The Scientist Winter 2022

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Contents ON THE COVER: © ISTOCK.COM, SOMERSAULT18:24 WINTER 2022 | WWW.THE-SCIENTIST.COM | VOL. 36, ISSUE 4 28 Features 3x6x © ISTOCK.COM, ERANICLE; © ISTOCK.COM, DANI3315; MODIFIED FROM © ISTOCK.COM, ELENABS; © ISTOCK.COM, KRULUA 44 52 28 36 44 52 The Rise of Eukaryotes Micro Manipulators Protecting Pregnancy Top 10 Innovations Despite recent advances in the Biologists are learning how Carefully calibrated immuno- This year’s crop of winning study of eukaryogenesis, much intracellular bacteria hijack logical changes in mothers products features many with remains unresolved about the host cells—and they’re unveiling are critical for a healthy a clinical focus and others origin and evolution of the secrets of human cell biology pregnancy. Understanding that represent significant most complex domain of life. in the process. how the body balances advances in sequencing, immune tolerance and single-cell analysis, and more. BY AMANDA HEIDT BY CATHERINE OFFORD protection from infection will allow us to improve BY THE SCIENTIST STAFF pregnancy outcomes. BY TOBIAS R. KOLLMANN, ARNAUD MARCHANT, AND SING SING WAY WINTER 2022 | THE SCIENTIST 3

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Department Contents 8 FROM THE EDITOR THE LITERATURE Insights Abound Even 63 Gifted Guppies The relative sizes of specific parts at Journey’s End of the guppy brain may explain why Although my time at The Scientist some fish are better at learning certain has drawn to a close, I am consistently tasks than others. surprised by science. BY BOB GRANT 64 Some trees more susceptible to death by lightning; fat-processing pathways 11 SPEAKING OF SCIENCE in motor neuron diseases; infection CRITICS AT LARGE strategies of chytrid fungus; protein regulation by sweet taste receptors 12 12 Eating Our Way Out of Trouble in fruit flies The key to averting cataclysmic events, such as pandemics, climate change, and mass extinctions, lies partly in 66 BIO BUSINESS what’s on our plates. Revising the Genome BY GIULIA WEGNER AND KRIS A. MURRAY A biotech startup called Tessera Therapeutics has made a splash MODIFIED FROM © ISTOCK.COM, ILYALIREN; © ISTOCK.COM, HEATHER BROCCARD-BELL; © IKUMA KAYAMA, STUDIO KAYAMA 15 Gollum in the Ivory Tower with its claims to have developed Resource hoarding is an unfortunate “Gene Writing” technology. Is the reality of the research enterprise. excitement justified? The time has come to discuss it in BY DAN ROBITZSKI an open way. 70 CAREERS 19 NOTEBOOK Growth of the Green Lab Widespread avian deception; whale Across the world, scientists, students, skulls reveal clade’s history; how and administrative staff are working moths ward off bats; saving datasets to mitigate research’s impact on from extinction the environment. 23 SCIENTISTS TO WATCH BY NATALIA MESA 60 Ankur Jain: Neurodegeneration READING FRAMES Explorer 73 Fad of the Land Assistant Professor, Humans are psychologically susceptible to the latest diet trends. Department of Biology, MIT BY HANNAH THOMASY BY JANET CHRZAN 61 Chantell Evans: Mitochondria Trackers 75 Cats as Sociological Bellwethers Assistant Professor, Department of Cell Whether a feline is considered a pet or a Biology, Duke University pest depends not on what the animal does, but on what scientists and nonscientists BY HOLLY BARKER alike believe about cats’ place in the world. 62 MODUS OPERANDI BY BETHANY BROOKSHIRE Expert JeWell-ry Designers Imaging organoids has proven slow FOUNDATIONS and cumbersome for scientists. But a 77 Diagrammatic Wars, 1858 new technique may speed things up, BY ANDY CARSTENS producing 3D images of hundreds of 62 organoids per hour. 80 Trans Medicine, 1919 BY NATALIA MESA BY NATALIA MESA WINTER 2022 | THE SCIENTIST 5

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FROM THE EDITOR Insights Abound Even at Journey’s End Although my time at The Scientist has drawn to a close, I am consistently surprised by science. BY BOB GRANT mention their evolutionary ancestors, per- can’t vomit. Horses, too, are part of the ANDRZEJ KRAUZE sist without the capacity to forcefully eject puke-proof club. Fascinating. And it was For more than 15 years, I have had toxins or otherwise unpalatable substances only recently that researchers began to the pleasure of helping The Scientist from their digestive tracts? What, indeed, explore why it is that rodents lack what cover everything from breaking does a mouse do when it finds itself in the would seem to be an advantageous reflex. news on an emerging pandemic to the lat- precarious position of having ingested (Spoiler alert: The answer lies deep within est research breakthroughs that chip away something that might cause many other the brain stem, where the neurological at long-standing mysteries. Depending on mammals to lose their lunch, perhaps sav- components necessary to initiate vomit- the day, this job is a mixture of challenging, ing their lives in the process? ing appear to be missing.) delightful, and enlightening. Some days are more challenging. Others contain more These questions pestered me enough With regard to the recent study, delights. But one thing has remained con- to do some cursory reconnaissance, which deftly covered for our website by intern stant throughout the entirety of my tenure taught me that mice aren’t the only spe- Katherine Irving, the authors creatively at this publication: Science and the world cies in that particular boat. Rodents writ circumnavigated the curious murine it probes never cease to amaze me. large—squirrels, rats, gophers, etc.— deficiency by using a proxy for nausea Recently, I have been reminded of this fact in a beautifully mundane way. During an early-November news meet- ing—the type we hold weekly to explore the life science research goings-on— members of the editorial staff discussed a study that purported to uncover the neu- ral circuitry responsible for controlling vomiting. The research, published in a November issue of Cell, used mice as experimental models. The authors of the paper exposed the animals to bacterial toxins and a chemotherapeutic drug to induce a behavioral reaction, and then traced the signaling cascade that caused the response. But here’s the catch: Mice can’t vomit. It’s not that they won’t vomit or that it’s exceedingly difficult to elicit that partic- ular behavior in Mus musculus. Mice, by dint of their physiology, cannot vomit. Now, anyone who writes about or conducts science, especially biomedical science, is fully aware that the humble mouse is one of, if not the, most common experimental organisms. We at The Scientist are virtu- ally awash in mice, as our remit is to cover basic biological research, for which mice have long served as subjects. And yet, this simple fact of mouse biology had escaped my appreciation for all these years. That physiological reality stopped me in my tracks. How did modern mice, not to 8 THE SCIENTIST | the-scientist.com

It’s an exciting and oddly learning something so fundamental I am moving on from The Scientist, comforting feeling to know about the biology of a ubiquitous lab- and I leave behind a body of work that that we don’t need to peer oratory animal reminded me that, for I hope captures my wonder and amaze- into the darkest reaches of all that humanity has learned about the ment with the natural world and of the space to feel afloat in a sea natural world, surprises still abound. If concerted human effort to understand of potential knowledge. we extend the perimeters of our inquiry its intricacies. But I sincerely hope I beyond Earth and into the universe, there never move past the giddy fascination involving contorted facial expressions are even more massive unknowns. Dark that I feel whenever I brush against indi- and contracted abdominal muscles. matter, dark energy, the nature and lifes- viduals driven by a similar impulse, be The rest is living history, with a neatly pan of black holes, just to name a few. they science journalists covering emerg- described pathway from toxin to sero- ing concepts or researchers on the front tonin to a specific region of the mouse It’s an exciting and oddly comforting lines of discovery. g brain, which houses neurons that fire to feeling to know that we don’t need to peer initiate retching. into the darkest reaches of space to feel Editor-in-Chief afloat in a sea of potential knowledge. [email protected] This particular example involves me, We can find pockets of discovery and a nonscientist, being caught off guard by astonishment much closer to home. In a scientific fact that is surely known by a mice, for example. And deep within the great many scientists. Nevertheless, cells and molecules of our own bodies— indeed, within the very brains we use for all this puzzling—lie mysteries untapped, insights waiting to be unearthed. LIKE US ONCREDIT LINE FACEBOOK WINTE1R0.22002221 | T HE S CIE N T IST 9 Did you know that more than 2 million people follow The Scientist on Facebook? Like our page to see the latest news, videos, infographics, and more, right in your news feed. facebook.com/TheScientistMagazine

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QUOTES Speaking of Science “At some level, I made a choice that I don’t want to support, personally, his ecosystem.” —Astronomer Mark McCaughrean of the European Space Agency, speaking to Science about his decision to start using a di erent social media plat- form after Elon Musk purchased Twitter in October (November 4) “[This period in science is] by no means just a return to business as usual. There is much more interest in academe in training researchers in public engagement, very much including training in communication.” —Mary Woolley, president of Research! America, speaking with Inside Higher Ed about an Elsevier report she contributed to on the pandemic-era research environment (November 8) “Currently, avian flu outbreaks have been “I think, inside baseball, many doctors of limited in humans because the virus doesn’t academic centers are aware that he’s on spread easily between us. But this is a the Columbia faculty and feel angry about it.” ticking timebomb. A mutation that makes this virus circulate more easily between —New York University bioethicist Arthur Caplan, speaking with The Eye about humans is possible.” cardiothoracic surgeon Mehmet Oz. Oz, who last month lost a bid for the US Senate, has drawn fire for years for promoting what critics —Devi Sridhar, chair of global public health at the University say is pseudoscience. (November 2) of Edinburgh, in a recent story in The Guardian about the ongoing bird flu epidemic (November 9) © SHUTTERSTOCK, SATTALAT PHUKKUM “There should be a unified response, “I was looking forward to a robust discussion where everybody realizes that the enemy on the topic of backlash against public health is the virus, not each other. We need to do o cials. Unfortunately, there are some people everything we can to protect ourselves and who have made their wishes known that they protect each other.” oppose such crucial civil discourse.” —Anthony Fauci, director of the National Institute of Allergy and Infectious —Public health expert Leana Wen in a statement explaining why she would Diseases (NIAID), speaking with Wired about his experiences during the not participate in a panel at the American Public Health Association COVID-19 pandemic, in advance of his retirement at the end of the year after threats were made on her safety (November 8) (November 8) WINTER 2022 | THE SCIENTIST 11

CRITIC AT LARGE Eating Our Way Out of Trouble The key to averting cataclysmic events such as pandemics, climate change, and mass extinctions, lies partly in what’s on our plates. BY GIULIA WEGNER AND KRIS A. MURRAY The world may be at greater risk of infectious diseases that orig- inate in wildlife because people are increasingly encroaching on natural habitats in the tropics to graze livestock and hunt wild animals. Devastating pandemics such as HIV/AIDS, Ebola, and COVID-19, all of which likely originated in wildlife, are reminders of how environmental destruction and infectious disease are inter- twined. Tropical deforestation and overhunting are also at the root of global warming and mass species extinction. All of these phenomena suggest that what we choose to eat has a fundamental impact on our health and that of the planet. We recently conducted a review of the scientific literature to explore how wildlife-origin diseases, global warming, and mass species extinction are linked to the global food system. Our sec- ond objective was to explore reparative actions that governments, NGOs, and each one of us can undertake. From the perspective of individual consumers, the global pop- ulation needs to shift to diets low in livestock-sourced foods to stem human encroachment on tropical areas of wilderness. Sec- ond, there is a need to curb wildmeat demand in tropical cities. Eating less foods from livestock warming can be kept well below 2°C and that the rate of species © ISTOCK.COM, ILYALIREN Closer to the equator, biodiversity becomes richer. These tropi- extinction can be slowed. This is because livestock production has cal regions have historically seen less development and are typi- the largest environmental footprint of all food production sys- cally teeming with wildlife and carbon stored in the form of abun- tems in terms of land and water use, greenhouse gas emissions, dant vegetation. But in recent decades, agricultural frontiers have and pollution of terrestrial and aquatic systems. expanded rapidly into tropical forests. This unprecedented expan- sion of farmland for grazing and feed production may be increasing Asking everyone to become vegan is not realistic or even contact between wildlife, people, and livestock, which may enhance desirable. But flexitarian diets could feed the growing world the likelihood of pathogens jumping from one to the other. population without further expanding farmland into tropical wildlands and with reductions in greenhouse gas emissions. Such habitat destruction also has a negative impact on large These diets consist of large amounts of plant-based foods, herbivores and predators, as they lose sources of food and breed- including vegetable proteins like pulses, nuts, and seeds; mod- ing grounds. This can lead to an increase in generalist species of est amounts of fish, poultry, eggs, and dairy; and small quanti- rodents, bats, birds, and primates that are better adapted to thriv- ties of red meat and processed animal proteins. ing in human-modified landscapes. Some of these species are known reservoirs for infectious diseases of livestock and humans. For exam- Paired with  conversion to environmentally friendly or ple, the white-footed mouse (Peromyscus leucopus) is a reservoir organic farming and reductions in food losses and wastage, diets host for the bacterium Borrelia burgdorferi, which causes Lyme dis- low in livestock-sourced foods are therefore a key component of ease, while some fruit bats (family Pteropodidae) are reservoir hosts a sustainable global food system. Such a dietary shift would have for Nipah virus and probably Ebola virus. Intensive livestock farms other public health benefits too, such as reducing overweight and further increase the likelihood that domesticated animals can serve obesity, diabetes, heart diseases, and colorectal cancer. as intermediate hosts for wildlife-origin diseases, thereby amplifying the risk of human contagion. (See illustration on page 13.) Measures available to governments, civil society, and businesses to promote healthier and more sustainable levels of consumption In addition, if the human population continues to grow and adopt diets rich in livestock-sourced foods, it’s unlikely that global 12 THE SCIENTIST | the-scientist.com

BENEFITS OF A GLOBAL SHIFT TO FLEXITARIAN DIETS HIGH Fruits and vegetables Pulses and legumes Whole grains Nuts and seeds Unsaturated plant oils MODEST Fish, Poultry Dairy, Eggs Low Red meat Processed meat Saturated fats Added sugar Refined grains Highly processed goods REDUCED GHG EMISSIONS REDUCED BIODIVERSITY LOSS IMPROVED HUMAN HEALTH REDUCED RISK OF ZOONOSES ILLUSTRATOR: EMILY WRIGHT. TAKEN FROM WEGNER ET AL., eCLINICALMEDICINE, 2022 of livestock-sourced foods include education in schools, training to biosecurity measures necessary to prevent contagion from of physicians and pediatricians, eco-labels on food packaging, tax- wildlife-borne diseases. ation of meat and dairy products, a statutory duty for retail and hospitality sectors, and food procurement for workplaces, schools, Outright bans can have other undesired effects. While in and hospitals. most large cities, legume, fish, and livestock-sourced proteins are easily available at affordable prices, there are Indigenous Governments tend to dodge such interventions for fear of people and rural communities who rely on hunted meat for public backlash. But the public tends to expect government lead- vital nutrition and income. Their rights to sustainably pro- ership in tackling such a complex challenge. vision themselves within their customary territories should be safeguarded. Curbing wildmeat demand in tropical cities In the tropical forests of Africa, Asia, and South America, hunting The ideal course of action would be to contain tropical wild- pressure to supply nearby cities has dramatically increased over meat hunting and trade by curbing demand in urban areas and the past 30 years. In addition to imperiling vulnerable animal extractive outposts, while supporting hunting rights and biosecu- populations, a vigorous wildmeat trade may increase the risk of rity measures among communities in remote subsistence areas. zoonotic disease transmission. Avoiding biohazards from animal-sourced food But in the absence of effective state law enforcement and Interventions in rural communities should provide wildmeat hunters, sustained campaigns to reduce consumer demand, bans  do traders, and butchers with training in inexpensive biosecurity mea- not work. In fact, consumers’ strong preferences for wild- sures they can easily adopt to avoid infection from contact with wild meat mean that they may continue to purchase it despite animals. Biosecurity measures should also be extended to livestock price increases induced by a ban, boosting black markets. In and wildlife farms, abattoirs, food markets, and restaurants. These the case of “luxury meat,” increased price and rarity may even measures include wearing protective clothing when handling wild ani- drive higher demand. Bans could also shift the wildmeat trade mals, wrapping carcasses to prevent blood from contacting cuts in to illegal, unregulated channels where less attention is paid people’s skin, and cooking wildmeat thoroughly before eating. WINTER 2022 | THE SCIENTIST 13

Flexitarian diets could feed the growing are inhospitable to crop cultivation would instead continue to world population without further expanding rely on animals for nutrition. Nonetheless, the minor environ- farmland into tropical wildlands and with mental impacts of their subsistence way of living are not compa- reductions in greenhouse gas emissions. rable to those of dense and better-off urban populations. Other physical distancing measures should be taken in farms, pas- Our future depends on urgent change tures, and live-animal markets. These include fencing and reducing The incidence of infectious diseases originating in wild ani- livestock densities to minimize contact with wild herbivores, planting mals is high and may be increasing. This may be yet another fruit trees visited by bats at a sufficient distance from livestock sites, warning signal that our degradation of ecosystems is under- and limiting the number of animals on sale in live-bird markets. mining the capacity of planet Earth to sustain human health and well-being. Di erent strategies across di erent regions Levels of consumption of livestock-source foods, and the degree of Dietary shifts away from livestock-sourced foods and reduc- reliance of human communities on animal-source proteins, vary dra- tions in tropical urban wildmeat demand are crucial to simul- matically. Efforts to reduce livestock production should focus on curb- taneously protect the environment, safeguard resource-limited ing excessive consumption in wealthier countries and expanding met- vulnerable communities, and reduce the risk of further disease ro-polises in less developed and emerging economies. In the poorer outbreaks and pandemics. We all share the responsibility to act rural areas of resource-limited countries, home gardening as well as now to prevent pollution, floods, drought, famine, and epidemics smallholder livestock development programs can help decrease mal- from becoming increasingly prevalent. g nutrition with limited environmental and public health impacts. Giulia Wegner is a socioenvironmental researcher at the Wildlife Pastoralist communities in arid rangelands and hunter-gath- Conservation Research Unit (WildCRU) of the University of Oxford erer communities in tropical rainforests and arctic locales that in the UK. Kris Murray is an associate professor in Environment and Health at the MRC Unit The Gambia and the MRC Centre for Global Infectious Disease Analysis at Imperial College London. THE SCIENTIST PODCASTS Our podcasts, The Scientist Speaks, TS LabTalk, and Science Philosophy in a Flash, are for scientists and by scientists. In every episode, we explore newsworthy discoveries at the leading edge of innovative research. the-scientist.com/podcasts CREDIT LINE 14 THE SCIENTIST | the-scientist.com OCTOBER 2022 | ISSUE 1 | TS DIGEST 14

CRITIC AT LARGE Gollum in the Ivory Tower Resource hoarding is an unfortunate reality of the research enterprise. The time has come to discuss it in an open way. BY JOSE VALDEZ AND SANDEEP SHARMA © SHUTTERSTOCK.COM, AM-STUDIO Humans have likely been hoarding and fiercely guarding heads down and voices low, deeply anxious that any noise would resources since the start of recorded history. Those with jeopardize the projects they had planned and prepared for years access to resources and the means to defend them typi- and maybe even compromise their careers. cally have a higher chance of survival. This tactic and the hostil- ity it engenders are still part of the human psyche, and currently In another example, a young scientist submitted a research extend into scientific spheres. Just like greedy Gollum tirelessly paper, the culmination of years of hard work and long nights, to a seeking and defending the One Ring in J.R.R. Tolkien’s The Lord highly regarded journal. Months later they received an email con- of the Rings, some researchers possessively guard precious study taining reviews and eagerly began reading. However, instead of the sites, model organisms, research topics, and even entire scien- expected constructive feedback, they found that one of the reviewers tific fields. These Gollums of the academic ivory tower are willing levied an extremely harsh and disparaging review. The reviewer not to defend their “rings” at all costs, preventing other competitors only attacked the work but lobbed personal criticisms at the author from getting too close to their research arena and severely hin- as well. While journal editors often ignore such ad hominem attacks dering scientific progress along the way. and let the review stand, this particular editor realized the nega- tive review represented the resource guarding of a Gollum and did In one of the best-known cases of academic rivalry, paleontol- not reflect the quality of the work. The editor-in-chief of the jour- ogists Othniel Charles Marsh and Edward Drinker Cope took this nal got personally involved and contacted the reviewer, letting them Gollum effect to the extreme with turf battles that became known know that their tone and accusations were inappropriate, that their as the “Bone Wars.” Across the second half of the 19th century, attitude ran contrary to the advancement of science, and that they these researchers resorted to bullying, sabotage, theft, and even would not be invited to serve as a reviewer again. In this case, the the destruction of rare fossils and precious research sites to hin- journal’s editorial team was extremely helpful and supportive. Nev- der access and prevent each other from making scientific discover- ies in newly unearthed and fossil-rich bone beds in the American West. While the Bone Wars represent a somewhat severe exam- ple, cases of bullying, harassment, gatekeeping, and threats are all too common experiences for many in today’s research community. Although this issue is rarely discussed, a recent opinion piece coau- thored by one of us (J.V.) hopes to bring the Gollum Effect into the light and encourage victims of such behaviors to discuss their past experiences so we can come together to find solutions. The published article was originally written after the authors and their colleagues, in their academic studies and early careers, had run-ins with several Gollums. This included supervisors using their positions of power to claim authorship for work they were not involved in or to discourage colleagues and other scien- tists from conducting experiments that they believed only they had the right to conduct. Things sometimes turned more acutely abusive, as with a particular mentor who had no direct connec- tions with a research project, but went out of their way to thwart the research plans. In our view, this person did this because they were already working on the target species—a particularly charis- matic species that was garnering a lot of grant money. In another situation, a senior scientist with a more defined territory in a particular field of research successfully plagiarized the ideas and data of a colleague, attempting to claim them as their own. In both cases, the junior researchers involved decided to keep their WINTER 2022 | THE SCIENTIST 15

CRITIC AT LARGE Gollums of the academic ivory tower are tives, become scarce and often controlled by a few individuals or willing to defend their “rings” at all costs, groups, further creating power imbalances. We have found that preventing other competitors from getting corruption, nepotism, and steep hierarchies, in both academic too close to their research arena and severely and government systems, only serve to feed the Gollum. hindering scientific progress along the way. These dynamics affect not only future generations of research- ertheless, for someone just starting their professional career, such ers but also the future of scientific pursuit. As we are all part of reviews can be demoralizing and can lead young authors to question the scientific community, combating this issue requires systemic their value as researchers. Situations like these have the potential to change and collaborative action by all of us, regardless of position lead individuals not only to give up their specific research aspira- or power. By encouraging a culture of ethical research etiquette tions, but to leave science entirely. and removing unjustifiable roadblocks, we can keep research- ers excited about science and foster an environment where any- Sometimes the damage of a Gollum’s behavior can extend one can freely study the subject they are passionate about. How- beyond individuals. For example, our colleagues in Asia have ever, to fully bring about a paradigm shift and increase scientific observed that whole research institutions, local and international openness, we must first be open and comfortable talking about NGOs, government agencies, and even foreign aid/development our own experiences. Sparking an honest conversation about this organizations can often behave like Gollums. This is common for issue can eventually lead to a new era in which science is practiced popular and well-known study areas, such as UNESCO World fairly and the pursuit of discovery is accessible to all. g Heritage Sites, or universally charismatic species such as tigers. This means that resources, mainly funding and financial incen- Jose Valdez and Sandeep Sharma are postdoctoral researchers at the German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig. THE SCIENTIST WEBINARS Listen to the details of research in progress, explore the latest results, and learn about new tools and technologies that spark experimental ideas and pave the way to discovery. the-scientist.com/webinars TSU TECHNIQUE TALKS 16 THE SCIENTIST | the-scientist.com

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Notebook WINTER 2022 MIGUEL ÁNGEL GÓMEZ-SERRANO The Lies through its beak. It contorted its wings TRUTH OR DARE: Birds such as this Kentish Birds Tell in what’s called the broken-wing display, plover (Charadrius alexandrinus) use deceptive feigning an injury that would make it tactics to protect their eggs from predators. About five years ago, Clinton Fran- seem unable to fly. Francis was already cis and a gaggle of ornithology familiar with this sort of bird theater, really look into that for your research students were walking toward typically performed for earthbound diur- question for this class.” Taking the advice the ocean at San Simeon Beach State Park nal predators in the hopes that, instead and diving in, Thompson found sporadic in California when they noticed a type of of finding the killdeer’s nest, they’d see a examples across avian species through an plover called a killdeer about 60 feet away, plump, apparently wounded parent as an exhaustive literature search, followed by calling Dee! Dee! Dee! They hadn’t seen easy meal. When this deceptive behavior surveys sent to ornithologists, avian ecol- the shorebird flush from its ground nest, works, the predator charges the killdeer, ogists, and experienced birders around the but Francis, an ecologist at California which then launches skyward to escape. world. In the end, she and her colleagues Polytechnic State University, says that it uncovered evidence that 285 avian species would have crept slyly away from its eggs While watching the bird, Francis perform the broken-wing display (Proc R after registering the herd of humans as recalls, one of his students asked: “What Soc B, 289:20220058, 2022). potential predators. other species do that display?” Francis knew the behavior was commonly asso- Mapping those behaviors onto the Now that it had an audience, the kill- ciated with shorebirds, but beyond that, avian phylogenetic tree revealed that the deer (Charadrius vociferus) began to lie he wasn’t sure. In response, he told the trait spans from some of the most basal student, Wren Thompson, “You should WINTER 2022 | THE SCIENTIST 19

NOTEBOOK bird families, including pheasants and TOP ACT: A female Kentish plover assumes. When the risk is lower, a plo- ducks, to more recently evolved taxa such performs a broken-wing display. ver may fake an injury while running, giv- as songbirds. “It’s pretty amazing,” Fran- ing the deceiver momentum to fly off and cis says, adding that he was surprised how If this doesn’t work, they may escalate to escape. “If nothing seems to work, or the “particular clades on the avian tree of life so-called false brooding: lying down to risk of losing their offspring seems obvi- really just light up,” including blackbirds, simulate incubating their eggs—some- ous—for example a predator that is right warblers, and sparrows. The frequent and thing that could trick a predator into look- next to the nest,” Gómez-Serrano says, “the disjointed appearance of the behavior ing for the nest away from its true location. birds take even more risk by [enacting] across the tree suggests it evolved inde- Or a plover may begin what’s known as a the broken-wing display statically near the pendently several times, he adds. rodent run, mimicking a flightless mousy predator,” imperiling themselves by prox- snack to entice the predator into chas- imity as well as by losing their running The analysis, published earlier this ing an apparently easy meal away from start. Previous work by Gómez-Serrano’s year, also indicates that predation risk the nest. “The bird runs crouched for- group has found that when Kentish plo- has driven the trait’s evolution. “Birds that ward with its chest close to the ground,” vers (Charadrius alexandrinus) engaged experience higher levels of predation, by says Gómez-Serrano. “Often plovers place more in risky stationary displays, their visual predators in particular, tend to use the tail folded towards the legs to [better] nests survived longer, providing evidence the display more than those that do not,” resemble the shape of a mouse.” that the potential cost pays off (Behav Francis says. The team found that the far- Ecol, 28:260–69, 2016). ther the birds’ breeding zones were from The degree of predation risk seems to the equator, the more likely the animals dictate the form that a bird’s dishonesty Sometimes, though, the price for lying were to use the broken-wing display. One is death. In 2008, on a beach in Spain, possible explanation for this relationship, Gómez-Serrano saw a Kentish plover Francis says, is that the portfolio of pred- enacting an in-motion broken-wing dis- ators becomes increasingly diurnal—and play for a small predator hidden in the more visual—towards the Earth’s poles. surrounding vegetation. While trying to lure that foe away from a nest contain- “It is certainly surprising to see that ing days-old chicks, the plover was itself broken-wing display is so widespread in too distracted to notice a different preda- phylogenetically distant groups of birds,” tor: a kestrel that swooped out of the sky, Miguel Ángel Gómez-Serrano, a conserva- snatched it up, and flew inland, likely to tion ecologist at the University of Valencia feed its own chicks. who studies deceptive nest defense behav- iors but was not involved in this research, In addition to broken-wing, false tells The Scientist by email. Plovers have a brooding, and the rodent run, other docu- lot of tactics to distract predators beyond mented dishonest behaviors include play- feigning broken wings, he adds. They may ing dead, feigned exhaustion, false feeding, begin by calling to catch a predator’s eye. MIGUEL ÁNGEL GÓMEZ-SERRANO; ANDRZEJ KRAUZE 20 THE SCIENTIST | the-scientist.com

and pseudo-sleeping. Gómez-Serrano says The Shape tory. They host the brain, the sensory some birds fake eating, pecking at nothing of Whales organs, and the teeth, all of which can tell on the ground—perhaps giving predators researchers about the animals’ behavior the impression they’re distracted and easy Whales are weird. The Ceta- and diet. For several years now, Coombs to sneak up on. Some birds vocalize their cea clade contains the largest has been studying whale skull peculiar- lies. Burrowing owls (Athene cunicularia) animal to ever live—the blue ities—such as the structure’s unusual hiss like rattlesnakes to protect against whale—as well as other gigantic baleen asymmetry in some species—and their ground squirrels, and fork-tailed drongos whales and a diverse array of toothed implications for cetacean evolution. (Dicrurus adsimilis) mimic meerkat alarm whales, including dolphins, porpoises, calls to scare the mammals into abandon- narwhals, sperm whales, and more. The She first started collecting 3D scans of ing food. “I think there’s some other really group contains some of the only fully whale skulls in 2018, when she was a PhD interesting deceptive tactics out there aquatic mammals that give birth to live student at the Natural History Museum that are worth exploring,” and we may be young in saltwater. Whales’ nostrils are on in London. She aimed to collate data on unaware of many, Francis says. the tops of their heads. The list of bizarre skulls that came from not only different characteristics goes on. periods across whales’ evolutionary his- Filipe Cunha, a behavioral ecologist tory, but also various geographies, from at Wageningen University & Research in Whales’ skulls are one of their crown- Europe and North America to Peru and the Netherlands, happened upon a par- ing oddities. Skulls in general are a pale- New Zealand. The basic procedure was ticularly unusual case of avian deception ontological treasure trove, explains straightforward. Using a 3D scanner, while studying Siberian jays (Perisoreus paleontologist and macroevolutionary infaustus). “They’re definitely liars,” he ecologist Ellen Coombs, a postdoc at SKULL SCAN: Ellen Coombs uses a 3D says, explaining how the territorial birds the National Museum of Natural His- scanner on skulls at the Los Angeles County fake an alarm call that’s typically reserved Museum of Natural History. for alerting group members to the pres- ence of predators such as sparrowhawks. Cunha determined that the jays deceive neighboring groups of Siberian jays to A plover may fake an injury while running. VANESSA RHUE, LOS ANGELES COUNTY MUSEUM scare them into fleeing, after which the liars steal caches of scavenged meat that the tricked birds had hidden to survive the Arctic winter (Sci Adv, 7:eaba2862, 2021). He says that he hopes studying within-spe- cies dishonesty will shed light on how trust evolved in our own species. Research on avian deception high- lights the importance and diversity of these behaviors as survival tools, Francis says. Consider a familiar example of a bird without known deception or indeed any other predation-avoidance behaviors: the extinct dodo, “which [people] were able to just walk up to and club because they had no evolutionary response to approach- ing humans or any other type of predator,” Francis says. “It’s worth keeping this quiver of tactics because otherwise reproductive success is zero.” —Andy Carstens WINTER 2022 | THE SCIENTIST 21

NOTEBOOK she’d take several images, then process experts and evolutionary modelers could Computer model of a blue whale (Balaenoptera ELLEN COOMBS them, clean them up, and merge them infer when particular changes in struc- musculus) skull into a single, coherent 3D model. ture had taken place—and how quickly. The findings, published around 15 million That’s easier said than done when this year, show that years ago at the emergence you’re scanning hundreds of skulls, espe- whales’ cranial of Delphinoidea, the largest group of cially when they’re from whales. The skull evolution came toothed whales and the taxon containing of a vaquita (Phocoena sinus), the world’s in three waves dolphins (Anat Rec, 281A:1247–55.E4, smallest cetacean, is pretty manageable, (Curr Biol, 32:P2233–47. 2004). “So this study does support and as it’s around the size of a melon. But the E4, 2022). The first was right at the begin- extend previous studies and does so very skull of a blue whale (Balaenoptera mus- ning of whale evolution, just shy of 50 mil- nicely,” Manger says. culus) is more on the scale of a family lion years ago, when the archaeocetes— sedan. Scanning a single skull could take the ancestors of modern cetaceans, which Abdullah Gohar, a cetacean paleobi- Coombs anywhere from 30 minutes to an emerged in the Eocene Epoch—were first ologist at Mansoura University in Egypt entire day. entering the water. “Within eight to twelve who was also not involved in the research, million years,” she says, “they went from writes in an email that the paper was “a Computer model of an orca (Orcinus orca) skull being fully terrestrial to fully aquatic.” fabulous work. It’s fantastic to see this monumental effort come to fruition!” He Once she’d assembled The next major shift came roughly says that the extreme specialization of the images, Coombs could place digi- 39 million years ago when the two sub- cetacean skulls makes them an excellent tal markers on them to note the position orders of whales—the mysticetes (baleen target for study, as they “capture many of of particular structures. For each of the whales) and the odontocetes—went their the extreme shifts in feeding, respiration, 200 or so skulls she studied, she placed separate ways. The baleen whales began and sensation.” more than 2,000 markers, for more than developing the long keratin sheets that 400,000 markers in total. “It took me the enable filter feeding. That carried on Whales’ cranial evolution good part of a year to finish,” she says. came in three waves. Coombs adds that she also listened to a until about 23 million years ago, when lot of podcasts during that time. their rate of skull evolution slowed The sheer scale of the database is to a crawl. The toothed whales, worth noting too, he says. “Large data- Some findings jumped out right away, meanwhile, developed echoloca- bases take a long time to compile, but she notes. For example, the odontocetes, tion, which enabled them to hunt they allow scientists to throw light on or toothed whales, “have very asymmetri- in low-light conditions and in dif- larger trends rather than making qualita- cal skulls.” In 2020, Coombs coauthored a ficult terrain, such as murky rivers tive findings based on a single fossil.” He paper on some of her initial findings, which adds that he hopes future studies “incor- revealed that skulls of the toothed whales clogged with rocks or ice. porate these findings to better understand had evolved to accommodate the melon, a In the final wave of evolution, from cetacean evolution.” mass of fatty tissue that amplifies the high- pitched calls that these whales produce for roughly 18 million to 10 million years Coombs says that she’s already had echolocation (BMC Biol, 18:86). ago, there was an explosion in diversity several researchers, including other evo- among the toothed whales. Echolocation, lutionary biologists, climate scientists, and Looking deeper by mapping the skull unlike baleen, was a tool that could help behavioral ecologists, asking to use the markers onto the cetacean phyloge- the animals exploit many different niches, dataset for further research, and adds that netic tree, she and a team of fellow whale Coombs explains, thereby encouraging she’s not finished with it either. “There’s so new adaptations and creating new species, many questions we can ask using this data- from the river dolphins to the deep-diving set alone, but there’s more we can add to it sperm whales. too. I’m super proud.” Anatomical scientist Paul Manger —Connor Lynch of the University of the Witwatersrand, Johannesburg, who was not involved in the work, says that one of the study’s most interesting findings is that these three occurrences of rapid changes in the anatomy of the skull “correlate with changes in brain [size during] evolution.” He notes, for example, the there was a significant increase in brain size right at the origin of odontocetes, and again 22 THE SCIENTIST | the-scientist.com

© ISTOCK.COM, HEATHER BROCCARD-BELL Bat Repellent tors’ acoustic signals. Many have evolved A MOTH’S METHOD: Lymantria species make ears that can hear the calls of bats. Some ultrasonic, mechanical rasping noises when Spending months in hostels in far- moths make ultrasonic squeaks, chirps, or they hear bats nearby. flung locales is more often the clicks to warn their predators (honestly or province of graduate students than not) that they are poisonous. Others gen- zona—a gathering that Barber describes of established researchers. But it’s been erate near-constant, ultrasonic buzzes as “a raging good time.” During the course the side project of a lifetime for Jesse Bar- capable of jamming bat sonar. of the doctoral work he’d just completed, ber and Akito Kawahara, two scientists Barber had stumbled across a quirk of who have spent more than a decade criss- While such abilities have been docu- moth behavior: Some hawkmoths (family crossing continents to catch moths, play mented in a range of moths, it’s less clear Sphingidae) respond to recordings of bat bat sounds at them, and see if—and how— whether these behaviors are rare evo- echolocation by squeaking back at them, they squeak back. lutionary quirks or common strategies though it wasn’t immediately clear why. across the 160,000 or so moth species Like other nocturnal insects, moths worldwide. Barber, a sensory ecologist To find out more, “we got a grant to need to contend with bats. Unlike grass- at Boise State University, and Kawahara, study that system and started traveling hoppers or beetles, they have soft bodies an entomologist at the Florida Museum around the world, just the two of us, stay- without spines or hard cuticles to protect of Natural History, have been thinking ing in hostels, catching moths and playing them. Yet bats’ reliance on echolocation about this mystery since they first crossed bat sounds back at them,” Barber says. The has given moths a way to avoid ending paths about 17 years ago at a Lepidopter- pair would attract moths with ultraviolet up as food: by tapping into their preda- ists’ Society meeting in Sierra Vista, Ari- WINTER 2022 | THE SCIENTIST 23

NOTEBOOK light, gently hold smaller moths down poisonous—all copying one another’s sig- SIGNAL BLOCKER: The garden with locking forceps or use fishing line nals. “[It] is likely that ultrasonically sig- tiger moth (Arctia caja) produces to tether larger moths so that they could naling moths comprise one of the largest ultrasonic clicks in response fly but not escape, and play prerecorded mimicry complexes on earth,” the authors to bats. bat sonar through an ultrasonic speaker. write in their paper. Moths responded with all sorts of sounds in the bats’ brain makes this particular sig- of their own, which the pair recorded. University of Bristol behavioral and nal so efficient in protecting the prey?” The large Gonodonta bidens, for example, sensory ecologist Marc Holderied, who was made a short, light buzz that, when slowed not involved in the work, says that while Now-retired behavioral ecologist down, sounds like a small handful of rice researchers knew that bats and moths were Michael Greenfield, formerly of the Uni- being poured into a plastic container, versity of Kansas, compliments the col- while the mechanical rasps of Lymantria laborative nature of the project. “When I species sounded more like the noise made started in ecology and evolution, it was the by a rattlesnake. era of the rugged individual” and single- author publications, he says. But in this Over roughly the next decade, Barber paper the authors “made use of having says, “we went to French Guiana at least five a team: people [were] testing on differ- times, Borneo at least five times; we went to ent continents, on many different spe- Mozambique a couple of times, Ecuador a cies,” which made a paper of this scale couple of times,” among other places, rop- possible. Greenfield also notes that ing in more and more graduate students as while Barber, Kawahara, and colleagues they went. “We were just doing it as a side uncovered many novel examples of sound- project as other grants and projects carried producing moths, most were found in us around the world,” he explains, “so it was four superfamilies where they had already kind of pieced together over time.” been documented. After testing 252 genera across most of Athanasios Ntelezos, a graduate stu- the 28 large-bodied moth families—those dent in zoology and electrophysiology at that are big enough to be capable of mak- the University of Cambridge, writes in an ing a sound bats can hear from a distance— email to The Scientist that while the paper the researchers documented anti-bat ultra- adds to scientists’ understanding of “how sound production as a form of warning widespread this strategy is,” he would have signal of poisonous qualities in 52 genera liked to see data on the effects of moths’ (PNAS, 119:e2117485119, 2022). They also found evidence that sonar-jamming strat- egies had evolved independently multiple times—at least twice in hawkmoths and four times in the Erebidae family—and Bats’ reliance on echolocation has given moths a way to avoid ending up as food. noted overlap between species that signal in an “acoustic arms race,” this paper pro- © ISTOCK.COM, RBIEDERMANN and species that jam. Interestingly, many vides new information on the distribution of the moths appeared to be converging on of these strategies across moth species. similar sounds, Barber says. “This is a very nice piece of research, and it’s well executed. . . . It’s something that Investigating a community of moths needed to be done and it’s been done very in Ecuador, Barber and Kawahara also well,” he says, adding that “the chapter on found evidence of complex acoustic mim- these acoustic signals has just increased in icry, featuring various combinations of volume multifold.” The findings on multi- moths—some jammers, some warners, ple convergent acoustic mimicry strategies some that do both, and some that make is particularly interesting, he says. “What warning noises even though they aren’t 24 THE SCIENTIST | the-scientist.com

signals. “Ideally one would want to test “Truly wild” is how University of Ari- and sharing of data was a time-consum- the function of the sounds produced by zona community ecologist and study coau- ing and rather low-grade task, and not moths by pitting them against bats and thor Ellen Bledsoe describes the scale of the usually funded.” comparing the effectiveness of the sound- Valdez data loss. Tallying it up “was defi- producing group to that of a control nitely eye-opening, just as a way of quan- The Living Data Project, which got its group,” he says, but “the new study is large- tifying monetarily how much data is lost.” funding from the Natural Sciences and scale and [it] would be very hard indeed Bledsoe and colleagues at the Canadian Engineering Research Council of Canada to test each moth species against bats.” Institute of Ecology and Evolution (CIEE) (NSERC), aims to address both the imme- published their estimate earlier this year diate problem of data loss and the under- The project has certainly been a massive alongside guidelines for the recovery and lying cultural causes. The project trains undertaking, Barber says. “A lot of the rea- archiving of important ecological data. As graduate students on data management, son it took us so long to publish it [was that] part of CIEE’s Living Data Project, their then matches them with data owners such we felt the story was so incomplete that, goal is to identify datasets in danger of loss as research organizations or retiring aca- what could we say?” After all, “to sample and take steps to preserve them before they demics. Students help clean and process enough animals in a phylogeny this diverse, disappear into the ether. Data rescue is the aging datasets, eventually sharing them in with this many species, is a lifetime task.” official term, but Bledsoe says she likes to an accessible repository. Yet the result is a testament not only to a think of it as “data necromancy”—bringing legion of collaborators the world over, but data back from the dead. “There are no courses in most biology to a long-standing friendship and partner- curricula that teach people how to man- ship, and the passion of everyone involved, The project tackles a common contra- age their data,” says Dominique Roche, he adds. “Something I can say about the diction in science. Without data, there is a postdoctoral fellow at the University entire list of authors: we all love moths. nothing to analyze and no way to test any of Neuchâtel in Switzerland and coau- And, you know, that’s sort of the type of sci- hypothesis. Yet once they have produced thor on the Living Data Project paper. “It entist and person you have to be to delve results and publications, data are some- seems like such an essential skill. I guess this deeply into this question without get- times treated as tools that have outlived it’s assumed that people who do research ting paid to do it.” their usefulness, rather than the valuable, know how to work with data, but that’s and often irreplaceable, records that they the biggest fallacy ever.” —Connor Lynch are. “Data have been seen as not exciting. They’re not science, they’re not proper TREASURE SECURED: Ecology professor Data Savers idea generation,” says CIEE board mem- George H. La Roi’s data—collected over 35 years ber Alison Specht. “They’re a means to an of studying North American boreal forests and Just after midnight on March 24, end, and the curation, the management, stored in notebooks, CD-ROMs, and slides—are 1989, the Exxon supertanker Valdez now preserved by the Living Data Project. slammed into Bligh Reef in Prince THE LIVING DATA PROJECT William Sound, Alaska. The resulting oil spill was an unprecedented disaster for the region, its fish and rich wildlife, and the peo- ple and industries who depended on them. In the aftermath, more than $150 million of civil suit settlement money was allocated to ecological research and monitoring efforts to help scientists understand and mitigate the long-term effects of the spill. Three decades later, most of the data collected in the wake of the disaster have gone missing. A five-year project that began in 2012 to recover the original data turned up just 30 percent—the rest were never digi- tized, never shared, or kept in a format inac- cessible to outside researchers. In purely financial terms, a new study estimates that more than $100 million was spent to collect data that, effectively, no longer exist (Proc R Soc B, 289:20220938, 2022). WINTER 2022 | THE SCIENTIST 25

NOTEBOOK The number of older projects in need dated media like floppy disks is especially IN STORAGE: The Living Data Project helped to of rescue can be daunting—sharing data vulnerable. Sometimes data are stored in archive these boxes of files from the basement was rare in ecology before journals and official university department space, but of the Atlantic Forestry Centre in Fredericton, funding agencies started to require it in just as often, they can end up in research- New Brunswick. the early 2010s. So the team’s new paper ers’ garages or handed down to their chil- gives guidelines for prioritizing certain dren. In their paper, Bledsoe and col- Seal, established in 2017 through an inter- projects over others, including studies that leagues describe the example of University national collaboration of organizations cover a long period of time, a large geo- of Alberta forest ecology professor George focused on data archiving and transparency, graphical area, or multiple species. These H. La Roi. Upon La Roi’s death, his chil- now grant certification to repositories that are likely to be the ones that are most use- dren bequeathed his collected notebooks, are sustainably maintained and updated. ful to future researchers, says Bledsoe, CD-ROMs, and slide images from 35 years although she acknowledges that there are of studying North American boreal forests Still, technological developments exceptions. If a biologist studies lions, a to one of his colleagues. The Living Data don’t address a lack of incentives to main- tain datasets in a usable state, says Mark Once they have produced results and publications, Westoby, a professor emeritus at Macqua- data are sometimes treated as tools that have outlived rie University who is not involved in the their usefulness. Living Data Project. “Academic careers run on publication,” he says. “It’s by far small but detailed dataset of lion behavior Project was able to match the new owner the most important incentive for how aca- DIANE SRIVASTAVA could be more useful than a continental- with trained students to restore and pre- demics—probably government scientists scale, long-term ecological dataset that serve this irreplaceable ecological record. as well—decide how to spend their time.” doesn’t include lions. “It really is one man’s Westoby recently coauthored a paper trash is another man’s treasure.” Technical advances are making data calling for a new career currency for data preservation easier and more reliable than providers, apart from publications and Another factor in setting priorities for ever before. Repositories are much more journal impact scores—but such cultural rescue is the risk of permanent loss. Infor- common than they were even a few years changes take time, he says. While fund- mation stored only on paper or on out- ago, and programs such as CoreTrust- ing agencies and scientific journals are increasingly implementing data-sharing requirements, these can lead to a letter- of-the-law approach, he adds, where some 26 THE SCIENTIST | the-scientist.com

ANDRZEJ KRAUZE data are shared to meet requirements, but not necessarily in complete datasets or in a particularly legible format. Westoby is supportive of the Living Data Project’s efforts to rescue old data- sets, but notes that the group’s paper sidesteps the costs of doing so as well as the motivation issue. “Having guidelines to revive, resurrect, rescue data that oth- erwise might be lost is all good advice. It didn’t really tackle the question of how many person-hours and person-years are we talking about, and is it worth it?” Ultimately, everyone who spoke to The Scientist agreed that the ideal sys- tem is one where rescue isn’t necessary at all. “Data rescue is a great concept,” says Roche, “but ideally what we want to do is get rid of data rescue. It would be a lot less work for people if they thought of data management and sharing from the very onset of a project, so that data are not at risk of being lost.” —Ian Rose Check out Words for Nerds, the science-themed wordle game where you can challenge yourself and share with your colleagues to see who comes out on top. There is a new word every day! THE-SCIENTIST.COM WINTER 2022 | THE SCIENTIST 27

The Rise of © ISTOCK.COM, ERANICLE ukar tes Despite recent advances in the study of eukaryogenesis, much remains unresolved about the origin and evolution of the most complex domain of life. BY AMANDA HEIDT 28 THE SCIENTIST | the-scientist.com

This year, University of Paris-Saclay ing alliances that turned permanent over [Eukaryogenesis biologist Purificación López-García time, López-García says. In this way, is] arguably embarked with colleagues on a jour- individuals of different microbial species e of the mo ney into life’s ancient past. The researchers could have nested within one another traveled to the altiplanos of the northern to create a host with one or even several port t events Atacama Desert, high-altitude stretches of symbionts. This is exactly what scientists in the history rocky soil and shrubbery in South Amer- suspect happened to form a whole new of life, after the ica that are among the driest places in the type of cell, the eukaryote, which thrived o n of life itself. world. Despite their inhospitable reputa- and subsequently diversified into the tion, these plateaus may hold clues about macroscopic array of life we see today, —Daniel Mills the very origins of complex life. Amidst including humans. So-called eukaryo- Ludwig-Maximilians-Universität München the dunes and barren mountains, there are genesis is not defined the same way by © ISTOCK.COM, VITALII DUMMA pockets of life—warm, briny pools crusted all researchers, but broadly, the term over with colorful microbial mats of cyano- describes an evolutionary surge toward bacteria and archaea stacked atop one increasing cellular complexity between 1 another like crepes. Long before Earth and 2 billion years ago. resembled its current state, López-García says, these microbial mats “were the forests During this time, some of the defin- of the past,” adding that scientists now use ing characteristics of modern eukaryotic these clumps of microscopic life “as analogs cells—the nucleus, mitochondria, cyto- of past ecosystems that certainly occurred at skeleton, cell membrane, and chloro- the time when eukaryotes first appear[ed].” plasts, among others—made their debut. These occurred between the first and last Each layer of these living mats is com- common ancestors of all living eukary- posed of different types of microbes that otes, known by their acronyms, FECA and rely upon one another. At the surface, LECA, respectively. Most of the details of where light and oxygen are plentiful, pho- these evolutionary leaps, however, remain tosynthesizing cyanobacteria dominate, unsettled. Researchers do not uniformly while just below, heterotrophs that can agree on which branch of life eukaryotes persist in low-oxygen environments feed sprang from, which microbial players on their byproducts. Deeper down, the might have contributed to the process, or mats become dark and smelly, the result on the order of specific evolutionary mile- of the sulfate reducers and methanogens stones along the way. But the recent iden- that populate these oxygen-bereft zones. tification of the Asgard archaea, thought Here, these partnerships become even to be the closest living relatives to mod- more essential, with the castoffs of one ern eukaryotes, has enlivened discussions group serving as fuel for another. about eukaryogenesis. These close metabolic associations Today, at the microbial mats in the Ata- between organisms, a type of symbiosis cama Desert and other sites throughout the known as syntrophy, may have prefaced world, scientists are investigating what the the evolution of complex life by creat- earliest eukaryotic cells may have looked

EARLY INCUBATORS: Microbial mats such as these taken from the altiplanos of South America’s Atacama Desert may mimic the conditions on early Earth that gave rise to eukaryotic life. like, the partnerships they may have struck there they were. Wanting to understand below the surface of the Arctic Ocean, DIVERSITY, ECOLOGY AND EVOLUTION OF MICROBES (DEEM)/PURIFICACIÓN LÓPEZ-GARCÍA; COURTESY OF SUSSANAH PORTER up with other organisms, and how their just what was going on, Spang joined the between Greenland and Norway. Ettema molecular machinery might have func- lab of Thijs Ettema, an evolutionary micro- told The New York Times that the initial tioned and evolved. Already, the discovery of biologist then at Uppsala University in sample amounted to less than a teaspoon- the Asgards has solidified certain aspects of Sweden, and set out in search of new data. ful of deep-sea muck. But almost immedi- eukaryogenesis while raising new questions ately, software responsible for annotating about others. “I think this is the most excit- The team extracted genomes from and analyzing the genetic material began ing development in biology right now. So sediments collected during a research to return odd results—it flagged ESP much is being discovered and so many pre- cruise to a deep-sea vent site called Loki’s homologs for actin, a distinctly eukary- dictions are being met,” says Daniel Mills, a Castle located more than 2,300 meters otic protein that gives cells their shape, geobiologist and postdoctoral researcher at in a genome that was otherwise clearly Ludwig-Maximilians-Universität München archaeal.1 The microbes turned out to be who recently coauthored a paper suggesting members of a new group that Spang and that eukaryotes likely evolved in the absence the team named the Lokiarchaeota when of oxygen. Eukaryogenesis, he adds, is “argu- they published their findings in Nature ably one of the most important events in the in 2015.2 In the years that followed, the history of life, after the origin of life itself.” team continued to flesh out this branch of the archaeal family tree, leading to the establishment of the Asgard super- phylum,3 which in addition to Lokiar- Arrival of the Asgards After receiving her PhD in 2013, evolu- tionary microbiologist Anja Spang was shopping around for a postdoc. For her dissertation, Spang had studied a group of archaea called the Thaumarchaeota (now Nitrososphaerota), and during that work, she’d picked up hints that the genomes of these and other archaea contained code for genes that produce what are known as eukaryotic signature proteins, or ESPs. These proteins should not have had recog- nizable counterparts in archaea, and yet, MINISCULE FOSSILS: While metagenomics have rapidly advanced the study of eukaryogenesis, the study of microfossils such as this 750-million-year- old Valeria lophostriata may also help shed light on when certain eukaryotic features first appeared. 30 THE SCIENTIST | the-scientist.com

THE PATH TO COMPLEXITY Eukaryogenesis is broadly defined as the evolutionary path taken by increasingly complex lifeforms as they diverged from the simpler prokaryotes that dominated the early part of Earth’s biological history. The functional period of eukaryogenesis started just prior to the symbiosis between two prokaryotes and ended when the last common ancestor of modern eukaryotes arose. During this time, many of the most recognizable eukaryotic features appeared, including organelles such as mitochondria, nuclei, and chloroplasts, as well as cellular processes such as phagocytosis. The ordering of these events in time remains unclear. ORIGINAL HOST UNKNOWN FIRST EUKARYOTIC While the identity of original host in the COMMON ANCESTOR symbiotic partnership that birthed modern eukaryotic cells remains mysterious, some ~2-3 BYA researchers say the evidence suggests it was an archaeon rather than a bacterium. Alphaproteobacteria Scientists call this host, which lived more than a billion years ago, the first eukaryotic ORIGIN OF MITOCHONDRIA common ancestor, or FECA. At some point in the past, the prokaryote host formed a partnership with an alphapro- APPEARANCE OF - Nucleus teobacterium and permanently engulfed it, UNIQUE FEATURES - Rod-shaped chromosomes creating the mitochondrion. Researchers Numerous other features - Cytoskeleton debate whether phagocytosis was needed to and processes associated - Mitosis/Meiosis establish this relationship, but mitochondria with modern eukaryotic - Endoplasmic reticulum did help power much of eukaryotes’ subse- cells evolved during this - Chromatin quent radiation. time, including the nucleus and cytoskeleton. The order of their appearance is uncertain. LAST EUKARYOTIC BIRTH OF MODERN LIFE COMMON ANCESTOR The last eukaryotic ancestor (LECA) shared by all living eukaryotes today was already ~1-2 BYA a complex cell by the time eukaryotes began to radiate. Over hundreds of millions of years, LECA gave rise to the complex organisms that exist today, including fungi, protists, plants, and animals. © NICOLLE FULLER, SAYO STUDIO 31 TS DIGEST | the-scientist.com WINTER 2022 | THE SCIENTIST 31

Pe le were chaeota includes nods to other Norse “[It] verified that at least the metabolic already argu ng gods, including the Thor-, Odin-, and predictions for the Asgards were making for a o-d a Heimdallarchaeota. sense with actual experimental work.” sy before the Asgards Researchers have since identified other Lots of hypotheses, were discovered, ESPs in these groups, including homologs few answers but th ce of proteins involved in everything from These early observations precipitated a the Asgards ubiquitin signaling to gamete fusion. That flood of new research, with hundreds of were desc bed, ESPs are so common among Asgards sug- papers published as preprints on bioRxiv it ve ev gests that these microbes represent the touching on Asgards and eukaryogenesis more evid ce. closest living prokaryotic relatives to mod- in the last several years. The most immedi- ern eukaryotes and that modern eukary- ate effect of the discovery of Asgards was a —Andrew Roger, Dalhousie University otes may well have inherited aspects of their shift in support from a three-domain tree molecular machinery from archaea. Indeed, of life that included eukaryotes, prokary- most scientists now argue that an ancient otes, and archaea to a two-domain model, © ISTOCK.COM, VITALII DUMMA Asgard or another archaeon, and not a bac- often called the eocyte hypothesis, that terium or proto-eukaryote as many previ- lumps archaea and eukaryotes together. ously assumed, likely served as the first host (See illustration on page 34.) in the evolutionary process that ultimately resulted in a new type of cell. In the three-domain model, eukaryotes belong to a separate branch that shares a In 2019, researchers successfully cul- common ancestor with archaea. But phy- tured an Asgard archaeon for the first time, logenetic analyses suggest that complex allowing scientists to dive deeper into their cells emerged from within the archaea. biology.4 Using microscopy, Hiroyuki Ima- This results in two primary domains— chi of the Japan Agency for Marine-Earth bacteria and archaea—with eukaryotes Science and Technology and colleagues being nested within archaea. “People were found that the cultured species, for which already arguing for a two-domain system they proposed the name Candidatus Pro- before the Asgards were discovered, but metheoarchaeum syntrophicum, is small then once the Asgards were described, it and extremely slow-growing, dividing only gave even more evidence,” says Andrew every two to three weeks; some microbes Roger, a molecular biologist at Dalhousie can double in as little as a few minutes or University in Nova Scotia. He adds that hours. In addition, they found that Ca. the two-domain hypothesis also “supports P. syntrophicum lives in close associa- that the host during eukaryogenesis was tion with another archaeon called Meth- an archaeon” and not a type of proto-eu- anogenium. Ca. P. syntrophicum gets its karyote that formed a distinct lineage. energy by digesting amino acids and pep- tides for their nitrogen, and in turn, Meth- Researchers who spoke to The Scientist anogenium uses the hydrogen produced say that many scientists have rallied behind during that process to create its own fuel the idea that the first eukaryotes evolved and at the same time reduce environmental out of a syntrophy between an archaeal host hydrogen, which can induce cellular stress. and bacteria that somehow found their way This partnership confirms that Asgards inside to become the organelles, such as engage in the type of relationships that nuclei and mitochondria, that distinguish researchers suspect gave rise to eukaryotes. eukaryotes. The details of these relation- ships remain murky, but mitochondria pro- Hints of such a syntrophic relation- vide the most tantalizing clues to their origin ship had been gleaned from other archaeal story. “There’s DNA in mitochondria that we genomes, says Spang, who now oversees can somewhat clearly connect or trace back her own research group at the Royal Neth- to alphaproteobacteria,” says Laura Eme, erlands Institute for Sea Research, but Ca. an evolutionary microbiologist at France’s P. syntrophicum provides tangible evi- National Centre for Scientific Research dence. “I was really happy when I heard” of (CNRS). “Even if we don’t know exactly the preprint that first described the organ- which lineage, we have a smoking gun.” ism and its syntrophic lifestyle, she says.

There are contrasting hypotheses as to engulfment. When scientists first cultured the so-called lipid divide, another unset- how the alphaproteobacterium would have Ca. P. syntrophicum, they immediately tled aspect of eukaryogenesis in which the gotten inside an archaeal host, however. In noticed a series of thin projections coming off lipids that make up the cell membranes the eukaryogenesis version of the chick- of the microbes—extensions of their mem- of eukaryotes are more similar to those in en-and-egg conundrum, scientists go back brane system called blebs. This observation bacteria than to those in archaea.5 and forth on whether mitochondria would suggested that these blebs might be able to have been necessary to power the energet- surround an external entity—perhaps with A couple of years ago, López-García and ically expensive process of phagocytosis, the help of those actin homologs—and fuse her Paris-Saclay colleague David Moreira, or whether phagocytosis would have had together, trapping the foreign body inside. also affiliated with the CNRS, updated to arise first as the means of ingesting the The phagocytosis conundrum “is much less the hypothesis to reflect the discovery of symbiotic partner. An oscillation between of a problem now,” Eme tells The Scientist. Asgards, but rather than place an archaeon “mito-early” and “mito-late” hypotheses as the original host, they propose than an appears frequently in the literature, but When it comes to the nucleus, what archaeon—specifically a hydrogen-produc- intriguingly, there were no known exam- López-García calls “the typical diagnostic ing, Asgard-like archaeon—was the origi- ples of phagocytosis in prokaryotes until eukaryotic feature,” the picture is much nal nucleus.6 The host, they suggest, was very recently, when researchers identified a less clear. Hypotheses of its origin run likely a deltaproteobacterium, and the phagocytosis-like process of engulfment in the gamut from a bacterial endosymbiont ancestor of mitochondria an alphapro- a bacterium. “[M]any people were saying it within an amoeboid host to the remnants teobacterium. This idea is supported, they is impossible to have the ancestor of mito- of a giant virus. (See “Sidebar” on page say, by the fact that most genes in mod- chondria incorporated in any cell because 35.) In the 1990s, López-García proposed ern eukaryotes are actually bacterial, and phagocytosis is not known in the prokary- the Syntrophy hypothesis for the origin of not archaeal, in origin, and that eukaryotic otic world,” says Eme. “Well, now we know eukaryotes, which posited a three-party membranes are made up of phospholipids that phagocytosis exists in bacteria, at least.” metabolic symbiosis between two bacte- that more closely resemble bacterial ones. ria and an archaeon. She maintains that “Our model is one potential model—it may Moreover, initial observations of the this hypothesis is the only one that explains be wrong, [or it] may be right—but the Asgards point to other mechanisms of not only the origins of the nucleus, but also others don’t explain these discrepancies,” López-García says. “And at some point, I HIROYUKI IMACHI, MASARU K. NOBU, AND JAMSTEC think they should.” Michelle Leger, a postdoctoral researcher and evolutionary microbiologist at the Insti- tute of Evolutionary Biology in Barcelona, is currently scouring the genomes of extant archaeal species to support or refute the many hypotheses floating around. With respect to the Syntrophy hypothesis, for example, “if I were to imagine that there was the deltaproteobacteria in that relation- ship as well, I would expect a similarly clear [genomic] signal” to that of the alphapro- teobacteria in the mitochondrial genome, Leger tells The Scientist. She hasn’t found such a signal yet, but she says she thinks the evidence does support an archaeal origin for the nucleus. Although archaeal genes make up a small fraction of the nuclear genome, the genes that play roles in highly conserved processes within the nucleus itself, such HELLO COUSIN: Researchers first identified Asgard archaea, thought to be the closest liv- ing prokaryotic relatives to modern eukaryotes, from metagenomic data in 2015. A few years later, the first Asgard was cultured, revealing unique aspects of its biology. WINTER 2022 | THE SCIENTIST 33

FROM THREE DOMAINS TO TWO ern eukaryotes to yield clues about how individual genes and proteins may have The question of where exactly eukaryotes branch on the tree of life has been behaved in their early ancestors. While debated by scientists for decades. But the discovery of the Asgard archaea— there was only a single Asgard genome a the closest prokaryotic relatives to modern eukaryotes—has shifted most few years ago, today there are hundreds, researchers away from a three-domain tree in which eukaryotes are a distinct and researchers are mining them for details. lineage and toward a two-domain tree, in which eukaryotes emerged from “Now we have a clear idea of which genes within the archaea as a secondary domain. in eukaryotes have been inherited from Asgard archaea, and there’s a lot of novelty BACTERIA EUKARYOTES ARCHAEA here,” Eme says. “But what we don’t know, and that’s really important, is what these THREE-DOMAIN TREE genes did or are doing in Asgard currently.” TWO-DOMAIN TREE In 2020, researchers synthesized sus- pected homologs of eukaryotic actin pro- as DNA replication and transcription, are rise of early eukaryotic cells, many research- teins encoded in Asgard genomes. Injected © NICOLLE FULLER, SAYO STUDIO largely archaeal. So “it makes sense” that the ers tell The Scientist it’s entirely possi- into rabbit cells, these proteins bound to nucleus developed from an archaeon, Leger ble that some questions will never be fully eukaryotic actins and performed similar says. “But it’s not very clear what other part- answered. Too much time has passed since functions, including aiding the flow of cal- ners might have been involved.” eukaryotes first appeared on the evolution- cium across cell membranes.7 The findings ary scene, and too much DNA has been suggest that a calcium-controlled actin cyto- The next big frontier scrambled between too many groups, for skeleton likely existed in Asgards prior to the Even as the number of sequenced archaeal scientists to piece everything together. But emergence of eukaryotes. In another study, and bacterial genomes continues to that hasn’t stopped them from trying. researchers attempted to resolve the lipid increase, offering new clues about the rela- debate by expressing archaeal phospholipids tionship between these microbes and the Eme tells The Scientist that the “next big in E. coli, and found that the bacteria were frontier” will be functional studies in mod- able to successfully incorporate as much as 30 percent of the archaeal lipids into their cell membranes.8 The study doesn’t fully rec- oncile whether eukaryotes would have been able to transition their membranes from bacterial to archaeal lipids—López-García notes that bacteria with membranes com- posed of more than 30 percent archaeal lip- ids begin to die—“but it does lay the ground- work for future research,” Eme says. Additional clues could come from the study of microfossils, microscopic impres- sions of early cells embedded in rock, says University of California, Santa Barbara, paleontologist Susannah Porter. When metagenomic sequencing came to the fore, it seemed as though fossils fell out of favor, she says, but many phylogenetic trees rely on a methodology called a molecular clock that uses fossils to anchor analyses in time. In addition, the fossils themselves can be useful, allowing scientists to deter- mine when certain external features first appeared, adds Porter, who is currently interrogating such specimens to order cer- tain events of early eukaryote evolution. “We do have a fossil record back 2 billion to 1 bil- lion years, but I don’t think it’s been taken 34 THE SCIENTIST | the-scientist.com

advantage of or leveraged to its full extent,” sil evidence. For example, Berend Snel, a That assumption was challenged by some, she says. “Maybe we could actually use these computational biologist at Utrecht Univer- and even Snel admits that “it may not be characteristics of the fossil record to be able sity in the Netherlands, recently used gene perfect,” but breaking the story of eukaryo- to piece together eukaryogenesis.” duplications to correlate the lengths of genesis into more manageable chunks may branches on phylogenetic trees with time— help resolve many of these unanswered Meanwhile, other researchers are devis- the assumption being that the number of questions, he says. “What I’m arguing for ing alternate methods for timing the events duplication events increases with time.9 is that it’s a lot of little, small stories, but if of eukaryogenesis to complement that fos- people would integrate these small stories in the right way, there should be a tapestry © ISTOCK.COM, DESIGNER29; © ISTOCK.COM, VITALII DUMMA VIRUSES OF THE ASGARD that ultimately weaves a real story.” While much about the origin of the nucleus is speculative, one Leger agrees that our understand- hypothesis suggests that the nucleus of modern eukaryotes ing of eukaryogenesis is likely to advance may have resulted from a partnership between a prokary- with baby steps. “Part of the nature of otic host and a virus. This idea was first suggested in a pair of these deep evolutionary questions is that papers published back-to-back in 2001 after two research- we will never know, we will never have a ers independently arrived at the same conclusion, and both clear proof of some of the hypotheses that groups recently published updates to their viral origin hypoth- we’re trying to develop,” she says. “But we eses following the field-rocking discovery of the Asgard archaea can keep refining our ideas.” g (Front Microbiol, 11:571831, 2020; Virus Res, 289:198168, 2020). References At the turn of the 21st century, Masaharu Takemura, then a molecular biologist at 1. C.W. Stairs, T.J.G. Ettema, “The archaeal roots of the the Nagoya University School of Medicine in Japan, noticed that one group of viruses, the poxviruses, had DNA polymerases that were extremely similar to those found in eukaryotic dynamic actin cytoskeleton,” Curr Biol, eukaryotes, and that poxviruses replicate inside their hosts by creating self-contained 30:R521–26, 2020. compartments. Meanwhile, Philip Bell, the head of research for the biotechnology 2. A. Spang et al., “Complex archaea that bridge the company MicroBioGen, was similarly puzzled by the di erences between eukaryotes gap between prokaryotes and eukaryotes,” Nature, and the bacteria that led to organelles such as mitochondria. Eukaryotic chromo- 521:173–79, 2015. somes are linear, for example, while bacterial ones are circular. Many features of the 3. K. Zaremba-Niedzwiedzka et al., “Asgard archaea nucleus just didn’t support a bacterial origin. illuminate the origin of eukaryotic cellular complexity,” Nature, 541:353–58, 2017. Since that time, researchers have identified the so-called giant viruses, first 4. H. Imachi et al., “Isolation of an archaeon at the described in 2003. These viruses are much larger than most, with fittingly mas- prokaryote–eukaryote interface,” Nature, 577:519– sive genomes, and they’ve since been found to harbor genes associated with var- 25, 2020. ious metabolic processes. Now, Takemura, Bell, and others say that a giant virus 5. L. Villanueva et al., “Bridging the membrane lipid could have been the original nucleus. Giant viruses replicate within complex com- divide: bacteria of the FCB group superphylum have partments that look very similar to modern nuclei—they’re large and include both the potential to synthesize archaeal ether lipids,” inner and outer membranes—and also carry versions of genes that produce pro- ISME J, 15:168–82, 2021. teins involved in essential host cell processes. 6. P. López-García, D. Moreira, “The Syntrophy hypothesis for the origin of eukaryotes revisited,” The idea that the nucleus could have been a virus has been a tough sell, how- Nat Microbiol, 5:655–67, 2020. ever. According to Purificación López-García, a biologist at the University of Par- 7. C. Akıl et al., “Insights into the evolution of regulated is-Saclay, “there is no structural evidence” to support it. Michelle Leger, an evolu- actin dynamics via characterization of primitive tionary microbiologist at the Institute of Evolutionary Biology in Barcelona, agrees gelsolin/cofilin proteins from Asgard archaea,” that the hypothesis is not supported by existing data, which she argues more PNAS, 117:19904–13, 2020. clearly point to an archaeon as the organism that became the eukaryotic nucleus. 8. A. Caforio et al., “Converting Escherichia coli into an archaebacterium with a hybrid heterochiral But Valerie De Anda, a microbiologist at the University of Texas at Aus- membrane,” PNAS, 115:3704–09, 2018. tin Marine Science Institute who studies early prokaryote metabolism, isn’t dis- 9. J. Vosseberg et al., “Timing the origin of eukaryotic suaded by the current lack of evidence from the idea that a virus may well be cellular complexity with ancient duplications,” Nat the source of the eukaryotic nucleus. She and her colleagues are currently look- Ecol Evol, 5:92–100, 2021. ing for mRNA-capping genes involved in transcription and translation that were suggested by Bell to have been derived from a long-ago “first eukaryotic nuclear ancestor” (Nat Microbiol, 7:953–61, 2022). “People don’t take seriously great ideas right at the beginning . . . and then it turns out to be true,” De Anda says.

Micro Manipulators Biologists are learning how intracellular bacteria hijack host cells— and they’re unveiling secrets of human cell biology in the process. BY CATHERINE OFFORD 36 THE SCIENTIST | the-scientist.com

© ISTOCK.COM, DANI3315 WINTER 2022 | THE SCIENTIST 37

As a grad student in cell biology, Shaeri Mukherjee was Get the gear always on the lookout for new ways to fiddle with In the late 1980s, bacteriologist Daniel Portnoy visited actin cells’ internal structures. It was the early 2000s, and expert Lewis Tilney at the University of Pennsylvania to discuss Mukherjee was working in Dennis Shields’s lab at a new research idea. Or as Tilney later relayed the experience to Albert Einstein College of Medicine, studying how the Journal of Cell Biology: “Portnoy crashed a department pic- cells organize the internal transport of proteins and other cargo. nic and insisted I look at his damn Listeria.” She was particularly interested in the Golgi apparatus, a cluster of membrane-bound compartments that help coordinate this traf- By then it was known that Listeria infects cells such as mac- ficking, and spent much of her time manipulating the organelle’s rophages—motile human immune cells that engulf pathogens activity to try to better understand how it works. Genetics meth- and cellular debris—by being taken up into vacuoles and break- ods could slow down or alter the organelle’s structure in days; ing out of those vacuoles into the cytoplasm. Researchers had certain pharmacological agents made it disintegrate in less than also described the bacteria quickly spreading among neighboring half an hour. But in 2008, Mukherjee stumbled across a new and cells. But Portnoy, who joined UPenn’s medical school in 1988, much faster way to cause intracellular mayhem. had found he could block this cell-to-cell spread by chemically inhibiting the polymerization of actin, a protein that cells use The technique came from a paper by Craig Roy at Yale Uni- to build an intracellular cytoskeleton to aid cell motility, divi- versity School of Medicine. Roy’s team had found that “this sion, and other important processes. Intrigued, Tilney took on protein called AnkX, when microinjected into cells—even at the project, and together the pair showed that after breaking out picomole levels—could cause the entire Golgi to fragment in, of the vacuole, Listeria managed, somehow, to construct its own like, five minutes,” Mukherjee says. Remarkably, AnkX hadn’t tail-like structure out of actin filaments. been made by cell biologists or a pharmaceutical company. Rather, it was produced by a tiny intracellular bacterium Studying bacterial interactions known as Legionella pneumophila, the pathogen behind a seri- with actin is still throwing up ous lung infection called Legionnaire’s disease.1 For Mukher- new mysteries. jee, the paper was a revelation: not only did it identify the fast- est way yet to target Golgi biology, it suggested that scientists The resulting little Listeria “comet,” as the pair called it, used could use intracellular bacteria “as a lens to understand basic its new actin motility to whiz around the cytoplasm and even- processes inside the cell.” tually hurl itself at the plasma membrane, causing a protrusion that extended into a neighboring macrophage. This protrusion Intrigued by this powerful little microbe, Mukherjee applied got engulfed by the recipient cell to form a vacuole, and Liste- for a postdoc in Roy’s lab, where she would study in detail how ria then simply had to muscle out of its new compartment to Legionella attacks human cells from the inside. She learned that complete infection.2 (See illustration on opposite page.) Portnoy researchers had identified more than 300 Legionella peptides that and Tilney described the whole process in a 1989 paper, observ- mimic host proteins or otherwise hijack existing cellular pathways ing that their findings “should be important to those concerned to the bacterium’s advantage. And she gained a new appreciation with stages in the cell biology of infection by parasites and . . . for the myriad other types of intracellular bacteria, a diverse group exciting to cell biologists who want to know how actin filaments that includes many medically significant pathogens such as Salmo- become organized in cells.” nella, Listeria, and Chlamydia, as well as the causative agents of tuberculosis and leprosy. (See Bug Box on page 42). These microbes all enjoy at least part of their lives shielded from the onslaught of white blood cells, antibodies, and other immune defenses that the body launches against pathogens that live outside of host cells. As a trade-off, they have had to come up with ways to bypass a cell’s internal immune system, navigate the complicated, busy environment of the cell cytoplasm, and ulti- mately escape that environment to infect other cells—becoming tiny maestros of manipulation in the process. Research on how intracellular bacteria take control of their hosts is not only informing scientists about how these microbes cause disease, but revealing secrets of mammalian biology, says Mukherjee, who now heads up a lab at the University of Califor- nia (UC), San Francisco. These bugs have a knack for pinpoint- ing critical cell functions, she says, adding fondly that Legionella is continuing to help her explore how eukaryotic cells work. “It’s an excellent cell biologist.” 38 THE SCIENTIST | the-scientist.com

Many other scientists have since joined in the study of to dodge the cell’s immune defenses and survive a chemical Listeria’s actin co-option. Pascale Cossart, a microbiologist environment they have little control over. Some bacteria avoid who was studying Listeria virulence at the Pasteur Institute these inconveniences by instead occupying organelle-like com- in the 1990s, soon identified a bacterial protein, ActA, that partments that separate them from the rest of the cell. These the microbes require to build their tails.3 Cell biologist Mat- microbes can and do still interact with actin—some secrete thew Welch, then at UC San Francisco, and colleagues next iso- proteins that cause rearrangements in the cell cytoskeleton lated a host cell protein complex, Arp2/3, that is also necessary to help take up the bacterium from outside, or to form high- for Listeria to become motile. The team found that Listeria’s way-like protrusions into other cells, for example. But many ActA was recruiting the Arp2/3 complex to the bacterial cell have also mastered a different sort of target that allows them surface, and this was what was initiating actin polymeriza- to wield control over the rest of the cell without venturing into tion—confirming that the bacterium was co-opting the cell’s the cytoplasm: namely, lipid membranes. own machinery and raw materials for personal use.4 The work hinted that eukaryotes might possess their own Arp2/3-ac- It was Legionella’s ability to take over and even mimic intra- tivating proteins, and sure enough, researchers have since cellular membranes that occupied Mukherjee during her post- described a whole family of host actin nucleation–promoting doc at Yale. It turned out that AnkX, the same microbial protein factors, which Listeria’s ActA successfully mimics. that had caused the Golgi apparatus to disintegrate, was part of a larger scheme to coerce the host into preparing a bacte- A number of other intracellular bacterial taxa—including Shi- ria-friendly compartment. Legionella was using AnkX, among gella, Rickettsia, Mycobacterium, and Burkholderia—have been other peptides, to target host enzymes known as Rab GTPases, observed constructing their own actin tails, often by hijacking which sit on the surface of organelles such as the endoplasmic Arp2/3. And while many take a Listeria-like approach to infect- reticulum and the Golgi apparatus and regulate the trafficking ing new hosts (shoving into neighbors and being taken into vac- of protein cargo around the cell. (See illustration on page 40.) uoles), it’s not the only way. Welch, now at UC Berkeley, and grad student Nora Kostow recently used live cell imaging and Specifically, Mukherjee, Roy, and colleagues showed that other technologies to study Burkholderia thailandensis, which by making an unusual type of modification known as phos- spreads by causing neighboring cells to fuse. The bacteria essen- tially expand “the available environment for them to grow,” says ACTIN TAILS Welch. “They can do that repeatedly, so you can get hundreds of cells fusing together in some cases.” He and Kostow showed Some intracellular bacteria use the host cell’s actin supplies to that actin-powered B. thailandensis achieves this spread by push- build their own transport system. The foodborne pathogen Liste- ing on the plasma membrane to create protrusions that, rather ria monocytogenes infects immune cells called macrophages by than create vacuoles in a neighboring cell, cause those two cells to become one.5 This melding appears to be dependent on specific being taken up into a vacuole 1 before entering the cytoplasm proteins secreted by the bacterium as it forms the protrusions— where it lives and replicates 2 . There, it uses a protein called an insight that could help cell biologists understand cell fusion more generally, the authors write in their paper. ActA to recruit the host cell’s actin polymerization machinery Studying variations on these bacterial interactions with to construct a tail of actin filaments behind it 3 . This process actin is still throwing up new mysteries. While investigating Mycobacterium marinum, a close relative of M. tuberculosis, gives the bacterium a means to propel itself around and lets it Welch and postdoc Norbert Hill recently found that microbial push on the host cell membrane, forming protrusions into neigh- proteins could confer actin motility not just on the bacterium, but also on another sort of intracellular object: lipid= droplets.6 boring cells 4 . Those neighbors take up these protrusions as It’s not yet clear how this lipid movement relates to Mycobac- terium’s presence, “but it’s tempting to speculate that it could vacuoles, from which Listeria escapes to access the cytoplasm happen during infection,” either to the bacterium’s benefit or as some cellular response to infection, Welch says. Several lines and begin the cycle again 5 . of research suggest that Mycobacterium species might use lipid droplets as a source of chemical energy, among other things, he Listeria adds, so perhaps it’s in the bacterium’s interest to have those monocytogenes droplets whizzing around too. Macrophage Master the membrane The cytoplasm isn’t for everyone. While bugs such as Liste- 1 ria gain access to building materials like actin, they also have © SCOTT LEIGHTON 2 5 3 Vacuole ActA Actin 4 filaments WINTER 2022 | T HE S CIE N T IST 3399

Legionella pneumophila 2 1 Vacuole E ector protein 3 REROUTING MEMBRANE TRAFFIC Ribosomes 4 Endoplasmic Some intracellular bacteria, such as Legionella pneumophila, reticulum inhabit membrane-bound compartments inside host cells 1 . Golgi apparatus Once there, the microbes typically interact with host membranes and secrete so-called e ector proteins that help the microbes wield control over them 2 . Legionella in particular interacts with the Golgi apparatus and the endoplasmic reticulum, pilfering some of the organelles proteins and rerouting their vesicular tra c. Later, the newly formed membranes become studded with ribosomes 3 that may help the bacterium make certain host pro- teins—or could simply be a byproduct of the membrane’s ER-like identity. Legionella replicates inside this compartment before bursting out of the cell 4 . phocholination to one of the cell’s Rab proteins, Legionella partment, while rerouting the organelle’s vesicles to itself as was able to cause a “massive and quick collapse of the [host] a source of lipids. trafficking pathway,” Mukherjee says.7 This was in addition to its recruitment of that same Rab protein through a sepa- Other intracellular bugs have found different ways to mess rate mechanism to the surface of its own intracellular com- with a cell’s membranes. The single-cell parasite Toxoplasma gon- partment, converting its hideaway into something resembling dii, which the Centers for Disease Control and Prevention esti- the endoplasmic reticulum. Labs including Roy’s have since mates currently infects more than 40 million people in the US showed how this membrane conversion is part of a process alone, survives in an intracellular vacuole, from which it deploys that preps Legionella’s compartment for bacterial replica- proteins to subvert host cell function. Researchers observed tion. Similar membrane-copying or -hijacking processes have decades ago that the T. gondii vacuoles, like several types of been described in other microbes, too. The sexually transmit- bacterial compartments, often become surrounded by mito- ted pathogen Chlamydia trachomatis, for example, conspires chondria—a phenomenon that’s now thought to be related to a to reorganize Golgi membranes around its intracellular com- cellular anti-pathogen response, says Lena Pernas, a parasitolo- gist-turned-cell-biologist at the Max Planck Institute for the Biol- “If you slow down the ogy of Ageing in Cologne, Germany. leading ribosome, the ribosome after it goes Pernas’s team recently found that T. gondii is able to sub- and hits it . . . just like vert and exploit this mitochondrial mobbing by secreting a pro- a pile-up in a freeway.” tein that causes the organelles to cast off the outer of their two membranes.8 “We’re not sure exactly how that happens . . . and —Shaeri Mukherjee, UC San Francisco this is the subject of ongoing work in the lab,” Pernas says. But her team’s experiments do suggest that the shedding behavior is a natural mitochondrial response to outer membrane stress that can occur even in uninfected cells, and that T. gondii has hijacked this process—perhaps by mimicking a host protein that normally triggers the reaction. Whether other pathogens exploit this or related pathways remains to be seen, although some researchers have noted that at least one of the mitochon- drial proteins mentioned in Pernas’s study also seems to be tar- geted by viruses such as SARS-CoV-2. It wouldn’t be surprising to discover new types of mem- brane manipulation, Mukherjee says, adding that the behavior offers a versatile way to exert influence over everything from cell division to the intracellular positioning of organelles and even pathogens themselves. “That’s why various bacteria target var- ious membranes inside the cell.” 40 THE SCIENTIST | the-scientist.com

Altering hosts’ destiny Some intracellular bacteria appear to take a different tack: Intracellular bacteria and other parasites carry their own pro- instead of prompting cells to self-destruct, they can cause tein-making machinery, so it might sometimes make sense for changes in their host’s cell type. The University of Edinburgh’s them to shut down or pause most of the host’s protein produc- Anura Rambukkana has studied reprogramming by Myco- tion. “The host will most likely make proteins that are del- bacterium leprae, which causes leprosy. These bacteria infect eterious for the bacteria,” explains Mukherjee, who recently Schwann cells, glial cells that surround neurons and help showed that Legionella is able to block protein synthesis by develop and repair peripheral nerves. Infection typically triggers targeting a host peptide involved in protein folding.9 On the widespread neurological injury and, eventually, loss of other hand, an intracellular bacterium doesn’t want to kill sensitivity to pain or touch in affected limbs. But in 2013, Ram- off its host before it’s ready to move on, or to miss out on the bukkana and colleagues reported results from a series of in vitro opportunity to get the host to perform energy-intensive tasks and mouse experiments that suggested the bacterium was first on its behalf. hijacking their hosts’ gene expression, apparently reprogram- ming Schwann cells back into a stem-cell-like state.11 (See illus- Faced with these trade-offs, some bacteria launch a tration below.) well-choreographed effort to manipulate what a cell can and can’t make at different times during infection. For example, This tweaking of gene expression seems to aid M. leprae’s Mukherjee and colleagues recently identified a tRNA-mim- spread in at least two ways. First, altered cells can go on to icking toxin secreted by Legionella that stalls the movement differentiate into other cell types, including muscle cells, says of host ribosomes along RNA, causing collisions. “If you slow Rambukkana, potentially seeding the bacteria in these other down the leading ribosome, the ribosome after it goes and hits tissues. Second, reprogrammed cells attract macrophages, it . . . just like a pile-up in a freeway.” This sets off a cascade of which themselves can pick up the infection and spread it to events in the cell, the researchers found, including large-scale other tissues. The team is currently working to understand alterations to gene expression that allow just a few key tran- more about the mechanisms underlying this cellular rewir- scripts to bypass the traffic jam and get translated into proteins. ing, as well as exploring potential therapeutic applications of The response leads to controlled cell death, which is good news the phenomenon. For example, studying the factors the bac- for Legionella: the host breaks open, releasing the bacteria to teria use to reprogram cell state might offer new techniques go on to infect other cells.10 It’s yet another case of a microbe for regenerative medicine, Rambukkana says. The team is teaching biologists about how cells work, says Mukherjee, who currently testing some of these principles in nine-banded described the research in a preprint on bioRxiv—the team only armadillos (Dasypus novemcinctus)—not an ideal model for discovered the genetic response to ribosome collisions thanks human biology, but one of M. leprae’s few natural hosts other to Legionella’s ability to target that pathway. than humans. REPROGRAMMING THE HOST Muscle cells WINTER 2022 | T HE S CIE N T IST 4411 Mycobacterium leprae, which causes leprosy, takes cell reprogramming to an extreme by reverting its Schwann cell host into a stem cell–like state 1 . These cells can then redi erentiate into muscle cells, for example, perhaps spreading the bacterium to other tissues 2 . The reprogrammed cells can also pass the infection on to macrophages, which then form structures known as granulomas before going on to spread the infection themselves 3 . ILLUSTRATIONS BY © SCOTT LEIGHTON 2 Mycobacterium 1 leprae 3 Infected Schwann cell Stem cell–like cell Macrophage

Cossart, now a visiting scientist at EMBL Heidelberg in want to study fundamental processes,” she says. That work can Germany, calls the work on Schwann cell reprogramming a “have an impact down the road.” g “very interesting” line of research and notes that these kinds of findings highlight just how varied intracellular pathogens Some bacteria launch a are in their attempts to subvert cell function. “There are dif- well-choreographed effort to ferent types of result with different types of pathogens,” she manipulate what a cell can notes, adding that in addition to studying species differences, and can’t make at different researchers should dig into variation among different strains of times during infection. bacteria and under different conditions if they want to under- stand the biological consequences of infection. It’s only rel- atively recently, for example, that scientists have started to consider intracellular bacteria’s interactions—direct or indi- rect—with the microbiome of the organisms they infect, a research area that Cossart says deserves more attention. In many cases, though, the wider impact of research using intracellular microbes may be hard to estimate in advance, says Mukherjee, noting that tools such as CRISPR grew out of basic research—in that case, on a system bacteria use to defend them- selves from infection by viruses. “We are basic scientists, we BUG BOX References © ISTOCK.COM, CIPHOTOS; © ISTOCK.COM, GILNATURE 1. X. Pan et al., “Ankyrin repeat proteins comprise a diverse family of bacterial Intracellular bacteria vary considerably in how dependent they are on their hosts. So-called facultative intracellular bacteria type IV effectors,” Science, 320:1651–54, 2008. such as Listeria monocytogenes and Legionella pneumophila do 2. L.G Tilney, D.A. Portnoy, “Actin filaments and the growth, movement, and not need to be inside a host cell to reproduce. By contrast, obligate intracellular bacteria such as Chlamydia trachoma- spread of the intracellular bacterial parasite, Listeria monocytogenes,” J Cell tis and Mycobacterium leprae do, and this trait makes them a Bio, 109:1597–608, 1989. challenge to culture and study in the lab. Obligate intracellular 3. C. Kocks et al., “L. monocytogenes-induced actin assembly requires the actA pathogens will often have reduced genomes compared to the gene product, a surface protein,” Cell, 68: 521–31, 1992. facultative variety, a genetic tendency that is reflective of their 4. M.D. Welch et al., “Actin polymerization is induced by Arp2/3 protein complex more limited lifestyle. at the surface of Listeria monocytogenes,” Nature, 385:265–69, 1997. 5. N. Kostow, M.D. Welch, “Plasma membrane protrusions mediate host cell-cell Listeria monocytogenes fusion induced by Burkholderia thailandensis,” Mol Biol Cell, 33:ar70, 2022. 6. N.S. Hill, M.D. Welch, “A glycine-rich PE_PGRS protein governs Chlamydia trachomatis mycobacterial actin-based motility,” Nat Commun, 13:3608, 2022. 7. S. Mukherjee et al., “Modulation of Rab GTPase function by a protein 4422 TTSHDE ISGCEISETN|TtIhSeT-s| ctiheen-tsicstie.cnotmist.com phosphocholine transferase,” Nature, 477:103–6, 2011. 8. X. Li et al., “Mitochondria shed their outer membrane in response to infection-induced stress,” Science, 375:eabi4343, 2022. 9. S.M. Moss et al., “A Legionella pneumophila kinase phosphorylates the Hsp70 chaperone family to inhibit eukaryotic protein synthesis,” Cell Host Microbe, 25: 454–62.E6, 2019. 10. A. Subramanian et al., “A Legionella toxin mimics tRNA and glycosylates the translation machinery to trigger a ribotoxic stress response,” bioRxiv, doi:10.1101/2022.06.10.495705, 2022. 11. T. Masaki et al., “Reprogramming adult Schwann cells to stem cell-like cells by leprosy bacilli promotes dissemination of infection,” Cell, 152: 51–67, 2013.

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Protecting Pregnancy Carefully calibrated immunological changes in mothers are critical for a healthy pregnancy. Understanding how the body balances immune tolerance and protection from infection will allow us to improve pregnancy outcomes. BY TOBIAS R. KOLLMANN, ARNAUD MARCHANT, AND SING SING WAY MODIFIED FROM © ISTOCK.COM, ELENABS We first met Kate and her husband Adam in 2016 when don’t make it as long as James did, dying even before delivery. she was 26 weeks pregnant and in labor. Within Every 16 seconds a baby is stillborn somewhere in the world; hours, she gave birth to twins, James and Fraser. this amounts to more than 2 million stillborn babies globally The newborns weighed in at just around 1 kilogram each. “See- every year. Of babies that are born alive, shockingly high num- ing them—so tiny and fragile, but alive—flooded my body with bers of them are born too early. A baby is born prematurely every sheer relief,” Kate wrote of the experience in an email. “I touched two seconds, resulting in 15 million preterm babies every year. their little hands before they were wheeled away into the Neona- Sadly, 1 million of these preterm babies die every year due to tal Intensive Care Unit (NICU).” direct complications from preterm birth, and another 800,000 of them die from infections associated with preterm birth. Kate pumped breast milk that was fed to the newborns to Preterm birth remains the leading cause of death for babies and help them grow. But before long, James took a turn for the worse, young children the world over. developing a devastating intestinal condition known as necrotiz- ing enterocolitis. Surgeons needed to cut a tiny hole in his belly Preterm birth is also the leading cause of childhood dis- to allow gas to be released from his bowel, but bacteria from his ability, with 1.3 million preemies every year suffering major damaged colon had spread through his body. After just three and disabilities such as breathing difficulties, blindness, and cere- a half weeks, we had to tell Kate and Adam that James wouldn’t bral palsy. Moreover, susceptibility in the perinatal window is survive, and that it was time to say goodbye. not limited to babies. Nearly 300,000 mothers die every year due to complications of pregnancy and childbirth. Together, Unfortunately, James’s story is not unique. Millions of little adverse pregnancy outcomes and the associated deaths and lives are lost around the time of birth every year. Some babies WINTER 2022 | THE SCIENTIST 45

disabilities constitute the deadliest and longest pandemic of pregnancy stimulates maternal T cells to adopt functionally unique human history. properties. Researchers have shown, for example, that maternal CD8+ killer T cells develop an exhaustion-prone phenotype, mean- Despite the high and steady death toll, vulnerability during ing that they selectively silence killer-cell properties upon re-en- pregnancy and early in life has for too long been accepted as countering fetal antigens in subsequent pregnancies.2,3 At the same unavoidable. Although adverse pregnancy outcomes consis- time, one of us (S.S.W.) and colleagues have shown that pregnancy tently rate as one of the top three causes of death across the entire stimulates the differentiation of CD4+ T cells, which are dedicated human lifespan, research to address it receives less than 1 percent to suppressing, instead of activating, other immune cells.4 Per- of total funding. This disconnect has been thrown into stark relief sistence of these immune-suppressive T cells after pregnancy may by the ongoing COVID-19 pandemic. Not only does SARS-CoV-2 explain why the incidence of pregnancy complications is sharply represent yet another pathogen that increases risk for stillbirth, reduced in second compared with first pregnancies5,6—and why preterm birth, and maternal death, uncertainty surrounding the these protective benefits appear to be paternity-specific.7 Such risks to pregnant people and their fetuses who are exposed to the immune tolerance may be further enforced by fetal cells that con- virus highlights the broader reality that the immunology of preg- tinue to circulate in the mother’s bloodstream.8 nancy remains largely enigmatic and understudied. A mother cannot afford to totally suppress her immune sys- Indeed, much remains unknown about the factors associated tem, however, as pathogens are an ever-present threat. In addi- with adverse pregnancy outcomes. Nevertheless, the little that is tion to warding off infection as well as possible during pregnancy, known strongly supports the idea that modulation of the mother’s a mother’s body will send immune sentinels across the placenta to immune system—for example, through diet or maternal vaccina- provide protection to the baby after it’s born. For example, we and tion—can improve pregnancy outcomes. Furthermore, given the others have found that transfer of maternal antibodies to the fetus scalability of these interventions, finally addressing this massive occurs in utero, ramping up significantly at 30–34 weeks gesta- crisis is within reach. tion.9 Transfer of immunological experience continues postnatally through breast milk, which provides protective benefits to babies For the duration of pregnancy, immune tolerance of the baby, beyond the neonatal window. who is genetically foreign to the mother’s body, is critical. So is immune resilience—avoiding undue inflammation, for example, Adverse pregnancy outcomes and the in the face of benign commensal microbes. But inflammation is associated fetal, neonatal, and maternal required for the separation of the maternal and fetal layers of the deaths constitute the longest, deadliest placenta that occurs leading up to birth. The timing and induc- pandemic of human history. tion of this inflammation is tightly controlled by physiological signals from both the fetus and the mother around 37 to 42 ges- Although such vertical transmission of antibodies has long tational weeks. Anything that activates this inflammatory cas- been recognized, details of such immune sharing continue to be cade too early—what’s known as aberrant immune activation— unveiled. Earlier this year, one of us (S.S.W.) and colleagues found can result in the premature separation of the maternal and fetal that pregnancy actively modifies the molecular structure of anti- placental layers, ultimately causing preterm birth. Interventions bodies, expanding their protective scope beyond extracellular that avert unnecessary inflammation thus should reduce the risk pathogens to include immunity against microbes that live inside of pregnancy complications. By applying the tools of modern sci- cells.10 This resolves a long-standing conundrum for how antibod- ence to understand the immunological dynamics of gestation, we ies work against pathogens such as HIV, tuberculosis, or Zika virus may be able to save millions of lives and put an end to this sub- that live inside cells and thus were once thought to be hidden from stantial cause of suffering. antibodies. It also implies that maternal antibodies are not simply immunological effectors, but also serve to activate and regulate an Immunobiology of pregnancy infant’s developing immune system, supporting the idea that vac- Pregnancy is an immunological marvel, representing the only nat- cinating expecting mothers or reproductive-age women (and other ural physiological state where genetically foreign cells and tissues individuals capable of pregnancy) prior to conception helps young lie in close physical contact with the host immune system with- babies in developing their own defense against microbes. out rejection. What prevents maternal immune cells from attack- ing fetal tissues remains unclear. Aberrant activation of maternal Of course, not all microbes that we encounter are pathogenic; immune components associated with pregnancy complications many are harmless or even beneficial. In the context of pregnancy, such as prematurity likely represents defects in pregnancy- controlling inflammation induced by microbes in the birth canal induced immune tolerance and resilience. is likely important, as vaginal dysbiosis has increasingly been Interestingly, prior pregnancies appear to protect against such complications in future pregnancies. Mothers of sons immuno- logically remember their babies thanks to long-lived T cells with specificity for Y-chromosome-encoded antigens.1 Recent charac- terizations of these fetal-specific T cells in mice have revealed that 46 THE SCIENTIST | the-scientist.com

MODIFIED FROM © ISTOCK.COM, ELENABS linked with prematurity and other pregnancy complications. For pregnancy.13 This suggests that maternal vaccination could example, spontaneous preterm birth is consistently linked with be deployed to intentionally modulate the immune system of depletion of Lactobacillus crispatus species and high diversity pregnant women to reduce aberrant immune activation and of other vaginal microbiota.11 From the babies’ perspective, rec- thereby protect against adverse pregnancy outcomes. For ognizing the difference between microbial friend and foe is crit- example, mothers experienced improved pregnancy outcomes ical at birth, as they undergo an abrupt transition to the external following maternal influenza vaccination even outside of flu world and its plethora of commensal microbes.12 In this context, season, indicating pathogen-agnostic rather than only patho- microbe-induced inflammation is likely to be more damaging gen-specific benefits following vaccination during pregnancy. than helpful. Here again, immune molecules, including antibod- Additionally, a recent study demonstrated that BCG immuni- ies, transferred from the mother to the newborn are likely key for zation of women prior to pregnancy also reduced the incidence the regulation of baby’s response to unharmful microbes. of adverse pregnancy outcomes, suggesting vaccine-induced modulation of immune trajectories impacting pregnancy may The intricacy of immune regulation in pregnancy remains extend to before the gravid period.14 largely a black box, with many fundamental questions left unan- swered. Answering such questions will be essential to under- Given that the upstream causes of adverse pregnancy out- standing and addressing the aberrant maternal immune activa- comes are not sufficiently well understood, it comes as no surprise tion that can lead to adverse pregnancy outcomes. that insights into vaccine-induced pathogen-agnostic immune- modulatory effects of maternal vaccination improving pregnancy Immunological interventions to improve outcomes are limited. Mechanisms could relate to overall immune pregnancy outcomes regulation, such as increased resilience to various immune per- Even with the current, relatively rudimentary understand- turbations. They also could relate to increased innate immunity ing of the immunological processes at play during pregnancy, providing broad pathogen-agnostic protection from a variety of there are immune-modulatory approaches clinicians are potential microbial culprits, akin to the concept of trained immunity. already employing to protect pregnancies and newborns. The most direct approach relates to maternal vaccination against Even less is known about how more-indirect immune- common diseases. As infections are generally associated with modulatory approaches such as dietary interventions reduce adverse pregnancy outcomes, protecting mothers against adverse pregnancy outcomes. For example, omega-3 fatty acids infection can help reduce the risk of preterm births and still- supplements, which have been shown to protect against preterm births. Such protective effects have been noted with maternal labor in populations where omega-3 deficiency is common, may influenza and pertussis immunization already, where reduc- act via systemic immune modulators of fatty acid origin (eicosa- tion of risk for stillbirth or preterm birth was as high as 50 noids). Another supplement, the amino acid L-arginine, simi- percent in mothers who received either influenza or pertussis larly appears to protect against preterm birth, as well as stillbirth, vaccinations, or both. When it comes to COVID-19, data point especially in malaria-infected women, possibly due to a reduction to a higher risk of preterm birth and stillbirth following mater- of inflammatory processes in the placental vascular bed. nal infection, indicating that maternal vaccination not only protects the mother from severe disease but can also prevent Irrespective of the missing insight, data showing improved adverse pregnancy outcomes. pregnancy outcomes for vaccinated mothers or those taking omega-3 or L-arginine supplements are proof that the global Maternal vaccination against various pathogens has also long burden of pregnancy complications might be reduced through been recognized for its ability to protect newborn babies, thanks targeted interventions. Moreover, such interventions offer to the antibodies transferred in utero and in breast milk.9 For ideal opportunities to decipher underlying protective mecha- example, maternal tetanus vaccination, together with improved nisms. Our hope is that, in the future, maternal immunization birth and umbilical cord hygiene practices, has reduced neonatal and nutritional strategies can be improved and better inte- mortality from tetanus by nearly 90 percent over the last decade. grated to optimally protect both mother and child. Similarly, maternal pertussis vaccination prevents severe whoop- ing cough early in the baby’s life. Call to action The scale of human suffering during the early life developmen- Importantly, vaccines modulate the immune system in tal window from conception to birth and beyond constitutes an ways far beyond pathogen-specific immune responses as well. ongoing public health emergency of frightening proportions. This has been well documented in non-pregnant vaccine recip- Tackling this problem also constitutes a massive opportunity. ients but is likely also occurring in women vaccinated during Specifically, implementing interventions of promise to pro- WINTER 2022 | THE SCIENTIST 47

IMMUNOLOGY DURING PREGNANCY During pregnancy, the immune system adapts to support the baby’s development and coordinate birth. When immunity goes awry, so can the pregnancy, with adverse outcomes such as preterm birth and stillbirth often resulting from aberrant immune acti- vation. Diet or maternal vaccination are examples of how to modulate the immune system to improve pregnancy outcomes. IMMUNE TOLERANCE AND RESILIENCE MATERNAL IMMUNE Pregnant individuals must both tolerate a genetically foreign fetus FACTORS (immune tolerance) and avoid overreacting to the presence of microbes with inflammatory cascades that could jeopardize the pregnancy (immune resilience). To do this, they generate exhaustion-prone T cells that selec- tively silence killer-cell properties as well as long-lived immunosuppres- sive T cells. Both appear critical to a healthy pregnancy by averting aber- rant immune activation. Conversely, an imbalance in the commensal microbes of the birth canal can trigger immune responses that have been linked with prematurity and other pregnancy complications. BIRTH CANAL THE SCIENTIST STAFF; COMPOSITE FROM © ISTOCK.COM, GUZALIIA FILIMONOVA, VIKIVECTOR; RENDIXALEXTIAN; SFISCHKA VERTICAL TRANSFER OF MATERNAL IMMUNITY MATERNAL FETAL Antibodies and other immune factors can pass across the placenta from EXCHANGE mother to child, as well as through breast milk after birth. This means that a mother’s acquired immunity to pathogens, including through vaccination, can protect the baby after birth. In addition to providing postnatal protection against specific pathogens, maternal immune molecules transferred to the baby can regulate the fetal and newborn immune system. Such factors can support the baby’s in utero immune tolerance to the genetically foreign mother as well as its immune resil- ience before and after birth, avoiding excessive immune activation by commensal microbes. 48 THE SCIENTIST | the-scientist.com