steered by the pilot with a breath-based joystick, or the pilot can use the same interface to command the robot to execute tasks autonomously.

The Robotic Systems Lab pilot is Samuel Kunz, himself a mechanical engineer, who was paralyzed 10 years ago in a swimming accident. In February, he won a warmup competition where he was the only competitor to accomplish all four tasks on both runs. Kunz and ANYmal are the favorite in this month’s competition, which will challenge teams to complete 10 tasks.

Some of the technologies to be showcased at Cybathlon 2024, such as arm and leg prostheses, are mature and already widely used. But for others, the Cybathlon is a proving ground for new ideas. The event has led to new products in the past: The people behind the Switzerland-based start-up company Scewo, for example, developed a stair-climbing wheelchair, now called BRO, for the Cybathlon, and a spokesman for Scewo says they’ve since sold “well over 200 units.”

For all the enthusiasm, the future of the Cybathlon is far from assured. It’s challenging to get funding, says Riener. “We don’t have a big community.” The 2028 event is not yet fully funded. But if things work out as he hopes, the event might outgrow its Swiss roots and travel from place to place, like that other Olympics. “The goal,” he says, “is that we can last for a very long time.”

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Dana Mackenzie is a mathematician who went rogue and became a science writer. He can sometimes install a light bulb correctly but confesses to being unable to fold a fitted sheet.

HEALTH & DISEASE | VIEW ON WEBSITE

Studies of migraine’s many triggers offer paths to new therapies

One class of drugs has already found success in treating the painful, disorienting and common attacks. Excitement is building about a slew of additional drug targets.

By Amber Dance    10.15.2024

Lea en español

For Cherise Irons, chocolate, red wine and aged cheeses are dangerous. So are certain sounds, perfumes and other strong scents, cold weather and thunderstorms. Stress and lack of sleep, too.

She suspects all of these things can trigger her migraine attacks, which manifest in a variety of ways: pounding pain in the back of her head, exquisite sensitivity to the slightest sound, even blackouts and partial paralysis.

Irons, 48, of Coral Springs, Florida, once worked as a school assistant principal. Now, she’s on disability due to her migraine. Irons has tried so many migraine medications she’s lost count — but none has helped for long. Even a few of the much-touted new drugs that have quelled episodes for many people with migraine have failed for Irons.

Though not all are as impaired as Irons, migraine is a surprisingly common problem, affecting 14 percent to 15 percent of people. Yet scientists and physicians remain largely in the dark about how triggers like Irons’s lead to attacks. They have made progress nonetheless: The latest drugs, inhibitors of a body signaling molecule called CGRP, have been a blessing for many. For others, not so much. And it’s not clear why.

The complexity of migraine probably has something to do with it. “It’s a very diverse condition,” says Debbie Hay, a pharmacologist at the University of Otago in Dunedin, New Zealand. “There’s still huge debate as to what the causes are, what the consequences are.”

That’s true despite decades of research and the remarkable ability of scientists to trigger migraine attacks in the lab: Giving CGRP intravenously to people who get migraines gives some of them attacks. So do nitric oxide, a natural body molecule that relaxes blood vessels, and another signaling molecule called PACAP. In mice, too, CGRP and PACAP molecules can bring on migraine-like effects.

All these molecules act as “on” switches for migraine attacks, which suggests that there must be “off” switches out there too, says Amynah Pradhan, a neuroscientist at Washington University in St. Louis. Scientists have been actively seeking those “off” switches; the CGRP-blocking drugs were a major win in this line of research.

Despite the insights gleaned, migraine remains a tricky disease to understand and treat. For example, the steps between the molecular action of CGRP and a person experiencing a headache or other symptoms are still murky. But scientists have lots of other ideas for new drugs that might stave off migraine attacks, or stop ongoing ones.

“It’s important to have an expanded toolbox,” says Pradhan.

Deciphering migraine mechanisms

Migraine is the second most prevalent cause of disability in the world, affecting mainly women of childbearing age. A person may have one migraine attack per year, or several per week, or even ongoing symptoms.

Complicating the picture further, there’s not just one kind of migraine attack. Migraine can cause headache; nausea; sensitivity to light, sound or smell; or a panoply of other symptoms. Some people get visual auras; some don’t. Some women have migraine attacks associated with menstruation. Some people, particularly kids, have “abdominal migraine,” characterized not so much by headaches as by nausea, stomach pain and vomiting.

Initially, the throbbing nature of the head pain led researchers to suspect that the root problem was expansion of the blood vessels within the membranes surrounding the brain, with these vessels pulsing in time with the heartbeat. But, as it turns out, the throbbing doesn’t really match up with heart rate.

Then researchers noticed that many signs that presage migraine attack, such as light sensitivity and appetite changes, are all regulated by the brain, particularly a region called the hypothalamus. The pendulum swung toward suspicion of a within-brain origin.

Today, scientists wonder if both in-brain and beyond-brain factors, including blood vessels releasing pain-causing molecules, play a role, as may other contributors such as immune cells.

People may experience migraine in very different ways.

What all these proposed mechanisms ultimately point to, though, is pain created not in the brain itself but in the meninges — a multilayered “plastic bag around your brain,” as described by Messoud Ashina, a neurologist at the University of Copenhagen and director of the Human Migraine Research Unit at Rigshospitalet Glostrup in Denmark. These membranes contain cerebrospinal fluid that cushions the brain and holds it in place. They also support blood vessels and nerves that feed into the brain. The brain itself cannot feel pain, but nerves in the meninges, especially the trigeminal nerve between the face and brain, can. If they’re activated, they send the brain a major “ouch” message.

Physicians and pharmacists already possess a number of anti-migraine tools — some to prevent future attacks, others to treat an attack once it’s started. Options to stop a current migraine attack in its tracks include over-the-counter painkillers, such as aspirin and ibuprofen, or prescription opioids. Triptans, developed specifically to counter migraine attacks once they’ve begun, are drugs that tighten up blood vessels via interactions with serotonin receptors.

However, scientists later recognized that constricting blood vessels is not the main way triptans relieve migraine; their action to quiet nerve signals or inflammation may be more relevant. Ditans, a newer class of migraine drugs, also act on serotonin receptors but affect only nerves, not blood vessels, and they still work.

For migraine attack prevention, pre-CGRP-era tools still in use today include antidepressants, blood pressure medications, epilepsy drugs and injections of botulinum toxin that numb the pain-sensing nerves in the head and neck.

Most of these medicines, except triptans and ditans, weren’t designed specifically for migraine, and they often come with unpleasant side effects. It can take months for some preventive medicines to start working, and frequent use of triptans or painkillers can lead to another problem, the poorly understood “medication overuse headache.”

A powerful new player

The CGRP drugs provided a major expansion to the migraine pharmacopoeia, as they can both prevent attacks from happening and stop ones that have already started. They also mark the first time that clues from basic migraine research led to an “off” switch that prevents migraine attacks from even starting.

CGRP is a small snippet of protein made in various places in the body. A messenger molecule that normally clicks into another molecule, called a receptor, on a cell’s surface, CGRP can turn on activity in the receiving cell. It’s found in pain-sensing nerve fibers that run alongside meningeal blood vessels and in the trigeminal ganglia near the base of the skull where many nerves are rooted. The molecule is a powerful blood vessel dilator. It also acts on immune cells, nerve cells and the nerve-supporting cells called glia.

All of these features — a location in the meningeal nerve fibers with several actions that might be linked to migraine, like expanding blood vessels — pointed to CGRP being a migraine “on” switch. Further research also showed that CGRP is often found at higher levels in the body fluids of people who get migraines.

The CGRP receptors (blue) sit in the cell membrane (tan). On the cell’s exterior surface, CGRP (yellow) can bind to the receptor, kicking off signaling within the cell. But if an antibody (red) gets in the way, CGRP can’t reach its binding site on the receptor.

CREDIT: JUAN GAERTNER / SHUTTERSTOCK

In a small 2010 study, 12 out of 14 people with migraine did report a headache after receiving intravenous CGRP; four of them also experienced aura symptoms such as vision changes. Only two out of 11 people who don’t normally get migraine attacks also developed a headache after CGRP infusion.

CGRP also caused mice to be extra sensitive to light, suggesting it could have something to do with the light sensitivity in humans, too.

The steps between CGRP in the bloodstream or meninges as a trigger and migraine symptoms like light sensitivity aren’t fully understood, though scientists do have theories. Ashina is pursuing how CGRP, PACAP and other substances might trigger migraine attacks. These molecules all stick to receptors on the surface of cells, such as the ones in blood vessel walls. That binding kicks off a series of events inside the cell that includes generation of a substance called cyclic AMP and, ultimately, opening of channels that let potassium ions out of the cell. All that external potassium causes blood vessels to dilate — but it might also trigger nearby pain-sensing nerves, such as the trigeminal cluster, Ashina hypothesizes.

It’s a neat story, but far from proven. “We still don’t really know what CGRP does in the context of migraine,” says Greg Dussor, a neuroscientist at the University of Texas at Dallas.

In one possible model for migraine, various molecules can activate blood vessel cells to release potassium, which activates nearby neurons that send a pain signal to the brain. Various strategies that seek to interfere with this pathway, including the anti-CGRP drugs, are of great interest to migraine researchers.

Uncertainty about CGRP’s precise role in migraine hasn’t stopped progress in the clinic: There are now eight different blockers of CGRP, or its receptor, approved by the US Food and Drug Administration for migraine treatment or prevention. The American Headache Society recently released a statement saying that CGRP drugs should be considered first-line treatments for migraine. Despite CGRP’s widespread presence across the body, blocking it results in few and generally mild side effects, such as constipation.

“It’s a good drug,” says Dan Levy, a neurophysiologist at Beth Israel Deaconess Medical Center in Boston who recently described the role of the meninges in migraine for the Annual Review of Neuroscience.

Questions remain, though. One is whether, and how well, CGRP blockers work in men. Since three to four times as many women as men have migraine, the medicines were mostly tested in women. A recent review found that while CGRP blockers seem to prevent future headaches in both sexes, they haven’t been shown to stop acute migraine attacks in men as currently prescribed. (Notably, men made up less than a fifth of those included in the studies as a whole, making it more difficult to detect any low-level effects.)

More data may settle the question. Hsiangkuo Yuan, neurologist and director of clinical research at Thomas Jefferson University’s headache center in Philadelphia, says he’s been tracking effects of CGRP blockers in his patients, and hasn’t seen much difference between the sexes so far in terms of CGRP-blocking antibodies, though there may be a difference in how people respond to small molecules that block CGRP.

Access to CGRP inhibitors has also become an issue. Many insurers won’t pay for the new drugs until patients have tried and failed with a couple of other treatments first — which can take several months. This led Irons, the Florida patient, to try multiple medications that didn’t help her before she tried several CGRP blockers. In her case, one CGRP drug didn’t work at all; others worked for a time. But eventually they all failed.

Searching for new “off” switches

Her case illustrates the need for still more options to prevent or treat migraine attacks, even as the CGRP success story showed there’s hope for new medicines.

“CGRP has really paved the way,” says Andrew Russo, a neuroscientist at the University of Iowa in Iowa City who described CGRP as a new migraine target for the Annual Review of Pharmacology and Toxicology in 2015. “It’s a very exciting time for the field.”

Physicians have a number of therapies that can treat migraine — from familiar painkillers such as acetaminophen to the newer ditans and CGRP blockers. Yet, many patients still struggle to find consistent symptom relief, motivating scientists to continue to search for new medications.

Russo and Hay, of New Zealand, are interested in building on CGRP action with a potential novel therapy. It turns out CGRP doesn’t hit just one receptor on the surface of cells, like a key that matches only one lock. In addition to the traditional CGRP receptor, it also binds and activates the AMY_1 receptor — which itself can be activated by another molecule, amylin.

AMY_1 receptors are found at key sites for migraine pain, such as the trigeminal nerves. In a small study, Russo and Hay found that injecting a synthetic version of amylin creates migraine-like attacks in about 40 percent of people with migraine. The researchers also discovered that in mice, activating AMY_1 causes sensitivity to touch and light.

Again, that sounds like a migraine attack “on” switch, and Russo believes there’s a good chance that researchers can develop a drug that acts as an “off” switch.

Another promising “on” switch contender is PACAP. Like CGRP, it’s a small protein and signaling molecule. PACAP also appears in the trigeminal nerves that transmit migraine pain, and seems to be elevated in some people experiencing a migraine attack. In rodents, PACAP causes expansion of blood vessels, inflammation in the nervous system and hypersensitivity to touch and light. In a little over half of people with migraine, intravenous PACAP kicked off a fresh, migraine-like attack.

But, Russo says, “PACAP is more than just a CGRP wannabe.” It appears to work at least somewhat differently. In mice, antibodies that block PACAP do nothing against the light aversion activated by CGRP, and vice versa. That suggests that PACAP and CGRP could instigate two alternate pathways to a migraine attack, and some people might be prone to one or the other route. Thus, PACAP-blocking drugs might help people who don’t get relief from CGRP blockers.

Clinical research so far hints that anti-PACAP treatments indeed might help. In 2023, the Danish pharmaceutical company Lundbeck announced results of a trial in which they dosed 237 people with an antibody to PACAP. Those who received the highest dose had, on average, six fewer migraine days in the four weeks following the treatment than they did before receiving the medication, compared to a drop by only four days in people who received a placebo.

Then there’s Ashina’s work, which unites many of the “on”-switch clues to suggest that PACAP, CGRP and other molecules all act by triggering cyclic AMP, causing blood vessel cells to spew potassium. If that’s so, then drugs that act on cyclic AMP or potassium channels might serve as “on” or “off” switches for migraine attacks.

Ashina has tested that hypothesis with cilostazol, a blood vessel dilator used in people who have poor circulation in their legs. Cilostazol boosts production of cyclic AMP and, Ashina found, it caused attacks in a majority of people with migraine.

He also tried levcromakalim, another blood vessel opener that lowers blood pressure. It’s a potassium-channel opener, and this, too, caused migraine attacks for all 16 people in the study.

To Ashina, these experiments suggest that medicines that turn off migraine-inducing pathways at or before the point of potassium release could be of benefit. There might be side effects, such as changes in blood pressure, but Ashina notes there are potassium-channel subtypes that may be limited to blood vessels in the brain. Targeting those specific channels would be safer.

“I personally really like the potassium-channel track,” says Russo. “I think if we can find drugs targeting the ion channels, the potassium channels, that will be fruitful.”

Hopeful for opioids

Russo is also upbeat about work on a new kind of opioid. Traditional opioids, whether from poppies or pharmacies, work on a receptor called mu. Along with their remarkable pain-dulling abilities, they often create side effects including constipation and itching, plus euphoria and risk for addiction.

But there’s another class of opioid receptors, called delta receptors, that don’t cause euphoria, says Pradhan, who’s investigating them. When delta-targeting opioid molecules are offered to animals, the animals won’t self-administer the drugs as they do with mu-acting opioids such as morphine, suggesting that the drugs are less pleasurable and less likely to be habit-forming.

Delta receptors appear in parts of the nervous system linked to migraine, including the trigeminal ganglia. Pradhan has found that in mice, compounds acting on the delta opioid receptor seem to relieve hypersensitivity to touch, a marker for migraine-like symptoms, as well as brain activity associated with migraine aura.

Encouraged by early evidence that these receptors can be safely targeted in people, two companies — PharmNovo in Sweden and Pennsylvania-based Trevena — are pursuing alternative opioid treatments. Migraine is one potential use for such drugs.

Thus, the evolving story of migraine is one of many types of triggers, many types of attacks, many targets, and, with time, more potential treatments.

“I don’t think there’s one molecule that fits all,” says Levy. “Hopefully, in 10, 15 years, we’ll know, for a given person, what triggers it, and what can target that.”

Editor’s note: This story was updated on October 17, 2024, to correct the name of the University of Texas at Dallas.

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Amber Dance is a freelance science journalist in the Los Angeles area and a special contributor for Knowable Magazine.

HEALTH & DISEASE | VIEW ON WEBSITE

Why a diabetes drug fell short of anticancer hopes

Population and animal studies suggested it could treat cancer, but the clinical trials were a bust. Here’s what happened and what potential may remain.

By Amber Dance    10.09.2024

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Pamela Goodwin has received hundreds of emails from patients asking if they should take a cheap, readily available drug, metformin, to treat their cancer.

It’s a fair question: Metformin, commonly used to treat diabetes, has been investigated for treating a range of cancer types in thousands of studies on laboratory cells, animals and people. But Goodwin, an epidemiologist and medical oncologist treating breast cancer at the University of Toronto’s Mount Sinai Hospital, advises against it. No gold-standard trials have proved that metformin helps treat breast cancer — and her recent research suggests it doesn’t.

Metformin’s development was inspired by centuries of use of French lilac, or goat’s rue (Galega officinalis), for diabetes-like symptoms. In 1918, researchers discovered that a compound from the herb lowers blood sugar. Metformin, a chemical relative of that compound, has been a top type 2 diabetes treatment in the United States since it was approved in 1994. It’s cheap — less than a dollar per dose — and readily available, with few side effects. Today, more than 150 million people worldwide take the stuff.

The French lilac, Galega officinalis, has been used medicinally since medieval times, including for symptoms associated with diabetes. Investigations of the plant’s chemical galegine led to the development of metformin, a related molecule synthesized in the lab.

CREDIT: WIKIMEDIA COMMONS

Metformin has a variety of effects, such as improving immune function and the body’s responses to insulin, which in turn regulates blood sugar. It can also slow growth of cancer cells in the lab. Many of these benefits seem to stem from metformin’s action in the cell’s powerhouses, the mitochondria, where it slows the production of energy and limits the generation of damaging chemicals called free radicals.

Researchers have considered metformin for treating a plethora of conditions, from glaucoma to polycystic ovary syndrome to pimples. “It really has a reputation of being a potential wonder drug,” says Michael Pollak, an oncologist and researcher at McGill University in Montreal. “There’s still a lot of work to be done on metformin.” (Pollak consults for biotechnology companies interested in metformin analogs as medicines.)

But the latest research has convinced Pollak and some others that treatment of cancers should be taken off the list.

More studies, but no proof

One of the first hints linking metformin to anticancer effects came in a short note in the British Medical Journal in 2005. Researchers analyzed medical records of almost 12,000 people from the Tayside region of Scotland who were newly diagnosed with diabetes between 1993 and 2001. Of those, more than 900 went on to develop cancer. Interestingly, those who’d taken metformin at some point during the study period were 23 percent less likely to have received a later cancer diagnosis.

This finding fueled further research on people with diabetes taking metformin and the risk for breast cancer, liver cancer, ovarian and endometrial cancer, and other types. The authors of a 2013 analysis, covering more than 1 million patients in 41 observational studies like the original one, concluded that metformin “might be associated with a significant reduction in the risk of cancer.” But such associations are not proof.

Published studies on cancer and metformin have risen over the past two decades. (2024 data are incomplete.)

Researchers went on to explore the link in studies with cells in dishes and in lab animals, finding that metformin slowed growth of blood, breast, endometrial, lung, liver, stomach and thyroid cancer cells. It also seemed to make cancer cells extra sensitive to chemotherapy drugs. In one mouse study, scientists grafted human breast, prostate or lung cancer cells into the animals and treated them with either standard chemotherapy drugs, metformin, or a combination of both. The combination worked best, preventing tumor growth and prolonging relapse.

These findings made sense to researchers. Metformin treats metabolic problems in diabetes, and cancer has also been linked to metabolic issues such as obesity. Even before the 2005 British Medical Journal study, Goodwin had noticed that breast cancer patients with high insulin did worse than those with normal insulin levels.

That logic, plus the promising data, led scientists to conduct a number of randomized controlled trials — the gold-standard experiment in medicine. Researchers would enroll people with cancer and split them into two groups. One group would get standard cancer therapy plus metformin; the other group would get standard therapy plus a placebo, a pill containing no medication.

And metformin flopped, big time. While a number of studies are ongoing, trials for two types of cancer recently reported no benefit overall from metformin. In June 2024, at the American Society of Clinical Oncology meeting in Chicago, researchers reported a Canadian trial with 407 men with low-risk prostate cancer. The enrollees had been diagnosed within six months before starting the trial and had decided to monitor their cancer without starting immediate treatment. Half took metformin and half took a placebo. After biopsies at 18 and 36 months to test whether their disease had progressed, there was no difference between the two groups.

A larger British and Swiss trial including nearly 1,900 patients with newly diagnosed or relapsed prostate cancer that had spread to other body parts was reported at the European Society for Medical Oncology Congress in Barcelona, Spain, in September. This trial also found that metformin plus standard treatment, compared to standard treatment alone, did not improve overall prostate cancer survival in the study population.

A multinational study of breast cancer helmed by Goodwin also led to disappointment. The researchers enrolled more than 3,600 patients between 2010 and 2013; these patients had been diagnosed about a year before enrollment and had already undergone chemotherapy and surgery. In addition to standard cancer treatment, half received metformin and half received a placebo.

By 2016, it was clear that metformin wasn’t doing anything to enhance survival for about 1,100 participants with a particular cancer subtype. When the study wrapped in 2020, the researchers analyzed the rest of the patients, counting how many were alive and free of breast or any other form of cancer. Metformin made no difference in those results, or to survival overall, the team reported in 2022.

An important 2022 study found no benefit from taking metformin for breast cancer. This graphic describes the study’s design and main results.

Fatal flaws in the research

In retrospect, researchers think they know why earlier studies oversold metformin’s potential. Many of the studies that examined medical records had a crucial flaw, says Samy Suissa, a pharmacoepidemiologist at McGill.

Here’s what happens: Researchers sift through old medical records to see if someone ever took metformin. Then they compare cancer rates among people who took the drug at any point to those who never took it. But you have to be alive to take metformin. Anyone who died, of cancer or other causes, before having a chance at a metformin prescription is left out of the calculations. This skews the results; it’s called the “immortal time bias.” It makes any drug, metformin or otherwise, look like it helps patients to survive because it can only be taken by people who are alive, says Suissa.

Plus, scientists are more likely to publish studies that show metformin is promising than ones where it makes no difference, skewing the scientific literature.

As for those studies of cells in dishes and of lab animals, many experiments used much higher doses of metformin than are used in people. Too much metformin risks a buildup of lactate, a byproduct of low oxygen metabolism that acidifies the blood and can be fatal.

Researchers still suspect metformin might treat specific subgroups of cancer. For example, the authors of the prostate cancer trial presented in Barcelona suggested that metformin might help patients whose cancer has spread to other tissues or multiple sites in their bones. And Goodwin saw a hint in her trial that it might help women whose cancers contain a certain version of a cell-growth gene called ERBB2. But it would require another trial, focused on women with that particular cancer, to prove it.

And there are now better treatments for those patients than there were more than a decade ago when Goodwin started her study, reducing the opportunity to test metformin. Goodwin doesn’t currently have the funding to follow up on this theory.

It may also be that the clinical trials recruited patients with cancers that were too far along. “I always thought we were asking too much of metformin,” says Victoria Bae-Jump, a gynecological oncologist at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill. “Maybe it just needs to be earlier in the pathway of growth.” Bae-Jump is now testing metformin in women who have early-stage endometrial cancer or a precursor to it.

Others are investigating metformin for people who have precancerous lesions in their mouths. “The idea would be to keep them from progressing, or reverse the tissues to be more normal,” says Frank Ondrey, a head and neck cancer surgeon at the Masonic Cancer Center of the University of Minnesota in Minneapolis. In a small, uncontrolled study of 23 people, metformin halved lesion size in four of them. Ondrey is involved in two ongoing studies, one a randomized, controlled trial, to further test metformin in people with precancerous lesions; these should yield results within a few years.

Subdued expectations

Metformin is also being tested for other conditions such as dementia and a genetic disorder called fragile X syndrome. And perhaps the ultimate potential use for metformin is to slow aging itself. “I think it’s much easier to treat aging and prevent cancer than to treat cancer,” says Nir Barzilai, a geroscientist at Albert Einstein College of Medicine in New York and president of the nonprofit Academy for Health & Lifespan Research. Through its enhancement of insulin action and metabolism plus its minimization of free radical production, metformin influences all the key hallmarks of aging, such as problems with DNA, mitochondria and stem cells, says Barzilai.

He and colleagues are gathering funds for a randomized, controlled trial of metformin in 3,000 people age 65 through 79 who are showing signs of age-related disease already. The trial will test whether fewer people taking metformin die over six years. Barzilai, who is 68, says he is confident in metformin’s anti-aging ability and already takes the drug himself.

Others, mindful of what happened with cancer, are more circumspect. Pollak says that many of the studies in other areas of medicine are too small to prove metformin works, and Suissa notes that some of the studies finding benefits in populations taking metformin, including for longevity, have the same problems the oh-so-promising early cancer research did.

In short, Suissa says, “Don’t believe everything you hear.”

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Amber Dance is a freelance science journalist in the Los Angeles area and a special contributor for Knowable Magazine.

TECHNOLOGY | VIEW ON WEBSITE

Sustainable building effort reaches new heights with wooden skyscrapers

Wood engineered for strength and safety offers architects an alternative to carbon-intensive steel and concrete

By Kurt Kleiner    10.08.2024

Lea en español

At the University of Toronto, just across the street from the football stadium, workers are putting up a 14-story building with space for classrooms and faculty offices. What’s unusual is how they’re building it — by bolting together giant beams, columns and panels made of manufactured slabs of wood.

As each wood element is delivered by flatbed, a tall crane lifts it into place and holds it in position while workers attach it with metal connectors. In its half-finished state, the building resembles flat-pack furniture in the process of being assembled.

The tower uses a new technology called mass timber. In this kind of construction, massive, manufactured wood elements that can extend more than half the length of a football field replace steel beams and concrete. Though still relatively uncommon, it is growing in popularity and beginning to pop up in skylines around the world.

Mass timber can lend warmth and beauty to an interior. Pictured is a unit in the eight-story Carbon12 condominium in Portland, Oregon.

CREDIT: KAISER + PATH

Today, the tallest mass timber building is the 25-story Ascent skyscraper in Milwaukee, completed in 2022. As of that year, there were 84 mass timber buildings eight stories or higher either built or under construction worldwide, with another 55 proposed. Seventy percent of the existing and future buildings were in Europe, about 20 percent in North America and the rest in Australia and Asia, according to a report from the Council on Tall Buildings and Urban Habitat. When you include smaller buildings, at least 1,700 mass timber buildings had been constructed in the United States alone as of 2023.

Mass timber is an appealing alternative to energy-intensive concrete and steel, which together account for almost 15 percent of global carbon dioxide emissions. Though experts are still debating mass timber’s role in fighting climate change, many are betting it’s better for the environment than current approaches to construction. It relies on wood, after all, a renewable resource.

Mass timber also offers a different aesthetic that can make a building feel special. “People get sick and tired of steel and concrete,” says Ted Kesik, a building scientist at the University of Toronto’s Mass Timber Institute, which promotes mass timber research and development. With its warm, soothing appearance and natural variations, timber can be more visually pleasing. “People actually enjoy looking at wood.”

Same wood, stronger structure

Using wood for big buildings isn’t new, of course. Industrialization in the 18th and 19th centuries led to a demand for large factories and warehouses, which were often “brick and beam” construction — a frame of heavy wooden beams supporting exterior brick walls.

As buildings became ever taller, though, builders turned to concrete and steel for support. Wood construction became mostly limited to houses and other small buildings made from the standard-sized “dimensional” lumber you see stacked at Home Depot.

But about 30 years ago, builders in Germany and Austria began experimenting with techniques for making massive wood elements out of this readily available lumber. They used nails, dowels and glue to combine smaller pieces of wood into big, strong and solid masses that don’t require cutting down large old-growth trees.

Engineers including Julius Natterer, a German engineer based in Switzerland, pioneered new methods for building with the materials. And architects including Austria’s Hermann Kaufmann began gaining attention for mass timber projects, including the Ölzbündt apartments in Austria, completed in 1997, and Brock Commons, an 18-story student residence at the University of British Columbia, completed in 2017.

In principle, mass timber is like plywood but on a much larger scale: The smaller pieces are layered and glued together under pressure in large specialized presses. Today, beams up to 50 meters long, usually made of what’s called glue-laminated timber, or glulam, can replace steel elements. Panels up to 50 centimeters thick, typically cross-laminated timber, or CLT, replace concrete for walls and floors.

These wood composites can be surprisingly strong — stronger than steel by weight. But a mass timber element must be bulkier to achieve that same strength. As a building gets higher, the wooden supports must get thicker; at some point, they simply take up too much space. So for taller mass timber buildings, including the Ascent skyscraper, architects often turn to a combination of wood, steel and concrete.

Historically, one of the most obvious concerns with using mass timber for tall buildings was fire safety. Until recently, many building codes limited wood construction to low-rise buildings.

Though they don’t have to be completely fireproof, buildings need to resist collapse long enough to give firefighters a chance to bring the flames under control, and for occupants to get out. Materials used in conventional skyscrapers, for instance, are required to maintain their integrity in a fire for three hours or more.

To demonstrate mass timber’s fire resistance, engineers put the wood elements in gas-fired chambers and monitor their integrity. Other tests set fire to mock-ups of mass timber buildings and record the results.

These tests have gradually convinced regulators and customers that mass timber can resist burning long enough to be fire safe. That’s partly because a layer of char tends to form early on the outside of the timber, insulating the interior from much of the fire’s heat.

Mass timber got a major stamp of approval in 2021, when the International Code Council changed the International Building Code, which serves as a model for jurisdictions around the world, to allow mass timber construction up to 18 stories tall. With this change, more and more localities are expected to update their codes to routinely allow tall mass timber buildings, rather than requiring them to get special approvals.

There are other challenges, though. “Moisture is the real problem, not fire,” says Steffen Lehmann, an architect and scholar of urban sustainability at the University of Nevada, Las Vegas.

All buildings must control moisture, but it’s absolutely crucial for mass timber. Wet wood is vulnerable to deterioration from fungus and insects like termites. Builders are careful to prevent the wood from getting wet during transportation and construction, and they deploy a comprehensive moisture management plan, including designing heat and ventilation systems to keep moisture from accumulating. For extra protection from insects, wood can be treated with chemical pesticides or surrounded by mesh or other physical barriers where it meets the ground.

Another problem is acoustics, since wood transmits sound so well. Designers use sound insulation materials, leave space between walls and install raised floors, among other methods.

Potential upsides of mass timber

Combating global warming means reducing greenhouse gas emissions from the building sector, which is responsible for 39 percent of emissions globally. Diana Ürge-Vorsatz, an environmental scientist at the Central European University in Vienna, says mass timber and other bio-based materials could be an important part of that effort.

In a 2020 paper in the Annual Review of Environment and Resources, she and colleagues cite an estimate from the lumber industry that the 18-story Brock Commons, in British Columbia, avoided the equivalent of 2,432 metric tons of CO_2 emissions compared with a similar building of concrete and steel. Of those savings, 679 tons came from the fact that less greenhouse gas emissions are generated in the manufacture of wood versus concrete and steel. Another 1,753 metric tons of CO_2 equivalent were locked away in the building’s wood.

“If you use bio-based material, we have a double win,” Ürge-Vorsatz says.

Like Ikea furniture, mass timber buildings are assembled out of prefabricated pieces. The Origine condo in Quebec City went up an estimated 25 percent faster than a conventional building.

CREDIT: CECOBOIS

But a lot of the current enthusiasm over mass timber’s climate benefits is based on some big assumptions. The accounting often assumes, for instance, that any wood used in a mass timber building will be replaced by the growth of new trees, and that those new trees will take the same amount of CO_2 out of the atmosphere across time. But if old-growth trees are replaced with new tree plantations, the new trees may never reach the same size as the original trees, some environmental groups argue. There are also concerns that increasing demand for wood could lead to more deforestation and less land for food production.

Studies also tend to assume that once the wood is in a building, the carbon is locked up for good. But not all the wood from a felled tree ends up in the finished product. Branches, roots and lumber mill waste may decompose or get burned. And when the building is torn down, if the wood ends up in a landfill, the carbon can find its way out in the form of methane and other emissions.

“A lot of architects are scratching their heads,” says Stephanie Carlisle, an architect and environmental researcher at the nonprofit Carbon Leadership Forum, wondering whether mass timber always has a net benefit. “Is that real?” She believes climate benefits do exist. But she says understanding the extent of those benefits will require more research.

In the meantime, mass timber is at the forefront of a whole different model of construction called integrated design. In traditional construction, an architect designs a building first and then multiple firms are hired to handle different parts of the construction, from laying the foundation, to building the frame, to installing the ventilation system and so on.

In integrated design, says Kesik, the design phase is much more detailed and involves the various firms from the beginning. The way different components will fit and work together is figured out in advance. Exact sizes and shapes of elements are predetermined, and holes can even be pre-drilled for attachment points. That means many of the components can be manufactured off-site, often with advanced computer-controlled machinery.

A lot of architects like this because it gives them more control over the building elements. And because so much of the work is done in advance, the buildings tend to go up faster on-site — up to 40 percent faster than other buildings, Lehmann says.

Mass timber buildings tend to be manufactured more like automobiles, Kesik says, with all the separate pieces shipped to a final location for assembly. “When the mass timber building shows up on-site, it’s really just like an oversized piece of Ikea furniture,” he says. “Everything sort of goes together.”

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Kurt Kleiner is a freelance writer living in Toronto.

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Are you my baby? The clever ways that brood parasites trick other birds

Cuckoos, cowbirds and other species outsource their parental duties. Scientists are uncovering new twists in this sneaky — and often treacherous — game of survival.

By Sofia Quaglia    10.02.2024

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Parenting can be lots of work for a bird: all that flying back and forth transporting grubs and insects to a nest of demanding young. But some birds manage to forgo caring for their chicks — while still ensuring they’re well looked after. These birds lay their eggs in the nests of other birds that unknowingly adopt the hatchlings, nourishing and protecting them as their own.

Only about 1 percent of all bird species resort to this sneaky family planning method, called obligate brood parasitism, but it has evolved at least seven separate times in the history of birds and is a way of life for at least 100 species. Since some brood parasites rely on several different bird species as foster parents, more than a sixth of all species in the avian world care for chicks that aren’t their own at some point.

Throughout the millennia, these trespassers have evolved ingenious ways to fool the hosts, and the hosts have developed equally clever ways to protect themselves and their own. At each stage of the nesting cycle, it’s a game of subterfuge that plays out in color, sound and behavior.

“There’s always something new — it’s like, ‘Oh, man, this group of birds went down a slightly different pathway,’” says behavioral ecologist Bruce Lyon of the University of California, Santa Cruz, who studies the black-headed duck (Heteronetta atricapilla), the sole obligate parasitic duck species.

While many mysteries remain, new research is constantly unearthing just how intense this evolutionary tug-of-war can get.

Some brood parasites have evolved to look like predators, which can scare a potential host bird, prompting it to fly off and leave the nest open to intruders. The plumage of this parasitic common cuckoo (left) bears a striking resemblance to the Eurasian sparrowhawk (right), a predator of woodland birds.

CREDITS: TOM MURRAY (LEFT), TAT’YANA VYSOTSKAYA (RIGHT) / iNATURALIST

From mimicry to murder

Breaching another bird’s nest is the parasite’s first move. Sometimes this is accomplished via deception: The female cuckoo-finch (Anomalospiza imberbis), for example, has evolved to look like a harmless, non-parasitic bird that lives in the same area, allowing it to sneak into host nests unchallenged. The common cuckoo (Cuculus canorus) takes another tack — it has evolved to mimic the look of a predatory raptor, prompting host mothers to fly off in fear and leave their nest unattended.

But sometimes, parasites get to the party too late and they don’t find nests into which they can plop their eggs; the eggs are almost ready to crack open, or everybody’s already hatched. In this case, they may fling out chirping chicks and sometimes will ransack the nest. This can prompt the hosts to make new nests from scratch, giving the intruder a brand-new nest to parasitize.

Scientists had some evidence of this strategy — called farming, because the parasites “farm” new nests — but recently, they caught birds in the murderous act and watched them parasitize the new nest as well.

Ornithologist Jinggang Zhang was running a long-term study with Daurian redstarts (Phoenicurus auroreus) in northeastern China. In one nestbox, two Daurian redstarts were caring for a family of seven, and when the chicks were just 5 days old, a common cuckoo showed up and, in less than a minute, plucked all of the newborns and chucked them to their deaths. “I was surprised and confused,” says Zhang. Two days later, the resilient redstart parents made themselves a new nest about 15 feet from the murder scene, and the cuckoo laid one of its eggs inside it. It’s the first time that farming of nestlings had been documented on camera, says Zhang, who recently reported the event in Ecology and Evolution.

Host birds, of course, have evolved strategies to defend their nest and brood. Some sit tight and guard their nests, others may attack the intruder — yellow warblers even have a unique bird call that warns nearby birds of a parasite in the neighborhood.

American robins are exceptionally good at knowing their own eggs — and will get rid of eggs that don’t belong, a defensive tactic seen in this short video.

CREDIT: ANALÍA V. LÓPEZ

And some hosts may try to totally preempt any parasitism risk. Behavioral ecologist Iliana Medina Guzman of the University of Melbourne theorizes that pressure from parasites has led some hosts, like the yellow-rumped thornbill (Acanthiza chrysorrhoa), to breed earlier than many of their peers, thus avoiding breeding at the same time as their parasite.

Breeding earlier, says Zhang, might also have spurred the evolution of farming — as a counterstrategy to finding nests already full.

Mimicking eggs and spotting imposters

When a parasite makes it into another family’s nest, it usually will nudge out one or two of the host’s eggs to make space for its own. And while nonparasitic birds take about 20 minutes to lay an egg, parasites like cuckoos and honeyguides are fast. “They swoop into the nest and they squeeze out an egg in three seconds flat,” says Rosalyn Gloag, an evolutionary biologist from the University of Sydney. Some parasites have also evolved thicker-shelled eggs that are less likely to crack when hastily dropped.

And there are parasites that go the extra mile to ensure their eggs aren’t detected and rejected: They mimic the look of the eggs of their hosts. In some birds, such as cuckoo finches, this egg coloration trait is passed from mothers to daughters: Female cuckoo finches mimic the eggs that their mother mimicked. So some cuckoo finches lay blue eggs mottled with brown, while another may specialize in eggs with red speckles, depending on which host nest they grew up in.

Still, these tricks don’t always work, says ornithologist Mark Hauber of the Graduate Center of the City University of New York. He has long been researching what makes some birds better than others at recognizing intruders’ eggs, and his data suggest that some hosts can eject eggs that are off in terms of color and size.

Other hosts, like weaver finches and warblers, have perfected laying eggs speckled with signature colors, patterns and squiggles that seem to be impossible to mimic and are easier to tell apart from the intruders’.

“There’s something about the markings, the entropy of the spotting, that is more consistent within the host’s own egg,” says Hauber. It’s so precise that he hasn’t been able to replicate the patterns in his lab despite making hundreds of artificially speckled eggs.

The eggs of a brood parasite often look nothing like the eggs of its host bird, as seen here with the speckled cowbird eggs among the blue eggs of an American robin (left). But the cowbird eggs are harder to distinguish from that of the Eastern Meadowlark (right) another host species.

CREDITS: MARK HAUBER (LEFT), SARAH K. WINNICKI (RIGHT)

New research by Hauber suggests that older birds with more breeding experience are better than younger birds at telling foreign eggs from their own. Hauber introduced fake, 3D-printed eggs into the nests of American robins (Turdus migratorius); the eggs were painted robin blue or the beiges and browns of a parasitic cowbird’s egg. Monitoring the robins revealed that hosts can learn and become better at rejecting intruder eggs from their nests, Hauber and colleagues reported in 2023.

Outgrowing, or outlasting, the competition

Once the eggs are safely in the nest, many parasites hatch earlier than their foster siblings, giving the invaders a head start.

Australian bronze cuckoos, for instance, hatch two days earlier and emerge looking just like their nestmates (had the latter not been shoved out of the nest as eggs). They barely arouse suspicion.

But most bird species don’t need to fool their new guardians with subtle looks. The primary way that birds recognize their young is just “Is it my nest?” Gloag says. “We’re like, ‘How can those parents not recognize that that chick is not their own chick? It’s five times the size of them!’”

Intruder chicks also trick their parents into feeding them more than their siblings — that’s how they get the real advantage. In a nest where everybody is related, there is a benefit to everyone surviving — shared genes mean that individuals aren’t incentivized to be as greedy, says Gloag. It’s different for parasites sharing a nest with total strangers.

And for a wide range of other bird species, faking being really hungry, and crying and begging a lot, does the job, says ornithologist Rafaela Vitti Ferneda, a master’s student at São Paulo State University in Brazil.

Ferneda spent two years investigating whether pale-breasted thrushes (Turdus leucomelas) realize they are feeding intruding nestlings of shiny cowbirds (Molothrus bonariensis). Deep down, she expected that the parents could recognize their own chicks. But she was surprised when it didn’t look like it. The parasitic cowbirds were fed more quickly and more frequently than the thrushes, and the thrushes didn’t even try to keep up with the intruders’ level of begging, Ferneda reported in June 2024. That cowbird melodrama — extra squawking, begging and tilting of the head — may be what allows it to parasitize a wide variety of host species without specialized looks or sounds, Ferneda says.

Terrible though brood parasitism may sound, it is not a calamity for the exploited species. “A parasite will be really annoying and it might destroy a reproductive attempt,” says William Feeney, a behavioral ecologist at Doñana Biological Station in Spain and coauthor of a look at coevolution between parasites and their hosts in the Annual Review of Ecology, Evolution, and Systematics. “But birds typically have more than one of them in their lives.”

The relationship between cowbirds and thrushes, honeyguides and swallows, or cuckoos and their various and diverse hosts is one of constant change. Parasites and hosts are waging a war through evolutionary time, such that what scientists see now is just a snapshot in a longstanding battle. And somewhere in there, the birds are finding balance: tactical tradeoffs that allow both parasite and host to persist.

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Sofia Quaglia is a freelance journalist writing about all things science and nature, and how we talk about them. Her work regularly appears in New Scientist, the Guardian, the New York Times, BBC, National Geographic and more.

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We are family: Tracing the evolution of animals

To understand the origins of multicelled life, researchers are studying a motley assortment of simpler animal relatives. The commonalities they’re unearthing offer a trove of clues about our mutual past.

By Amber Dance    09.30.2024

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Once upon a time, there were a bunch of one-celled microbes, swimming, eating, reproducing, doing all the things that a one-cell bit of life can do.

Then, some time later, there were their descendants, the early animals: multicelled creatures, still swimming, eating, reproducing, but doing it all as teams of cells.

Exactly what happened between those points is a nigh-unfathomable mystery. But that in no way stops scientists from wondering and hypothesizing and investigating how the transition, about 600 million years ago, might have gone down.

The question is an old one, but researchers have made great progress in the past two decades, thanks to the genetic sequencing of single-celled life forms that are animals’ closest kin. It turns out that the unicellular ancestors of animals, way back then, were already remarkably well-equipped to take on teamwork. They probably could adopt a variety of cell shapes and do a number of jobs that came in handy for multicellularity. In fact, they might even have acted as groups, rather than single cells, from time to time.

“They were experimenting with multicellularity,” says Iñaki Ruiz-Trillo, an evolutionary biologist at the Institute of Evolutionary Biology in Barcelona, Spain.

And at some point, that experiment became permanent.

Advantages of upsizing

It was an experiment more than 3 billion years in the making. The earliest living cells appeared about 3.5 billion years ago, and some of them took a big step on the route to animals approximately 2 billion years ago when they added a nucleus in which to store their DNA. These nucleated microbes spawned complex, multicellular lineages several times during evolutionary history, creating fungi, plants and algae. They also gave rise to animals some 600 million or so years ago.

The vast majority of living things have held to a unicellular lifestyle for billions of years, with excellent evolutionary success, so cellular teamwork is hardly guaranteed to arise and far from certain to provide a superior lifestyle. “Multicellularity takes time and energy and resources to develop,” says Thibaut Brunet, an evolutionary cell biologist at the Institut Pasteur in Paris. But for those life forms that made the leap and made it stick, multicellularity presumably offered advantages that outweighed the costs.

This evolutionary tree shows Metazoa, the group that includes most animals, along with four unicellular cousins and the Holomycota, which includes fungi, as an outgroup for comparison.

CREDIT: ADAPTED FROM IÑAKI RUIZ-TRILLO

Size, for one, was probably a factor. Being big means there are more things you can eat, and fewer things that can eat you. Multicellularity also allows you to have different parts that do different things at the same time: nerves to think, muscles to move, a stomach to digest food, and so on.

Researchers speculate that something major must have happened in the world to make teaming up such a good deal. “It must be environmental, to a large degree,” says Will Ratcliff, an evolutionary biologist at Georgia Tech in Atlanta. Two major kinds of Earthly changes stand out as possibilities.

One is the end of the Snowball Earth phase of the planet. This was an age, from roughly 710 to 640 million years ago, with at least two periods when the Earth was, if not wholly icy, at least pretty slushy. A warming climate might have somehow created an opportunity for multicellularity to evolve, Ruiz-Trillo suggests.

Building Bodies

Building a multicellular body with all its different organs and systems took a lot of evolutionary wrangling. A body like our own needs a front and back, an up and down, a left and right — and then rules for constructing and positioning the right number of heads, organs, intestines and so much more. Read our special report on how these decisions get made.

Another possibility is changes to Earth’s oxygen levels. These were initially much lower than today; early microbes did not require oxygen as modern animals do. The first time the planet’s oxygen supply swelled, during the Great Oxygenation Event about 2.4 billion years ago, was when cyanobacteria released oxygen as part of their photosynthesis. To the microbes of the time, the highly reactive gas was poison, and it decimated life forms. A second oxygenation event, of less certain causation, happened between about 850 and 540 million years ago, and this one may have set the stage for the emergence of animals.

Oxygen levels matter to large creatures that need oxygen, Ratcliff says, because the vital gas can diffuse only so far into tissues. For modern animals, the solution is circulatory systems that deliver oxygen through the body. The first big multicellular things, presumably, had not yet evolved such systems. The more oxygen there was on the outside, the more of it could diffuse deep into tissues, and the easier it would be to grow big.

Whatever pressures or opportunities induced our ancestor to commit to multicellularity, it did take that route — but who was “it”? That remains a mystery: Its cells were soft, squishy things that didn’t leave many fossils. “We don’t know what it looked like, and I don’t honestly think we ever will,” says Ratcliff. “It’s very difficult to try to reverse-engineer something that happened the better part of a billion years ago.”

Great-great-grandmama was a one-cell wonder

Still, researchers are trying. To hypothesize what the creatures might have been like, scientists like Ruiz-Trillo take a family-reunion kind of approach: Say you held a giant gathering, inviting all your cousins, second cousins, once-removeds, etc. Then, suppose you lined up all the relatives who share a common ancestor — say, the same great-great-great-grandmother — and looked for common features. If all those cousins have freckles and dimples, say, you could guess that great-great-great-grandmama, too, probably had them.

Scientists do similar studies, albeit of a more technical nature, comparing the genomes of animals with those of our very distant cousins. This is a strange family reunion indeed: In addition to the vast diversity of animals, including some of the earliest groups to branch off the animal family tree, the sponges and comb jellies, scientists know of four sets of one-celled cousins.

Most closely related to animals are the choanoflagellates. Found in fresh and salty waterways, they use whiplike tails called flagella to swim around or to waft bacteria toward them for supper. Rounding out the family reunion are the amoebalike or flagellated filastereans, the ichthyosporeans that often parasitize fish, and the amoeboid or immobile corallochytreans (also known as pluriformeans).

The choanoflagellate Choanoeca flexa can group together into colonies, with the tail structures either pointing in or out. The colonies switch to the tail-out shape in response to sudden darkness. These relatives of multicellular animals were discovered in splash pools on the Caribbean island of Curaçao and were christened “flexa” for the bendy sheet-like structures they formed.

CREDIT: THIBAUT BRUNET

None of these things, as they exist today, are the ancestor of animals. Rather, our lineage and theirs all split off from some common ancestor around 600 million years ago, and we’ve all evolved since then. But certain trait similarities between us and them suggest that our long-lost ancestor may have had those traits too.

Over the last decade, scientists have sequenced the genomes of 15 of those distant relatives. And therein lay surprises. These single-cell oddities contain almost as many genes as people, says Brunet, including DNA codes once thought to be animal exclusives. The critters have genes related to ones that make integrins and cadherins, proteins that help animal cells stick to each other. They have genes for control agents that guide cell identity, akin to the factors that tell an animal cell to be a brain cell or a muscle cell or a stomach cell. And they have genes involved in cell-to-cell communication.

In other words, these critters seem to be pre-adapted for multicellularity, and therefore our shared ancestor probably was too. But what would a unicellular pre-animal, all by its lonesome, have been doing with these kinds of genes?

In one-celled life forms, proteins like cadherins could have been useful because they are adhesive. “I compare them to Velcro,” says Jordi Paps, an evolutionary biologist at the University of Bristol, England. For a unicellular being, adhesive molecules could be a great way to capture passing bacteria for dinner.

Genes that govern cell identity may have helped the single-celled ancestors of animals take different forms at different times. All four close cousins of animals do this. Filastereans, for example, can adopt an amoeba-like shape, with long arms, that can divide into daughter cells, but they can also take on an armless, nondividing form.

Capsaspora owczarzaki is a filasterean originally found inside a freshwater snail in Puerto Rico. It can take on multiple shapes, including an amoeba-like form with fingerlike projections it uses to attach to surfaces.

CREDIT: MULTICELLGENOME LAB

Finally, all four close cousins of animals have times in their lives when they flirt with multicellularity. Some choanoflagellates can make colonies by not fully separating from each other when they divide. At least one filasterean can aggregate once-separated cells. Corallochytreans live with two or so nuclei for a least a little while, while ichthyosporeans divide repeatedly to make a big ball of dozens or hundreds of nuclei before suddenly exploding into separate entities. That suggests the animal precursor, too, may have transiently grouped cells together. It’s not certain why this was beneficial; scientists speculate that the cells might have gained protection by acting in a herd, or traveled or hunted en masse.

Ruiz-Trillo and colleagues suggest the single-celled pre-animal was undergoing serious makeovers during its life cycle. Maybe sometimes it was like an amoeba, able to crawl around seeking food, and maybe other times it grew a flagellum to swim. Perhaps it sometimes survived alone, and other times grouped cells together.

But at any given time, our one-cell cousins can hold only one form, and scientists expect that was probably true of the pre-animal ancestor too. If it was dividing, it probably wouldn’t be able to swim, or to eat, says Brunet. It had to pick. What this means is that even in a single-celled creature, division of labor could have existed and conferred a benefit — but it was managed over time, not space.

Corallochytrium limacisporum exist as single cells with one or more nuclei. This free-living species was first discovered in lagoons of islands in the Arabian Sea.

CREDIT: MULTICELLGENOME LAB / FLICKR

Scientists think a trick to multicellularity was to repurpose the genes that were responsible for those temporal changes to work across space instead, controlling the shapes and jobs that cells do in different body parts. Such gene recycling, or “co-option,” has happened again and again during evolution. Beetles, for example, create their horns with genes co-opted from the genesis of other appendages, such as legs and antennae. Similarly, fish fins for swimming were co-opted so animals could walk on land, and leaves for photosynthesis were co-opted by cacti as spiny defenses. Same genes, different functions.

Acting like animals

To further investigate the multicelled mystery, a key step is to move beyond genetic comparisons and examine the biology of the one-celled kin of animals, says Omaya Dudin, an evolutionary cell biologist at the University of Geneva. Exploring ichthyosporeans, his group found striking similarities to animal development. When ichthyosporeans create their big balls of nuclei and then separate them, the cells divide in a way that looks a lot like cells dividing in an early animal embryo (like an insect embryo in one species, like a frog or mouse embryo in another).

That doesn’t necessarily mean the shared ancestor of bugs, mammals and ichthyosporeans also performed embryo-like cell division, Dudin says. It could be that the common ancestor just had enough of the necessary genes and abilities for their descendants to evolve remarkably similar division processes.

Still, it does mean that even something that seems very animal-specific, like embryonic division, isn’t necessarily animal-unique.

Ichthyosporeans generate structures with many nuclei before separating into individual cells. This species, Sphaeroforma arctica, was found in an Arctic crustacean.

CREDIT: MULTICELLGENOME LAB / FLICKR

In fact, even having multiple cell types at the same time might not be an exclusively animal feature. Observing the multi-nucleate balls of the ichthyosporean Chromosphaera perkinsii, Dudin’s team noted something surprising: There were two kinds of cells, one with flagella and one without. Researchers have also spotted evidence of multiple cell types — most round, but some oblong — in choanoflagellate colonies. That suggests, just maybe, that the precursor of animals might have had moments not just of multicellularity but also of division of cellular labor.

Altogether, it seems clear that our unicellular ancestors were ready for multicellularity. While the act of simply teaming up could have happened quickly, “there was probably a lot of complexity to the origin of animals,” says Brunet. “The full extent of animal multicellular complexity certainly arose over thousands, and most probably millions, of years.”

There are still plenty of details for scientists to iron out: Did the pre-animal look like choanoflagellates, as one popular theory attests, or perhaps adopt a variety of forms at different times? Were the first animals like sponges, as traditionally presumed, or maybe more like comb jellies?

Ruiz-Trillo, who coauthored a look at the roots of multicellularity in the 2023 Annual Review of Microbiology, refuses to name a favorite hypothesis: “I think we don’t have enough data to say,” he says.

To get more data, he’ll have to invite more creatures to the family reunion. And he is busy doing just that, seeking as yet unknown microbes from aquatic sites around the world. So far, he’s identified at least eight new groups of animal cousins by analyzing their genes alone. If scientists can find, grow and study these creatures, they’ll likely find new clues to the origin of multicellular animal-kind.

It should be quite a party.

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Knowable Magazine contributor Amber Dance comes from a long line of multicellular life forms.

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Hummingbirds thrive on an extreme lifestyle. Here’s how.

Soldiering through nightly suspended animation, a (nearly) all-sugar diet, backwards flight and long migrations, the birds’ tiny physiques prove mighty

By Bob Holmes    09.25.2024

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Everyone loves to watch hummingbirds — tiny, brightly colored blurs that dart about, hovering at flowers and pugnaciously defending their ownership of a feeder.

But to the scientists who study them, hummingbirds offer much more than an entertaining spectacle. Their small size and blazing metabolism mean they live life on a knife-edge, sometimes needing to shut down their bodies almost completely just to conserve enough energy to survive the night — or to migrate thousands of miles, at times across open ocean.

Their nectar-rich diet leads to blood-sugar levels that would put a person in a coma. And their zipping, zooming flight sometimes generates g-forces high enough to make a fighter pilot black out. The more researchers look, the more surprises lurk within those tiny bodies, the smallest in the avian world.

“They’re the only bird in the world that can fly upside down and backwards,” says Holly Ernest, a conservation ecologist with the University of Wyoming. “They drink pure sugar and don’t die of diabetes.”

Ernest is one of a small number of researchers studying how hummingbirds cope with the extreme demands of their lifestyles. Here’s some of what scientists have learned about the unique adaptations of hummingbirds.

Put in the work

For years, most researchers had assumed that hummingbirds spent only about 30 percent of their day engaged in the energy-intensive business of flitting from flower to flower and guzzling nectar, while resting most of the other time. But when physiological ecologist Anusha Shankar looked closely, she found they’re often working a lot harder than that.

Shankar, now of the Tata Institute of Fundamental Research in Hyderabad, India, tried to figure out how broad-billed hummingbirds in Southern Arizona spend their days. Using a mix of experimental methods, she measured the birds’ metabolic rate during various activities and estimated their total daily energy expenditure. Adding in previous published data, Shankar was able to calculate the per-minute energy cost of perching, flying and hovering — basically a bird’s three options for spending time.

She then inferred how much time the birds must have spent feeding versus perching over the course of a day.

“We ended up finding that it’s super variable,” Shankar says. During the early part of the summer when flowers are abundant, birds could meet their daily energy needs with as little as a few hours of feeding, spending as much as 70 percent of the day just perching, she found. But when flowers became scarcer after the arrival of the summer monsoon rains, birds at one site perched just 20 percent of the time and used the rest of the day for feeding.

“That’s 13 hours a day!” Shankar says. “There’s no way I can spend 13 hours a day running. I don’t know how they do it.”

Seriously chill

Hummingbirds have a trick to help them eke out their energy reserves: When a bird is in danger of running out of energy, it may go torpid at night, dropping its body temperature nearly to that of the surrounding air — sometimes just a few degrees above freezing. While in torpor, the bird appears almost comatose, unable to respond quickly to stimuli, and breathing only intermittently. The strategy can save up to 95 percent of hourly metabolic costs during cold nights, Shankar has calculated. That can be essential after days when a bird has fed less than usual, such as after a thunderstorm. It also helps birds save energy to pack on fat before migration.

Shankar is now studying which parts of their physiology hummingbirds prioritize during torpor, by looking to see which gene products they can’t do without. “If you’re a hummingbird functioning at 10 percent of your normal metabolism, what is that 10 percent that’s keeping you alive?” she asks.

Many hummingbirds, such as this one, can enter a state of torpor, a form of hibernation in which they let their body temperature drop to near that of the air. Torpor saves the birds energy — especially important at night — but arousing from it can take many minutes and leave the birds vulnerable.

CREDIT: KELLYPLZ / POND5

One set of genes that the birds seem to leave untouched are those responsible for their internal clock. “It’s important for them to do things at the right time when they’re in torpor,” Shankar says. To be ready to meet the day, for example, the birds begin to rouse from their torpor about an hour before sunrise, well before visible light cues.

Deal with the sugar

To fuel their sky-high metabolic rate, hummingbirds suck down about 80 percent of their body weight in nectar each day. That’s the equivalent of a 150-pound person drinking nearly a hundred 20-ounce Cokes daily — and nectar is often much sweeter than a soda.

The human gut is incapable of absorbing sugar that fast, which is one reason why consuming too much soda or Halloween candy upsets the stomach, says Ken Welch, a comparative physiologist at the University of Toronto at Scarborough. Hummingbirds cope with the onslaught by having leaky guts so that sugars can enter the bloodstream between gut cells instead of only through them. This gets sugar out of the gut quickly, before it can cause upset. That rapid transport, and probably other adaptations as well, allows hummingbirds to reach blood sugar levels as much as six times higher than those seen in people, Welch says.

That much sugar in the blood leads to serious physiological problems in people. It causes more sugar molecules to glom onto body proteins, a process known as glycation; in the long run, excess glycation causes many of the complications of diabetes, such as nerve damage. It’s still unclear how hummingbirds avoid the problems of glycation, Welch says, but clues are beginning to emerge. One study, for example, found that bird proteins contain fewer of the amino acids most prone to glycation than mammal proteins, and those that remain are often tucked deep within the protein where they’re less exposed to circulating sugars.

CREDIT: TOM SIEGFRIED

Help for hummingbirds

Even as biologists learn more about the physiological antics of hummingbirds, populations are declining throughout the Americas. (The Anna’s hummingbird common in western North America is one exception.) “All of the researchers are very, very worried,” says conservation ecologist Holly Ernest, with the University of Wyoming, who coauthored a look at the conservation status of hummingbirds in the 2024 Annual Review of Animal Biosciences. “They were worried five or 10 years ago, and these last couple of years they’re extremely worried.”

To help support hummingbird populations, Ernest encourages people to plant hummingbird-friendly flowers, be cautious about pesticide use, and take precautions to keep hummingbirds from crashing into windows.

—Bob Holmes

Other, as yet unknown strategies to cope with high blood sugar may one day yield practical benefits for managing diabetes in people. “There could be a gold mine in the genome of the hummingbird,” says Welch.

Do a metabolic flip

By the end of its nightly fast, a hummingbird has nearly depleted its sugar stores — which poses an opposite metabolic challenge. “How does it wake up and fly?” Welch asks. “There’s nothing but fat available to burn.”

Hummingbirds have evolved to be remarkably nimble at switching their metabolism from sugar-burning to fat-burning, he has found. “This requires an enormous shift in the biochemical pathways that are involved,” Welch says — and it happens in mere minutes, far more quickly than other organisms can manage. “If we could have that kind of control over our fuel use, we’d love that.”

Save water — or not

Sugar isn’t the only challenge posed by a nectar-rich diet. After all, nectar is mostly water — and birds that drink in so much liquid must get rid of most of it, without losing electrolytes. As a result, hummingbird kidneys are highly adapted to recapture electrolytes before they are excreted. “They pee almost distilled water,” says Carlos Martinez del Rio, an ecophysiologist now retired from the University of Wyoming.

But that brings a further problem: If a hummingbird kept producing dilute urine overnight, it would die of dehydration before morning. To avoid that, hummingbirds shut down their kidneys every night. “They go into what, in a human, would be considered acute renal failure,” says Martinez del Rio. “Hummingbirds have to do this, or they would piss themselves to death.”

Fly high — gradually

The metabolic demands on a hummingbird are tough enough at sea level. But many species live at high elevations, where thin air contains less oxygen and offers less resistance to push against when hovering. Consider the giant hummingbird, the world’s largest, which can live in the Andes Mountains at elevations over 14,000 feet — higher than many helicopters can fly. To cope with these conditions, the birds have evolved more hemoglobin-rich blood, says Jessie Williamson, an ornithologist at Cornell University.

But some of the birds face an even steeper challenge, as Williamson found. Giant hummingbirds are large enough that researchers can attach satellite tracking tags, as well as smaller geolocators. So Williamson and her colleagues decided to fit the birds with trackers. After thousands of hours spent trying to capture birds with netting, the researchers managed to attach trackers to 57 birds using custom-made harnesses of elastic jewelry cord.

A giant hummingbird (such as the one pictured in inset) wore a GPS tracker during its migration from the Chilean coast to the heights of the Andes. Like human climbers gradually adapting to altitude, the bird ascended in a series of shorter climbs followed by pauses to adjust to the conditions at higher elevation. The whole journey took nearly three weeks.

CREDIT: J.L. WILLIAMSON ET AL / PNAS 2024

Though they recovered tracking data from only eight birds, even that tiny sample had a big surprise: Some of the birds lived in the high Andes year-round, while others — which turned out to be a separate, hitherto unrecognized species — migrate to the Andes annually from breeding grounds along the coast of Chile. That means they face not only the obvious challenges of a long migration — a round trip of roughly 5,000 miles — but also the need to adapt to thinner air as they travel.

Their secret? Do it gradually. “It looks a lot like how human mountaineers summit something like Mount Everest, with bursts of climbing and pauses to acclimatize,” Williamson says. “The journey takes months.”

As tracking technology becomes lighter and cheaper, researchers like Williamson hope to follow smaller hummingbird species as well. That, together with other progress in research technology, may offer plenty of new surprises about the biology of these tiny, amazing birds.

10.1146/knowable-092524-1

Bob Holmes is a science writer based in Edmonton, Canada, and a special contributor for Knowable Magazine.

LIVING WORLD | VIEW ON WEBSITE

Your cells are dying. All the time.

Some go gently into the night. Others die less prettily in freak accidents or deadly invasions, or after a showy display.

By Amber Dance    09.23.2024

Lea en español

Billions of cells die in your body every day. Some go out with a bang, others with a whimper.

They can die by accident if they’re injured or infected. Alternatively, should they outlive their natural lifespan or start to fail, they can carefully arrange for a desirable demise, with their remains neatly tidied away.

Originally, scientists thought those were the only two ways an animal cell could die, by accident or by that neat-and-tidy version. But over the past couple of decades, researchers have racked up many more novel cellular death scenarios, some specific to certain cell types or situations. Understanding this panoply of death modes could help scientists save good cells and kill bad ones, leading to treatments for infections, autoimmune diseases and cancer.

“There’s lots and lots of different flavors here,” says Michael Overholtzer, a cell biologist at Memorial Sloan Kettering Cancer Center in New York. He estimates that there are now more than 20 different names to describe cell death varieties.

Here, Knowable Magazine profiles a handful of classic and new modes by which cells kick the bucket.

The identification of new forms of cell death has sped up in recent years.

Unplanned cell death: Necrosis

Lots of bad things can happen to cells: They get injured or burned, poisoned or starved of oxygen, infected by microbes or otherwise diseased. When a cell dies by accident, it’s called necrosis.

There are several necrosis types, none of them pretty: In the case of gangrene, when cells are starved for blood, cells rot away. In other instances, dying cells liquefy, sometimes turning into yellow goop. Lung cells damaged by tuberculosis turn smushy and white — the technical name for this type, “caseous” necrosis, literally means “cheese-like.”

Any form of death other than necrosis is considered “programmed,” meaning it’s carried out intentionally by the cell because it’s damaged or has outlived its usefulness.

A good, clean death: Apoptosis

The two main categories of programmed cell death are “silent and violent,” says Thirumala-Devi Kanneganti, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. Apoptosis, first named in 1972, is the original silent type: It’s a neat, clean form of cell death that doesn’t wake the immune system.

That’s handy when cells are damaged or have served out their purpose. Apoptosis allows tadpoles to discard tail cells when they become frogs, for example, or human embryos to dispose of the webbing between developing fingers.

The cell shrinks and detaches from its neighbors. Genetic material in the nucleus breaks into pieces that scrunch together, and the nucleus itself fragments. The membrane bubbles and blisters, and the cell disintegrates. Other cells gobble up the bits, keeping the tissue tidy.

In necrosis, a cell dies by accident, releasing its contents and drawing immune cells to the site of damage by creating inflammation. In apoptosis, the cell collapses in on itself and the bits are cleared away without causing damaging inflammation.

Red flags: Necroptosis and pyroptosis

These are the violent kinds, and they helped expand the cell death repertoire beyond apoptosis and necrosis. They’re often engaged when cells have been hijacked by viruses or other infectious agents. Rather than be reduced to virus factories, they kill themselves. These cells go down waving big red flags, in the form of chemicals they release to alert the immune system to come in and save their neighbors.

In a 1998 study, a team disabled the ability of cells grown in dishes to undergo apoptosis, and the cells still died. But they did it in a messy way that came to be called necroptosis for its mix of apoptosis and necrosis features. As with necrosis, the cells and their organelles swell up and then the outer membrane ruptures. Necroptosis is a handy backup mechanism because some infectious agents can disable apoptosis.

Then there’s pyroptosis, first observed in 1992 among white blood cells infected with dysentery bacteria and christened in 2001. This is “the screaming, alarm-ringing pro-inflammatory death of a potentially dangerous cell,” the namers wrote. As with necroptosis, cells swell up. They activate enzymes that poke holes in the cell membrane, so their contents leak out, calling up an immune response.

Whether from pyroptosis or necroptosis, that immune response is needed to activate the body’s defenses against infection, such as the fever that cooks invaders, says Kanneganti, who coauthored an article about molecules involved in cell death in the 2020 Annual Review of Immunology. But if too many cells die or the immune system gets stuck in the “on” position, that can lead to ongoing inflammation or autoimmune disease.

Mix and match: PANoptosis

Immune cells, too, may need to die in the case of infection, inflammation or even cancer. As Kanneganti’s group investigated this process, they noticed an alternate mode of death that incorporated elements of apoptosis, necroptosis and pyroptosis. Using the first letter of each classic type, they dubbed it PANoptosis. Since then, researchers have found this hybrid death method in other kinds of cells, too.

In PANoptosis, the cell assembles a big protein machine called the PANoptosome. This activates enzymes to puncture the cell’s membranes. As it dies, the cell releases red-flag molecules that tell other immune cells there’s a problem.

Why do cells need so many ways to achieve the same fatal end? Cells probably evolved these different options during an arms race with disease-causing microbes, Kanneganti surmises. The microbes, aiming to survive, may try to turn off cell death. But if the cell has a wide menu of death mechanisms, it can commit suicide in another manner, sacrificing itself to thwart the pathogen.

Kamikaze killing: NETosis

Immune cells may sacrifice themselves even more dramatically, in a kamikaze action that takes out surrounding pathogens too. This sensational act is the purview of white blood cells called neutrophils, which patrol areas of infection and swallow invaders.

But sometimes the infectious agents are too large, or too numerous, to devour. The neutrophils switch tactics and vomit their own DNA over the pathogen, ensnaring the invaders in a kind of genomic net. It’s called NETosis (for neutrophil extracellular traps). Other cells then dispose of the entangled pathogens.

On occasion, the net-throwing cell is already dying or dead as this takes place, making it a zombie cell committing one final, altruistic act, says immunologist Ben Croker, who studies the phenomenon at the University of California San Diego School of Medicine.

Death metal: Cuproptosis and ferroptosis

While cancer cells seem ominous, they are, in fact, quite vulnerable to death, says Todd Golub, a cancer biologist at the Broad Institute in Cambridge, Massachusetts. “The key,” he adds, “is to find the right triggers.”

Golub’s group found a trigger in drugs that ferry copper into cells. The team is still working out how that makes the cells croak in a process they christened cuproptosis in 2022.

Iron, too, can be deadly to cancer cells, as chemical biologist Brent Stockwell at Columbia University in New York discovered. In addition to tumors, normal cells in the brain, liver and kidneys appear to be particularly susceptible to this form of cell death, which he named ferroptosis in 2012. Researchers have also observed ferroptosis in a wide range of organisms, even yeast and plants, says Stockwell, who cowrote a description of the key features of ferroptosis in the 2019 Annual Review of Cancer Biology.

Stockwell and other researchers are working to identify drugs or special diets that would activate ferroptosis to combat cancer, or block it to protect cells from dying in diseases such as Alzheimer’s.

Eat me: Entosis

Overholtzer, while studying breast cancer cells in the early 2000s, noticed something weird: cancer cells burrowing into other cells. He and his lab supervisor dubbed the phenomenon entosis in 2007.

The invading cell winds up enclosed in a big, membranous bubble. It may starve and undergo apoptosis, or be killed by the surrounding cell. Then the outer cell digests its remains.

During entosis, one cell inserts itself within another. In these images, blue indicates cellular DNA and green indicates the cytoplasm, a cell’s gelatinous interior. One cell may exist within another cell (A); a cell may exist within a cell within yet another cell (B); and an inner cell may undergo DNA division (C).

CREDIT: I. MLYNARCZUK-BIALY ET AL / CANCERS 2020

But sometimes, weirdly, it survives and pops out of the cell to live independently again. Noting this, some researchers have proposed that entosis gives cancer cells a way to temporarily hide out from the immune system or cancer drugs.

There’s still plenty to learn about cell deaths, and there are probably death modes still awaiting discovery, Golub speculates.

Ultimately, the study of life requires the investigation of cell death. As the Japanese author Haruki Murakami wrote, “Death exists, not as the opposite but as a part of life.”

Editor’s note: On September 24, 2024, the graphic titled “The many ways a cell can die — a discovery timeline” was updated to add PANoptosis, a type of cell death that had been omitted in the earlier version.

10.1146/knowable-092324-1

Amber Dance, a Knowable Magazine contributor in the Los Angeles area, killed many a cell during her years as a cell biologist.

Table of Contents

Knowable Magazine: 2024 Dec 8

All articles

The great green building makeover

Can desalination quench agriculture’s thirst?

String theory is not dead

Cracking the recipe for perfect plant-based eggs

The secrets of butterfly migration, written in pollen

She ain’t scary, she’s my mother

Frogs kick back against lethal fungus

Bustling through the physics of crowds

Severe irritability in children and teens: A new understanding

Night of the zombie insects

When ribosomes go rogue

How a child becomes bilingual — and what can be done to help them get there

The Cybathlon: Bionic athletes compete for the gold — and push assistive technologies forward

Studies of migraine’s many triggers offer paths to new therapies

Why a diabetes drug fell short of anticancer hopes

Sustainable building effort reaches new heights with wooden skyscrapers

Are you my baby? The clever ways that brood parasites trick other birds

We are family: Tracing the evolution of animals

Hummingbirds thrive on an extreme lifestyle. Here’s how.

Your cells are dying. All the time.