Volume 110, Number 3, May–June 2022 American Scientist

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The electric legacy of SHARKS' SIXTH SENSE

The roundabout path of the WORLD'S WEEDKILLER

Why wood duck moms ROVE OR STAY AT HOME

AMERICAN

Scientist May–June 2022

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The Rise of New Pathogens What causes mildmannered microbes to turn into human scourges?

AMERICAN

Scientist Departments 130 From the Editors 131 Letters to the Editors

Volume 110 • Number 3 • May–June 2022

Feature Articles

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134 Spotlight Mercury’s mountains • The chemistry of dahlia flower colors • The enduring legacy of the Maya • Briefings 144 Digital Feature Preview Putting eggs in many baskets John M. Eadie, Bruce E. Lyon, and Eli S. Bridge 148 Technologue Chemical maps, parasitic diseases, and drug development Laura-Isobel McCall 152 Perspective The discovery of the shark’s electric sense David Shiffman

162 How Bacterial Pathogens Emerge Can scientists predict where diseasecausing microbes will arise before they cause the next pandemic? Salvador Almagro-Moreno

170 How Glyphosate Cropped Up The controversial herbicide, originally developed in a quest for improved water softeners, became ubiquitous in modern agriculture long before its mode of action was understood. Philip A. Rea 178 The Chemical History of Superior Glass A glassmaker and a physicist teamed up to improve scientific lenses. Their developments revolutionized both laboratory equipment and domestic cookware. Ainissa Ramirez

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158 Engineering Frozen tomatoes and other construction materials Henry Petroski

Scientists’ Nightstand

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184 Book Reviews Vital signs • Exemplary science

189 Sigma Xi Today From the President: Of honor and honoring • 2022 International Forum on Research Excellence (IFoRE) • Faces of GIAR: Deborah Neher and Peteneinuo Rulu • Women in STEM

The Cov er The plague and cholera have killed millions of people over the past centuries. Each of these diseases is caused by a bacterium that began as a harmless ancestor microorganism but evolved to become one of humanity’s worst scourges. This process, known as pathogen emergence, is difficult to predict. In “How Bacterial Pathogens Emerge” (pages 162–169), Salvador Almagro-Moreno describes how his laboratory and others are trying to understand the biological rules and evolutionary forces that make a microorganism transition to causing disease in humans. For example, human-made ecological perturbations, such as climate change and pollution of ecosystems, are drastically affecting the spread and proliferation of disease-causing bacteria, accelerating the acquisition of antibiotic resistance, and increasing the likelihood that novel pathogens will emerge. Research in this area is beginning to provide the tools needed to forecast the events and drivers that lead to the emergence of novel infectious agents. Such research is pivotal for successful disease management and control. (Illustration by Joana C. Carvalho).

Everett Collection

From Sigma Xi

From the Editors

Incremental Steps

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Scientist www.americanscientist.org VOLUME 110, NUMBER 3

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ome content in this issue’s pages really isn’t in these pages at all. This issue showcases a snippet of a digital feature, available in full only on our website. The digital feature discusses the confusing behavior of wood ducks, a species that engages in nest parasitism, in which some ducks lay eggs in the nests of others. John M. Eadie and his colleagues have studied this wood duck behavior for decades, using radio-tracking tags, genetics, and videography to tease out the reasons a female would risk putting her eggs in the care of another bird. Is it nest scarcity, lack of experience, physiological stress, a way to increase reproductive output—or is it actually a form of cooperation? The preview (“Putting Eggs in Many Baskets,” pages 144–147) gives you a sense of the article’s content, but be sure to go online for the full story and experience, which includes an array of photographs, videos, animations, and data visualizations. And then let us know what you think of the digital feature format. The online platform allows us to integrate multimedia into articles seamlessly, while providing what we hope is an engaging experience. The development of understanding over time is a theme that comes up in “How Bacterial Pathogens Emerge” (pages 162–169), by Salvador Almagro-Moreno. Given the countless number of bacteria and viruses out there, very few become pathogenic. Almagro-Moreno explains the different mechanisms by which a microorganism might gain the genetic material to become dangerous to humans, and the ways that genetic preadaptations might make some strains more receptive to gene incorporation. He also discusses the pathways that microorganisms have evolved to temper their uptake of genes, which can sometimes cause them more harm than good, and how predation on bacteria— by protozoa and amoebae, for example—can lead bacteria to develop evasion mechanisms that have the accidental side effect of increasing their ability to colonize human hosts. Another convoluted story of discovery can be found in “How Glyphosate Cropped Up” (pages 170–177). As Phillip A. Rea details, this ubiquitous herbicide, more commonly known as Roundup, came to be widely applied to crops worldwide before its mechanisms or its health effects were well understood. The compound itself was discovered in a circuitous fashion; initially it was explored as a potential water softener to prevent the buildup of limescale. Through a series of tests, attempts to optimize the compound, and the serendipitous discovery of a resistant bacterium in a wastewater pipe, chemists were able to tease apart the compound’s effects on a pathway found only in plants (a key enzyme in this process is shown above) and use that to best advantage in agricultural production. Other articles in this issue detail a wide range of discoveries, from sharks’ electrosense (Perspective, pages 152–157), to chemical mapping of organs to track pathogen accumulation and body symptoms (Technologue, pages 148–151), to the history of the types of glass that were strong enough for lab experiments but found equal success in cookware (“The Chemical History of Superior Glass,” pages 178–183). We hope you enjoy unraveling these discoveries with us. —Fenella Saunders (@FenellaSaunders)

Editor-in-Chief Fenella Saunders Managing Editor Stacey Lutkoski Senior Consulting Editor Corey S. Powell Digital Features Editor Katie L. Burke Senior Contributing Editors Efraín E. RiveraSerrano and Sarah Webb Contributing Editors Sandra J. Ackerman, Marla Broadfoot, Emily Buehler, Christa Evans, Jeremy Hawkins, Jillian Mock, Amanda Rossillo, Morgan Ryan Editorial Associate Mia Evans Art Director Barbara J. Aulicino SCIENTISTS’ NIGHTSTAND Book Review Editor Flora Taylor AMERICAN SCIENTIST ONLINE Digital Managing Editor Robert Frederick Publisher Jamie L. Vernon EDITORIAL CORRESPONDENCE American Scientist P.O. Box 13975 Research Triangle Park, NC 27709 919-549-4691 • [email protected] CIRCULATION AND MARKETING NPS Media Group • Beth Ulman, account director ADVERTISING SALES [email protected] • 800-243-6534 SUBSCRIPTION CUSTOMER SERVICE American Scientist P.O. Box 193 Congers, NY 10920 800-282-0444 • [email protected] PUBLISHED BY SIGMA XI, THE SCIENTIFIC RESEARCH HONOR SOCIETY President Robert T. Pennock Treasurer David Baker President-Elect Nicholas A. Peppas Immediate Past President Sonya T. Smith Executive Director Jamie L. Vernon American Scientist gratefully acknowledges support for “Engineering” through the Leroy Record Fund. Sigma Xi, The Scientific Research Honor Society is a society of scientists and engineers, founded in 1886 to recognize scientific achievement. A diverse organization of members and chapters, the Society fosters interaction among science, technology, and society; encourages appreciation and support of original work in science and technology; and promotes ethics and excellence in scientific and engineering research. Printed in USA

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Letters and then explaining why casinos enjoy favorable odds. One night I realized that many of my students, having grown up in the Bible Belt, had never played poker. I asked them whether they would like to learn how to play at our next class, just before spring break. All hands shot up. I thought, “Why not teach them to play? I have tenure.” My cautionary lessons were successful, but not in the way I had expected. When my students returned from break, one of them couldn’t wait to give me his news: “Dr. Silver! Guess what! I won 150 bucks at a casino in Biloxi!”

Gambling Lessons To the Editors: Catalin Barboianu’s article, “Understanding the Odds” (Perspective, March–April), is well-informed and thoroughly enjoyable. His warning that the language of pure mathematics must be appropriately interpreted before its theorems can be applied is spot-on and too seldom heard. The author’s recollection that studies were begun several decades ago “to test the hypothesis that teaching basic statistics and applied probability theory to problem gamblers would change their behavior” brought back the memory of an evening class that I taught 10 years ago at the University of South Alabama. The curriculum included teaching the basic probabilities involved in poker

Daniel S. Silver Mobile, AL

Nuclear Distinction To the Editors: The caption for the first image in Naomi Oreskes’s article “Operational Oceanography” (March–April) states, “The advent of nuclear submarines made it crucial to understand the oceans’ depths, which led the U.S. Navy to fund oceanographic research into deep-sea currents.” Is this a reference to nuclearpowered submarines, or to submarines

armed with nuclear missiles? Perhaps both usages are intended, but the loose use of the word “nuclear” leaves the question up in the air. Linking nuclear power with nuclear weapons in a reader’s mind does our energy-dependent society no good. Michael Attas Pinawa, Manitoba

Predicting the Next Note To the Editors: I was interested to read Esther M. Morgan-Ellis’s section on mitigations to overcome internet latency for virtual choirs (“Virtual Community Singing During the COVID-19 Pandemic,” January–February). My research group at the NASA Ames Research Center has developed latency compensation for 10–20 milliseconds teleoperation lag using predictive filters. These techniques may well be applicable to audio signals to predict note, volume, and tone. The predictive filter basically is a technique to use the history of a signal to guess where it will be in the near future. In the case of the voice signals, this kind of predictor would anticipate

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Accessing the New Digital Edition The January–February 2022 issue kicked off an enhanced experience for subscribers who receive the digital edition of American Scientist. The updated digital edition offers automatic reformatting for mobile devices and the ability to listen to an audio version of articles. Digital subscribers receive an email notification with each new issue. For more information on how to access the new edition, visit https://www.americanscientist.org/content/digital-edition learn more and to hear about his research on energy expenditure in traditional societies. www.amsci.org/node/3916

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It’s Time to Stop Gatekeeping Medical Transition

More Eggs in More Baskets

Did our preview “Putting Eggs in Many Baskets” (page 144) leave you wanting more information about how and why wood ducks parasitize other birds’ nests? Get the full story in our interactive digital feature, which includes videos, animations, and some very cute ducklings. www.amsci.org/node/4891 Bird Powers

The board game Wingspan, now available as an app, is both a fun game of strategy and an enjoyable way of learning about the natural history of birds. www.amsci.org/node/3934 How Our Evolutionary Past Shapes Our Health Today

Evolutionary anthropologist Herman Pontzer discussed common myths about metabolism and weight loss in his Science by the Slice presentation. Check out the video of the event to

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Gender-affirming interventions have been shown to benefit the health and well-being of trans and gendernoncomforming people. But the medical system is set up to see symptoms of gender dysphoria as reasons to bar treatment, particularly when it comes to mental health. www.amsci.org/node/4867 Evolution’s Empathetic Advocate

When it came to creationism, the late E. O. Wilson hated the sin but loved the sinner. www.amsci.org/node/4893

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where the singers appear to be going musically in terms of note, timbre, and volume. It would then present listeners an advanced signal compensated for the time lag. In the case of virtual choir, the known musical score would be especially helpful because a predictor designer could use it to provide accurate prediction assistance. Morgan-Ellis alludes to this kind of signal processing as being possible but requiring unusually fast computers. The clock on my six-year-old Apple laptop compares favorably with the machine that we used in our predictive filter experiments. Many even faster laptops are now available. Predictive filtering for virtual choirs should now be possible with widely available fast hardware, though it may need to be partially coded in assembly language for speed. Stephen R. Ellis Oakland, CA

Rapid Evolution To the Editors: When I read the Briefings section of the January–February issue, I was struck by the story about elephants rapidly evolving away from growing tusks as the ivory tusks had become a liability placing them in great danger from poachers. I’ve always thought of evolution as being a slow process involving hundreds, if not thousands of generations. Now, I have a whole new perspective on how environmental pressures can rapidly affect even the biggest and strongest mammals on Earth. One can only speculate on how these environmental pressures are currently directing our own evolution as human beings. For example, are we as a species currently evolving toward an existence that assimilates environmental plastic as an intrinsic property of our organism? How goes the elephant tusk, goes the human race? Richard Simpson Enumclaw, WA How to Write to American Scientist

Brief letters commenting on articles appearing in the magazine are welcomed. The editors reserve the right to edit submissions. Please include an email address if possible. Address: Letters to the Editors, P.O. Box 13975, Research Triangle Park, NC 27709 or [email protected].

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Spotlight | Planetary formation mountains when they collide. However, Mercury’s crust is a single continuous shell. Because there are no plates that could crash into one another and form mountains, it was long The mysterious rocky planet has the most peaks where its crust is thought that Mercury’s widespread thickest, and more may still be forming. lobate scarps had formed as a result of the planet’s interior cooling over time, causing the crust to shrink and The Solar System’s innermost planet cooling, shrinking, slowly dying world. randomly wrinkle. may be hiding big surprises beneath But a new analysis suggests that lobate In a paper published in August 2021 its small, battered surface. One of Mer- scarps may actually be a sign of a hot, in Geophysical Research Letters, Thomas cury’s most distinctive features is its churning interior and a surface that re- Watters and Michelle Selvans of the long, linear mountain chains, called mains geologically active to this day. Smithsonian’s National Air and Space Earth’s surface is broken into mov- Museum and Peter James of Baylor lobate scarps. For years, most scientists interpreted the scarps as wrinkles on a ing sections, or plates, that create University discovered a pattern in the seemingly random distribution of these mountain chains: Lobate scarps are concentrated in areas of thicker crust, particularly in the southern hemisphere. They also found that these areas of thick crust had been pushed together more forcefully than areas of thinner crust. Although the global distribution of lobate scarps supports the idea that Mercury’s surface is indeed wrinkling, their concentration in regions underlain by strained, thick crust suggests that additional factors have influenced their formation. “Something is helping to organize the forces that are acting to produce these faults,” said Watters. The team developed models of Mercury’s crustal thickness based on topographic and gravitational data collected by NASA’s Mercury Surface, Space Environment, Geochemistry, and Ranging ( MESSENGER) mission, which was launched in 2004 and ended in 2015. The models suggest that 250 kilometers Mercury’s crust was Courtesy of NASA/Johns Hopkins University/Carnegie Institution of Washington/Smithsonian Institution pushed together in specific Mercury’s mountains are globally distributed but form in clusters (indicated by white arlocations because of geological activity rows), suggesting that their formation is not random. Thomas Watters of the National Air in the mantle, which sits between a and Space Museum and his colleagues used images and mathematical models to underplanet’s crust and core. “There’s this stand how crustal thickness may be tied to mountain formation in the absence of plate phenomenon called downward mantle tectonics. In this false-color photograph, lower elevations are depicted in shades of blue and higher elevations in shades of red. flow where the material in the mantle

Mercury’s Mountains

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is descending toward the core,” said Watters. “As it does, it pulls crustal material together, thickens it, and compresses it.” This thickening and compression causes the crust to crack and shift, producing lobate scarps. Watters believes that Mercury may still be geologically active today because it has a magnetic field, which NASA’s Mariner 10 mission discovered in the 1970s. “There’s still a hot outer core on Mercury that’s liquid, and possibly still moving and convecting to generate that magnetic field,” he said. “There’s no reason to believe that Mercury has stopped contracting.” This idea is supported by photographs that MESSENGER captured during the last 18 months of its mission. Very-high-resolution images revealed small, relatively young lobate scarps, suggesting that newly formed faults are actively modifying Mercury’s ancient surface. Studying Mercury up close is not an easy task. Spacecraft require a lot of fuel to stay in orbit because the Sun’s gravitational pull is incredibly strong. Once there, spacecraft must then withstand the Sun’s scorching heat and intense radiation. Although there have

been 48 missions to Mars, including failed attempts, only two missions had been sent to Mercury as of 2017: MESSENGER in the 2000s and Mariner 10 in the 1970s.

Very-high-resolution images revealed small, relatively young lobate scarps, suggesting that newly formed faults are still actively modifying Mercury’s ancient surface. In spite of these hurdles, the next voyage to Mercury is already underway. Planetary scientists are eagerly waiting for the BepiColombo spacecraft, jointly developed by the European Space Agency and the Japan

Aerospace Exploration Agency, to enter orbit around Mercury in 2025 following its 2018 launch. The spacecraft is named after Italian engineer Giuseppe “Bepi” Colombo, who discovered that Mariner 10 could use Venus’s gravity as a slingshot to fly by Mercury multiple times, ultimately allowing it to photograph nearly half of the planet’s surface. The BepiColombo spacecraft used this same maneuver to make its first Mercury flyby in October 2021. Mariner 10 and MESSENGER revealed surprising insights about Mercury’s turbulent interior, and BepiColombo is expected to do the same through detailed analyses of the planet’s core, chemical composition, and surface. Ultimately, learning more about this enigmatic planet will help inform efforts to understand distant planets outside of our Solar System. “We still have a lot to learn in our own Solar System about how these rocky bodies evolve as they’re losing their interior heat,” said Watters. “That’s going to give us important insight into what we may be finding when we can examine the variety of Earth-like exoplanets that are out there.”—Amanda Rossillo

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Infographic | Andy Brunning

THE CHEMISTRY OF DAHLIA FLOWER COLORS

WHAT CAUSES DIFFERENT COLORS?

WHY DON’T WE SEE BLUE DAHLIAS?

The colors of dahlia flowers are a result of anthocyanin-, chalcone-, and aurone-derived pigments. Colorless flavones interact with and stabilize anthocyanin pigments, which also influences dahlia flower color.

A single enzyme, flavonoid 3’,5’H-hydroxylase (F3’5’H), is responsible for generating the precursor to the anthocyanidin delphinidin. Delphinidin-derived anthocyanins give blue colors. Dahlias cannot make the F3’5’H enzyme, so blue dahlias aren’t possible.

PIGMENTS IN DIFFERENT COLORED DAHLIAS

DIHYDROKAEMPFEROL OH HO

YELLOW

ORANGE

PINK, MAGENTA, & RED

Other anthocyanin precursors

O

OH

“BLACK”

OH

F3’5’H enzyme

O

DIHYDROMYRICETIN OH

Chalcones and aurones

Anthocyanins

Derivatives of butein, sulfuretin, and isoliquiritigenin

Derivatives of pelargonidin and cyanidin

OH

O

O OH Anthocyanidin synthase (ANS)

OH

OH

OH O+

HO

OH

HO

HO

OH

O

OH

OH

DELPHINIDIN

OH

BUTEIN

OH

PELARGONIDIN

OH

OH HO

OH

O+

HO

O+

HO

O

OH

OH

HO

OH

O

Dihydroflavonol reductase (DFR)

OH

OH

OH SULFURETIN

Ci

136

CYANIDIN

© Andy Brunning/Compound Interest 2021 - www.compoundchem.com | Twitter: @compoundchem | This graphic is reproduced by American Scientist with permission.

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First Person | Anabel Ford

Anabel Ford first encountered the ancient Maya settlement of El Pilar, which straddles the border between Guatemala and Belize, in 1983, and she has been working at the site ever since. El Pilar was filled with plazas, temples, and palaces, which were built from 800 BC to 1000 AD. Ford is a proponent of what she calls “Archaeology Under the Canopy,” excavating the site while engaging local Indigenous people, many of whom are Maya descendants, for their knowledge of what materials would have been used to build houses, and what plants would thrive there. Indeed, in addition to the extant structures, Ford has focused on preserving the Maya’s carefully tailored forest ecology practices that supplied them with food and building materials. El Pilar is now designated as an archaeological reserve and a cultural monument, and Ford has helped to found the El Pilar forest garden network to preserve Indigenous knowledge of Maya land management. As a doctoral student, Ford received a Sigma Xi GIAR grant that she used to study the volcanic ash composition of Maya pottery. Ford spoke about her developing understanding of this Maya site with American Scientist editor in chief Fenella Saunders. This interview has been edited for length and clarity. What have you uncovered about the source of volcanic ash in Maya pottery?

I did not discover volcanic ash in Maya pottery, but I discovered what it meant to geologists. The Maya lowlands is hundreds of kilometers away from fresh volcanic sources. Ancient Maya ash-tempered pottery was first recognized in 1937, but ash temper was simply used as a chronological marker with no reflection on the source. The topic resurfaced in the 1980s with my work and the work of others. When I worked with volcanologists and did petrography on thin sections of the sherds, the volcanologists were just floored, because to them it looked like the sherds had captured a contemporary airfall of volcanic ash. It looked like fresh ash embedded in the pottery, and tons of it. There was no evidence of abrasion, no indication of human manipulation, and the sorting and size were consistent with wind distribution. I had to convince them even that some of my samples were not mud, that it was really pottery, it had been fired. I thought we were going to solve all the problems of the Maya by finding that they collected the ash because it fell into their hands during the Late Classic Period (600–900 AD), and the eruptions also brought fertilizing volcanic minerals into the lowlands, so it explained the rise of the Maya. And then when that ashfall stopped somehow, we didn’t know how that would have happened either, but that it would also explain the collapse. So we wanted to explain it in one volcawww.americanscientist.org

nic swoop. We did a whole bunch of studies that we thought were going to solve these problems, but all it did was make it more difficult to sort out, because nothing was obvious. We tested four sherds, and the constellation of elements that emerged made it look like the volcanic ash in each had different sources. Although the volcanic glass had gone through temperatures and pressures unheard of in open pottery firing, still, when we conducted experimental firings with local raw clay matrices and ash samples from one of the closest volcanoes, Ilopango, at four temperatures, we found significant changes in the volcanic glass with firing. The size of the ash particles also made a difference. I then got in contact with a researcher who looks at zircons, and he thought for sure that this was going to be the solving of all of it. Zircons are some of the most stable and longlived elements on Earth, and zircons crystallize in preeruptive magma associated with each volcanic eruption. The researcher had identified and dated zircons from the Ilopango eruption that we had considered our prime candidate for the Late Classic pottery temper. But our archeological zircons did not match the Ilopango zircons. Ilopango’s zircons dated around 10,000 years. The pottery’s zircons came up with ages that are greater than 30 million years! So the Maya were not using Ilopango ash. The project keeps going on. There will be no simple answer to the pres-

Anabel Ford received a grant while a PhD student in 1980, for “Volcanic Ash Temper in Prehistoric Lowland Maya Ceramics and its Significance to the Maya Economy.” See more about Ford’s project: https://www.sigmaxi.org/programs/grants-in-aid-of-research Anabel Ford/Mesoamerican Research Center, UCSB

The Enduring Legacy of the Maya

ence of volcanic ash in the Maya lowlands. But right now, my colleagues in Heidelberg have a whole bunch of my sherds, and they’re going to try to find more evidence. How did you first encounter your main study site, known as El Pilar?

I was doing a survey that was looking at settlement and environment in the Belize River valley. The site is 10 kilometers from the river, and the assumption using the Western view was that water and the river were very important both for drinking and for transport. But the river length is about 350 kilometers and the same distance on land is about 100 kilometers, probably a three-day walk. Paddling 350 kilometers is a lot harder and going downriver probably is okay, but in the wet season it would be treacherous, and in the dry season, there would be a number of portages. So I’ve never seen the waterways as a dependable component of transport in Mesoamerican life. However, the work that had been done had only been in the Belize valley near the river. So I did transects going out into the upland areas, and as I was doing it, I asked what people knew, and local people said that there was a big site. I went up and yes indeed, there was a big site. I had never mapped anything that big. How big was El Pilar?

I estimate that there were about 300 to 400 people per square kilometer in the city. And that makes the population 2022

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of the city of El Pilar, something like 4,000 people. A traditional Mayanist will count each structure as a house. So if at Tikal we have 200 structures per square kilometer, that means 1,000 people per square kilometer. But in fact, I don’t consider all of those structures to be houses; I consider a primary residential unit of structures. One structure is the kitchen, and one’s going to be the place where they live. If they use fire, they never have it inside, it’s really fire insurance, but you could not have a home without having the kitchen. So I actually define primary and secondary domestic architecture, and I only estimate population based on primary residential units with five people. I look at things very practically and how they might actually have thrived. What assumptions about the Maya have you had to counter in your research?

I think that my education implied that the people who became the Maya civilization somehow appeared in the lowlands already as agriculturalists. And in fact, I would say there was almost a feeling that there was no precedent, but when you look at human occupation, why wouldn’t that area have been occupied? People are everywhere. When you look at how much the tropical forest offers, you don’t have to do much, you can pick the fruit off the trees and there are animals all over. There was also another idea that forest dwellers could not be huntergatherers, which I never quite understood. The presumption was that hunters had to be out there in the bush, chasing big game. There isn’t big game like that in the forest, but in the teeming forest, every habitat has something. I actually went out with a hunter, and he strung up a hammock and took a snooze! I said, “Are we hunting?” And he was a sort of mischievous fellow, so he says, “Did you come with me because I’m a hunter or not?” So I said, “Okay, okay!” Soon enough, a little agouti comes up and he hammers it with the butt end of his shotgun, and there’s meat. He showed me that he put his hammock over the place where the animal was going to come, he was reading the signs of where it lived. I thought, well, you don’t have to run after things, they come to you, if you’re informed. The Western world also still wants to find canals and terraces, anything 138

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that’s hard-surface land use, to show intensive effort. They can’t imagine intensive agriculture that doesn’t leave any evidence. Yet the biggest center of the classic Maya period, Tikal, has no evidence of terraces or canals.

ter forest gardeners say there is no forest without the fields, and there are no fields without the forest.

What have you documented about Maya cultivation within the forest?

In 1995 I got a grant from the Ford Foundation and part of it was to create a way for traditional people to get engaged with El Pilar. I did it by excavating a Maya house, and I wanted to imagine a house in a forest garden. So I brought in forest gardeners to ask what could we do up at this Maya site? I wanted to have cacao, for example, but they said, no you can’t have cacao here. It wouldn’t work because that area has basic soil with lots of limestone and apparently cacao doesn’t like that. It wants to have a deep sort of clay soil. So there’s a lot to learn. Working with them was really instructive. I planted trees at my field base where I have a house, and I have a mahogany tree that is quite large now, it’s 15 or 16 years old. And I said, oh, it’s big enough to be a good post. And, oh, they laughed forever on that one. They said you never would make that a post because it would just deteriorate. It would not be something you could put in or near the ground. It would be good for other parts. I was going up to an area where I heard that there was running water, which is very rare in this place. Mostly, you don’t have surface water. And so this forest gardener knew something about that, and so he took me to it and I said, “How did you find it?” I discovered that it was because of a damselfly. I would say, “Oh, a bug, I don’t want it in my eyes,” but he would say, “That’s water.” So all those kinds of experiences add up to say that there’s skilled observation, things that I don’t see. I mean, I know what a stoplight is, but I don’t know that a damselfly means water. There are two rainy seasons in the Maya lowlands. One is the hurricane, and that’s governed by the InterTropical Convergence Zone. And then there’s the North Atlantic Oscillation in which the weather comes down from the southeast United States, and that’s cold as well as wet. They are different time periods and the distribution depends on when rain comes. If all the water came in October, that would destroy a crop, but if there was continued on page 140

Studies show that the forest today was shaped by practices developed

“The Western world still wants to find canals and terraces, anything that’s hard-surface land use, to show intensive effort. They can’t imagine intensive agriculture that doesn’t leave any evidence.” by the Maya millennia ago, using an Indigenous production system called the Milpa Cycle that continues to be practiced by forest gardeners today. Rocky soils are considered undesirable in European cultivation systems centered on the plow, but Maya did not use plows. It was inconceivable to observers that the Maya cultivation system could support large populations and complex societies without destroying the shallow tropical soils. Because components of the Milpa cycle include slash-and-burn fields, popular perception sees only shifting agriculture and discounts the majority of the landscape as abandoned. Milpas are mixed-plot lots. It is not unusual to find more than 30 different crops in one field, out of more than 100 possibilities. The Milpa cycle averages 20 years, starting with fields of traditional agricultural crops for about four years, progressing through a sequence of products obtained from selected secondary growth, and completing with a closed canopy forest over the original cleared area, which is ready to repeat the cycle again. Forest gardening strategies have also developed to be responsive to climate change, because they maintain land cover that enhances biodiversity, conserves water, and moderates temperatures. Mas-

What have you learned about land management from the Indigenous people of the region?

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Anabel Ford/Mesoamerican Research Center, UCSB

is going to cause erosion. Maya forest gardens invite plants, take recommendations from nature, and give something we can learn from, such as keeping moisture, inhibiting erosion, building biodiversity. Beautiful ferns they remove would not have hurt the monuments. So right now we’re starting the dry season, and everything looks dry even before the dry season. The rangers are responding to what they see as clean, and we are working to build a strategy that can bring the forest gardeners to the table. There is plenty there to do, I can tell you. Do people see the forest gardening approach as a way to reclaim their cultural heritage? This illustration recreates a Maya house that sits within the larger grounds of El Pilar, a site that covers a half a square kilometer across the border between Belize and Guatemala. Maya houses were surrounded by forest gardens that were heavily planned for practical use.

continued from page 138 very little rain but it came scheduled perfectly when needed, the crops would be fine. It’s a monthly and almost daily kind of thing that has to be dealt with. And it’s not just one season, it’s two seasons of rain. And that’s something I’ve learned from the forest gardeners. They have skills that are undervalued because they are not quantitative; you can’t measure them like linear kilometers of canals or meters of terraces. But it is investment. When I write papers, I have the forest gardeners read them for me and they’ll make critiques. The most recent paper I wrote, my forest gardener colleague Alfonso read the section on the milpa, because I know that he’ll find something wrong. But he said he didn’t have a quarrel with it, so I was quite happy. How have you used LIDAR to map and document the El Pilar site?

LIDAR is no magic wand, but it provides the entire topography. If I were to do a topographic map with the scale of LIDAR, it would take me years. I’m doing a project with a geospatial engineer this season; I’ve surveyed 14 square kilometers and we have targeted what I call go-to points in that area to compare with the LIDAR mapping. We’ve discovered things and we have rejected things from LIDAR. I feel like when I go out in the field, our go-to points are probably in the 80-percent range of accuracy, but we find things 140

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that you wouldn’t be able to see with LIDAR. I’m interested in land use, in finding out what proportion of the house sites we’re capturing versus what the LIDAR can see. LIDAR is terrific, but if we’re going to be sure we know something, we have to compare what we see on LIDAR with the boots on the ground. And then we could say how great it really is. With LIDAR, you

“We have been working toward creating a binational peace park at El Pilar.” know where the swamps and the uplands are, you can start seeing where you could put emphasis and where you don’t have to. I believe in sharing these data; we have created a Maya forest atlas online with our data, and we could make so much more progress if all the LIDAR data were made public. Does preservation of the site sometimes conflict with Indigenous practices?

The government approach to managing the monuments, the top-down approach, is the standard. For example, at the site, I envision Archeology Under the Canopy, and that means forest gardeners teaching people how to manage things. Yet park rangers are raking, clearing, taking plants away, sweeping away all the cover, which

After this COVID event, people want more sovereignty, want to be able to eat something that they know where it’s from, and even have something to eat without having to buy it. So there’s more interest in the forest garden now than there was before. We just signed a memorandum of understanding with the Belize National Institute of Culture and History to create a permanent exhibit on El Pilar and the forest gardens, which would link to the new Belizean education program. I think it’s going to affect how people perceive their own gardens and their own investment in plants. So many things that are part of that Maya forest garden approach have applications well beyond the Maya area. For instance, we have to conserve water, we have to consider biodiversity, we have to consider temperature. We have also been working toward creating a binational peace park at El Pilar. The space is bounded by both Belize and Guatemala. It’s contiguous, it’s well recognized in both countries, and the management planning themes are equal in both countries, so it could happen. I mean, maybe not in my lifetime, but my goodness, everyone said you couldn’t have a binational park. In 2019, both countries had voted in favor of a referendum to bring their longstanding territorial dispute to the International Court of Justice. And that’s moving along. And the current ambassador from Belize to Guatemala is someone I’ve known from agriculture. He’s very interested in the forest garden concept. And so maybe enough seeds are planted and maybe something can happen. I’m a cheerful pessimist, but that’s what I’d really like to see. Q

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Briefings asteroids have similar surface features, bolstering the theory that they came from the same parent object. After the asteroids were discovered, researchers reviewed celestial data going back to 2005 for evidence of their origins and orbits. Most asteroid pairs form from a larger asteroid that broke apart, but gravitational models with that assumed origin could not explain this pair’s odd elliptical orbit.

it features in 63 percent of words denoting roughness compared to 35 percent of words for smoothness. The stability of the trilled r’s association with roughness over time and place indicates that touch iconicity is a deeply rooted aspect of languages that warrants further study.

A new tool allows researchers to gain a more expansive understanding of the human genome, which could aid in the development of targeted disease treatments. A team at the University of California, Santa Cruz, Genomics Institute developed a bioinformatic method called Giraffe that focuses on the pangenome, which includes information about people with diverse genome sequences. Genomic studies often rely on a single reference genome from an individual as the basis for comparison to wider populations, but that approach fails to capture the diversity of the human population. For example, many of these reference genomes derive from the Human Genome Project, which overwhelmingly represents people of European descent; by contrast, some 97 percent of the African genome has not been studied. (See “Genetic Blind Spots,” July–August 2021.) When the genome of a person of African descent does not match the reference genome, it is labeled a variant, rather than an aspect of normal population diversity. By using the pangenome, Giraffe provides information about genetic variation across populations. This information could help researchers develop treatments for diseases that affect specific ethnic groups. Sirén, J., et al. Pangenomics enables genotyping of known structural variants in 5202 diverse genomes. Science doi:10.1126/science .abg8871 (December 17, 2021).

Baby Asteroids The discovery of a pair of near-Earth objects that may have formed less than 300 years ago provides evidence that the Solar System is still a work in progress. The objects are an asteroid pair—meaning they broke off from the same celestial body and have similar orbits around the Sun. They were both found in August 2019, but by different teams: A group at the Pan-STARRS survey in Hawai॒i identified 2019 PR2, and a team at the Catalina Sky Survey in Arizona found 2019 QR6. Further observations show that the 142

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UC Berkeley/SETI Institute

Broader Genomic Perspective

Further modeling of the orbit suggests that the asteroids may have broken off from a comet a mere 300 years ago, but if that were the case, there would be visible ice and frozen gas emanating from the asteroid pair. The origins of 2019 PR2 and 2019 QR6 remain a mystery, but their relative proximity to Earth provides astronomers with an unprecedented opportunity to study new and relatively close objects in the Solar System.

Winter, B., M. Sóskuthy, M. Perlman, and M. Dingemanse. Trilled /r/ is associated with roughness, linking sound and touch across spoken languages. Scientific Reports 12:1035 (January 20).

Ape First Aid Chimpanzees use insects to treat open wounds on themselves and others. This activity has not been observed before in any animal species. Over a period of 15 months, researchers documented 22 different chimpanzees using insects to treat wounds, and they all did so in the same manner. An ape would catch an insect and immobilize it by placing it between their lips. They would then use either their fingers or their lips to rub the insect on the wound. Finally, they would again use either their fingers or their lips to remove the insect. Despite having observed

Fatka, P., et al. Recent formation and likely cometary activity of near-Earth asteroid pair 2019 PR2–2019 QR6. Monthly Notices of the Royal Astronomical Society 510:6033– 6049 (February 2).

Textural Speech Across hundreds of languages, the word for rough includes a trilled r sound, demonstrating a common connection between how a word feels when spoken and its meaning. Iconicity—the correlation between the form of a word and its semantics—is found in all human languages, but the sense of touch has received little attention in that regard. A team of linguists led by Bodo Winter of the University of Birmingham examined how words that convey texture are expressed in 331 spoken languages across 84 language families, including both modern languages and Proto-Indo-European languages dating back 6,000 years. They found a remarkable stability in the iconicity of words that convey texture. In ancient languages that use a trilled r, the sound is used to denote roughness 44 percent of the time, whereas the same sound is used in only 8 percent of words meaning smooth. That correlation is even stronger in modern languages that use a trilled r;

this behavior being used to treat 76 open wounds, the researchers have not been able to identify the small, flying insect that the chimpanzees are using. Selfmedication among animals is not uncommon, but it usually takes the form of ingesting purgative plants. Nonhuman primates have been observed rubbing leaves or arthropods on wounds, but not insects. The chimpanzees’ repeated behavior indicates that they are using the insects either to treat or to soothe open wounds, and that they might know something about the healing properties of this insect that humans have yet to discover. The altruistic treatment of other chimpanzees’ wounds bolsters the theory that nonhuman species exhibit prosocial behaviors. Mascaro, A., L. M. Southern, T. Deschner, and S. Pika. Application of insects to wounds of self and others by chimpanzees in the wild. Current Biology 32:R97–R115 (February 7).

Tobias Deschner/Ozouga chimpanzee project

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Digital Feature Preview | John M. Eadie, Bruce E. Lyon, and Eli S. Bridge

Putting Eggs in Many Baskets Some wood duck hens lay eggs in nests that aren’t theirs, while others stay at home. The behavior isn’t simply cooperative or a con job. It’s complicated in the duck social “nestwork.”

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n April 17, 2016, a one-year-old female wood duck was taking her first steps tow ward motherhood by exploring nest sites. The T tawny bird with white eye rings and iridescent blue wing patches was investigatir rid d ing artificial nest boxes that our team had in ng several sev se v erected along a wooded stream near Davis, California. There was nothing unusual here, except that many of these nest boxes were already occupied by other females. That year, this female would go on to make 195 visits to 34 different nest boxes that were already in use, including 30 visits to her favorite box. It turns out that this duck, whom we call by her tag code E9BA0 (or E9 for short), wasn’t just exploring her neighborhood. Our genetic studies show she was laying eggs in the nests of other wood duck hens. She laid a total of 12 eggs in four nest boxes, all in a row and just a few boxes down from where she had hatched the year before. What’s more, E9 never incubated any of those eggs, relying instead on the nesting females in those boxes to do that. E9’s behavior wasn’t entirely surprising. Wood ducks are known to be conspecific brood parasites, meaning that they lay eggs in the nests of other birds of their species. The word parasite doesn’t normally invoke an image of a bird laying an egg in a nest. But this behavior is not so different from a worm in your gut. It potentially takes resources away from the mother who ends up caring for the egg. (That’s one hypothesis, anyway.) We thought initially when we began this work in 2014 that most wood duck hens would incubate their own eggs and 144 144

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Courtesy of Bruce Lyon

would set up home in one site, whereas a few others might travel around a bit, perhaps laying some eggs parasitically. We completely underestimated the wily wood duck. According to our data, some females visit an incredible number of nest sites, visit many nests repeatedly over an entire breeding season, and frequently lay eggs in other females’ nests. Such was the case with E9, and her sneakiness paid off—10 of her 12 eggs were hatched by the host mothers. E9 returned the following year, and we wondered whether she might settle down, but she did not. Instead, she visited even more boxes (42), never incubated a nest, and again laid 10 eggs parasitically, of which 8 were hatched by the foster mothers. Sneaking eggs into a neighbor’s nest is unusually common in waterfowl. Almost a third of the 256 bird species known to practice conspecific brood parasitism belong to this single family of birds, the Anatidae. Wood ducks, also known as woodies or Carolina ducks, are well known for their parasitic propensity. As early as 1901, Walter B. Sampson reported on “An Exceptional Set of Eggs of the Wood Duck” in the San Joaquin Valley, California, perhaps the first documentation that more than one hen would lay in the same nest at the same time. Subsequent records abound in the ornithological literature, including observations of nests with more than 40 eggs. As birds go, duck parents have it fairly easy. As soon as the offspring hatch, they are ready to fledge and can feed themselves (see photo on right). Female ducks provide a modicum of protection, warmth, and guidance—and that’s about it. This relatively light workload makes it possible

for female waterfowl to raise a lot of babies. What has long been a mystery is why a female would risk the investment in her eggs to the care of another female. As their name aptly implies, wood ducks such as E9 are cavity nesters: They require a tree hole in which to make a nest. Even in a healthy mature forest, cavities large enough to host a 600-gram female and an almost equal mass of eggs are likely at a premium. So, one challenge that hens may avoid through brood parasitism is the need to find an available nesting spot. Faced with the task of finding a vacant nest site, wood ducks may circumvent this limitation by using someone else’s.

Wood ducks can be aggressive or tolerant about nest sharing. In this video still, one wood duck hen lays an egg on the back of the nest owner, as the two nuzzle. Why these interactions are so variable is not yet known, but the authors and their collaborators are working on an answer. See the full video here: www.amsci.org/node/4891

John Eadie is a professor and the Dennis G. Raveling Endowed Chair in Waterfowl Biology in the department of wildlife, fish and, conservation biology at the University of California, Davis. Bruce Lyon is a professor in the department of ecology and evolution at the University of California, Santa Cruz. Eli Bridge is an associate professor in the Oklahoma Biological Survey at the University of Oklahoma. Email: [email protected]

Courtesy of Bruce Lyon

Wood ducks’ notoriety for laying eggs in one another’s nests made them an ideal study animal for exploring questions about this behavior and its evolution. However, we couldn’t get details such as those we collected about E9 until recently. Questions that long seemed unanswerable about where the birds go and which eggs end up where can now be addressed. With advances in radio-tracking tags, videography, and genetics, after more than 30 years studying brood parasitism in ducks, we’ve finally been able to get some answers. What we’ve found is a complex social network of wood ducks that we are still unraveling, one that defies single explanations for nest parasitism and instead shows that this behavior offers females flexibility to adjust their reproductive investments in the face of changing conditions.

Courtesy of Katharine Cook

What has long been a mystery is why a female would risk the investment in her eggs to the care of another female.

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Why Ducks Parasitize Other Nests

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aying eggs in another female’s nest once seemed so unusual and inexplicable that early authors dismissed it as an aberration and referred to it disparagingly as “egg dumping,” as though females were simply ridding themselves of excess or unwanted eggs. It was not until 1980 that an influential paper by Yoram Yom-Tov of Hebrew University changed our thinking by considering the behavior from an evolutionary perspective. Yom-Tov and subsequent authors proposed several hypotheses to explain why females might lay eggs in the nest of a nearby neighbor. Many females do establish a nest of their own, lay their eggs in that nest, and care for their offspring—this behavior is what we might think of as a typical nesting strategy for a bird (Option A on the facing page). However, other females are like E9 and lay some or all of their eggs as brood parasites. We wanted to know why this latter behavior might be advantageous enough to evolve in some ducks. One possibility is that females are constrained from breeding on their own (Option B).  Perhaps these females cannot compete successfully for a nest, or nest sites are in short supply, as is likely to be the case for a cavity-nesting wood duck. Alternatively, it might not “pay” (in reproductive terms) to nest on one’s own, because of physiological stress, lack of experience, or poor body condition. Nonetheless, some reproduction is possible by laying a few eggs parasitically, without having to go all in.  Another possibility (Option C) is that females get the best of both worlds. If there is a limit to how many eggs a female can tend in her own nest, laying additional eggs in another hen’s nest can increase total reproductive output without having to provide the care for those extra eggs and offspring. (The “gambler” variant of this hypothesis is that females put their eggs into many baskets to hedge their bets against losing all their eggs in a single nest to a predator—a catchy idea that unfortunately does not hold up under mathematical analysis.) Finally, some females may be pure parasites—they never raise their own young and only lay in the nests of other females (Option D). In doing so, these “professional” parasites

are freed from any parental care duties and instead invest the time and energy saved into making extra eggs or living longer. There is one other twist to this story. What seems to be parasitic behavior might actually be a form of cooperation. Cooperative behaviors that are costly on an individual level can evolve if they increase survival and reproduction of relatives that might not have reproduced otherwise (See “Why Some Animals Forgo Reproduction in Complex Societies,” July–August 2014.) In many duck species, daughters return to their natal (birth) area to breed, where they can closely interact with their relatives. (In most other species of birds, the male returns to his natal area.) Malte Andersson of the University of Gothenburg in Sweden offered a novel idea to explain why conspecific brood parasitism is disproportionately common in waterfowl: Perhaps it is an interaction among kin, female family members sharing the costs of parental care and enhancing their own evolutionary success through the shared genes they help propagate. This perspective turns the concept of parasitism on its head. Rather than a competitive dynamic, perhaps brood parasitism among females within the same species is instead a form of cooperation between relatives—less a case of parasitism and more one of shared duckling daycare. But if ducks don’t just parasitize the nests of their kin, there may be other reasons at play: Perhaps some cost to nesting can be avoided by a female that adopts brood parasitism, either partially or fully. The challenge we faced was how to test these hypotheses. To study this behavior, we first needed to know which females are the parasites. To do that, we needed to identify the nests females were visiting and how many of those visits resulted in an egg laid.

Read the full online interactive feature and learn what the authors figured out: www.amsci.org/node/4891

Courtesy of Bruce Lyon

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Technologue

Chemical Maps, Parasitic Diseases, and Drug Development Tracking molecules in the body using chemical cartography can help scientists identify new infectious disease treatments. Laura-Isobel McCall

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little girl is bitten by a kissing bug (also known as a triatomine bug). Trypanosoma cruzi (T. cruzi) parasites from the insect’s feces enter the bite wound and start spreading through her body. They invade her cells and multiply. Her immune system kills most of the parasites on its own, but some survive. Over decades, damage from the tiny invaders may accumulate in her heart, or her esophagus, or her colon, with often deadly and debilitating effects. There is no effective treatment for a late-stage T. cruzi infection, also known as Chagas disease. The location of this damage will shape the rest of her life. We know frustratingly little about how the parasite works, but researchers are now making progress in cracking the mysteries of Chagas disease. Scientists still don’t know all the factors that shape where infectious disease symptoms develop, which is particularly true with under-studied parasites such as T. cruzi. In such cases, a new technique called chemical cartography can help. Chemical cartography is the practice of building three-dimensional maps of metabolites, small molecules involved in energy generation, cell function regulation, and cell–cell communication. Uncovering the local effects of infection on these metabolites can help reveal how cellular processes are disrupted by any

infection. For example, by noticing that infection in the heart decreases the levels of specific lipids there, we can conclude the parasite is impairing energy generation in the cardiac muscle, hampering its ability to pump blood. My team and I are using chemical cartography to visualize metabolites in major organs such as the heart and colon, and to examine where these mol-

Scientists still don’t know what factors shape where infectious disease symptoms develop, which is particularly true with under-studied parasites such as T. cruzi. ecules are in relation to the locations of the parasites in the body and to the locations of the diseases they trigger. This approach has the potential to expand our insights into under-studied conditions such as Chagas disease and to help researchers develop effective drug therapies where none currently exist. For many people around the world, the experience of the little girl in our story is all too real. More than five mil-

lion people globally are currently infected with T. cruzi, including at least 300,000 in the United States. Most people become infected by T. cruzi, a single-celled, microscopic eukaryotic parasite, through the bite of a kissing bug. People can also be infected by drinking juice containing the parasites or by receiving an organ transplant from an infected donor. Infected mothers can also transmit the parasite to their child during pregnancy. The disease is endemic from the southern United States to South America. If infection is not caught early, low levels of parasites will persist in the body for years. Over decades, tissue damage from these persistent parasites accumulates in the heart (especially the bottom of the heart), the esophagus, or the large intestine. Those organs gradually become enlarged; the enlarged heart can’t pump blood as well, and food and waste move poorly through the enlarged esophagus and large intestine. Patients can also develop irregular heartbeats and swelling at the bottom of the heart. Meanwhile, existing treatments for chronic Chagas disease such as benznidazole come with adverse effects (such as gastrointestinal pain or severe rashes), don’t necessarily kill all the parasites in some patients, and are unable to reverse organ damage if treatment is started too late.

QUICK TAKE Chemical cartography allows researchers to create 3D maps of organs, which they can use to track where pathogens accumulate and where disease symptoms manifest in the body.

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Researchers have applied this technique to little-understood conditions such as Chagas disease to figure out what damage the illness inflicts on the body at the cellular level.

These maps can be used to develop treatments that can be both easily administered and highly targeted to a specific parasite or to persistent, dangerous disease symptoms.

parasite burden

metabolite positively correlated with parasite load

Chemical cartography allows researchers to create 3D models that trace where parasites appear in a particular organ and how organ metabolism may shape where they localize. In this example, three views of the same heart model show where Trypanosoma cruzi parasites accumulate in the organ (left, highest parasite levels in red) and two metabolites with divergent distribution. Methylated adenosine monophosphate

Model Organs To shed light on how Chagas and other infections inflict this damage, we have to trace the physical locations of both symptoms and microbes in the body. These are not always one and the same. The symptoms of an infectious disease may occur in the same place as the virus, bacteria, or parasite causing the disease. For example, with a virus such as the SARS-CoV-2 coronavirus, a lot of the virus ends up in the lungs, and the infected person has trouble breathing or develops a cough. However, in other cases the location of the microbes in the body and the places where a person experiences symptoms don’t match up: In chronic infections such as Chagas disease, patients can have very few parasites in the heart at a given point in time and still develop symptoms there. In some cases, no parasites are visible at the specific sites of heart damage. Symptoms can also persist after all the microbes or parasites have been killed, which may be the case in long COVID, where some patients report symptoms such as brain fog long after the original infection. We can track the diffuse impact of these pathogens in a body through www.americanscientist.org

metabolite negatively correlated with parasite load

(methyl-AMP) is concentrated in the same area as the parasites (middle, high methyl-AMP levels in red, intermediate levels in pale blue, and low levels in dark blue), whereas adenosine is highest at the opposite end of the heart (right, highest adenosine levels in red). These findings suggest that host metabolites may regulate where the parasite is localized in the heart. (Unless otherwise indicated, all images are courtesy of the author.)

metabolites. Anything we are exposed to—medication, pesticides, food, personal care products—contains and can transmit small molecules to our bodies. These small molecules are the building blocks of living organisms, including the amino acids that make up proteins, the nucleotides that make up DNA, and the lipids that enclose cells. They are also created by chemical reactions in the body. Pathogens such as parasites and bacteria also create their own unique metabolites. Although there are many ways to identify and study small molecules in the body, chemical cartography is unique in that it allows us to build virtual 3D models of entire organs, organ systems, and even whole bodies. We start with an organ, such as a heart or a colon, and we generate an initial 3D model. In our research so far, we have been working with harvested organs from animal infections. (Our approach could also be applied to biopsy samples, but otherwise it can’t be applied to living organisms, because we need access to organ samples.) We cut up the organs systematically into pieces and break each piece down in chemical solvents such as methanol. Then we

determine the weight of the molecules and molecule pieces in each sample (using a liquid chromatography–mass spectrometry instrument) and use that information to reconstruct the chemical structure and identity of each molecule. Next, we plot the identity and location of each molecule back onto the 3D model of the organ using computational tools developed by the Dorrestein group at the University of California, San Diego, and the Alexandrov group at the European Molecular Biology Laboratory. We can then compare these metabolite maps with the local pathogen levels, local immune responses, or local tissue damage; these are determined using a combination of microbiology, immunology, and histology techniques. For the past six years, my colleagues and I have been applying this technique to Chagas disease. We mapped the spatial distribution of metabolites in the hearts of animals with and without persistent T. cruzi parasites in their bodies after an infection. We found that parasites accumulated in specific regions of the heart. We also noticed interesting metabolite trends. For instance, some metabolites appeared in the same location in the heart as the parasites and 2022

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build computational 3D model of organs

Chemical cartography starts with the collection of organs from animal models or tissue biopsies. Researchers build a 3D computational model of the organ, then systematically cut the organ into parts and dissolve the pieces in a chemical solvent. This process releases metabolites, which they then analyze with a liquid chromatography–mass spectrometry (LC-MS) instrument to reconstruct the chemical structure and identity of each molecule. Finally, researchers map this data back onto the 3D model of the organ. This process allows scientists to visualize the location of parasites in certain organs, and what part of the organ they affect.

therefore may represent key nutrients that support the parasites. Other metabolites appeared only in heart tissue devoid of parasites and may represent nutrients that inhibit parasite growth. To confirm the role of these metabolites in parasite growth, we are planning experiments that will use drug treatments that modulate the levels of these key metabolites and then assess where the

Cleber Galvão / Wikimedia Commons

Existing treatments for chronic Chagas disease come with adverse effects and are unable to reverse organ damage if treatment is started too late.

Chagas disease is caused by the parasite T. cruzi, which is primarily spread by triatomine, or “kissing,” bugs. These insects are native to the southern United States, Central America, and South America. 150

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parasites localize after treatment. Building on these findings could help us find new ways to treat Chagas disease by manipulating and ultimately eliminating local parasites. We also used chemical cartography to gain granular insight into the location of Chagas disease symptoms. We showed that infection reshapes overall metabolism in the esophagus and the large intestine of the host. Over time, the levels of metabolites in these organs become more and more distinct from uninfected controls, even though there are fewer and fewer parasites in these organs and in the body overall. In other organs, such as the small intestine, which is not associated with Chagas disease symptoms, any early metabolic changes recede as the number of parasites decreases. Fine mapping of metabolic perturbations and parasites in the heart enabled us to demonstrate that infection induces metabolic perturbations in the lower part of the heart. This impaired metabolism at the tip of the heart may be the cause of localized defects in tissue function and structure, providing a metabolic explanation for the enlarged heart tip (apical aneurysm) observed in Chagas disease patients. Strikingly, the parts of the heart with changed metabolism are distinct from those areas with the highest parasite load. We are still investigating the specific causes of these persistent metabolic perturbations, although we believe that parasite-specific characteristics, how the immune system responds differ-

systematically section organs

ently in various parts of the body, and the ability of tissues in each organ to regenerate all play a role. For example, some parts of the body may be more sensitive to the parasite’s metabolites, some parts may be able to regenerate, and some parts may trigger more active damage from the parasite. Understanding these mechanisms will provide us with fundamental insights into the processes that lead to Chagas disease development specifically, and tissue repair processes in general. These results may also provide novel avenues for intervention to treat Chagas disease. Treatment Tracking Right now, drugs that kill T. cruzi are insufficient to cure advanced Chagas disease, which suggests that both the parasites themselves and the body’s response to the parasites contribute to disease symptoms. Targeting the host response, rather than the pathogen, could theoretically improve disease symptoms, because it impacts the knock-on metabolic changes, or persistent tissue damage triggered by the parasite. We conducted a chemical cartography analysis that revealed that T. cruzi triggered changes to a metabolic process called acylcarnitine metabolism, which generates energy from fatty acids. Building on these findings, we treated sick T. cruzi–infected mice with carnitine, a molecule necessary for this process to take place. The treatment prevented the mice from dying from acute T. cruzi infection, even though the treated mice had the same number of parasites as the control mice that died of the infection. Instead of killing the parasites, the carnitine treatment brought the levels of metabolites in the hearts and intestines of the infected animals back toward the normal levels found in uninfected mice.

sively in feces, plasma, urine, or saliva. These metabolite biomarkers could then be used to monitor disease progression, provide disease prognosis, and monitor treatment success. In the end, our approach shows that, when it comes to disease, it’s location, location, location, and also chemistry, chemistry, chemistry!

extract metabolites from each segment

Bibliography

perform LC-MS/MS on each extract

computationally map metabolite position in 3D

Dean, D. A., et al. 2021. Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas disease. PLoS Neglected Tropical Diseases 15:e0009819. Garg, N., et al. 2017. Three-dimensional microbiome and metabolome cartography of a diseased human lung. Cell Host & Microbe 22:705–716. Hossain, E., et al. 2020. Mapping of host-parasitemicrobiome interactions reveals metabolic determinants of tropism and tolerance in Chagas disease. Science Advances 6:eaaz2015. McCall, L.-I., et al. 2017. Mass spectrometry– based chemical cartography of a cardiac parasitic infection. Analytical Chemistry 89:10414–10421. Protsyuk, I., et al. 2018. 3D molecular cartography using LC-MS facilitated by Optimus and ‘ili software. Nature Protocols 13:134–154.

Strikingly, even though we administered carnitine in the mice’s drinking water, which in theory would enable the molecule to reach and affect all organs, we saw an effect only in the cardiovascular system. The metabolic changes caused by T. cruzi infection in the esophagus, for example, were not affected by the treatment. These findings indicate we can target specific organs and organ systems with systemically administered drugs. In other words, chemical cartography could lead to relatively simple, whole-body drugs that naturally reach critical sites in the body to treat ongoing disease symptoms. Drug discovery and drug development can take decades, and the use of chemical cartography data to guide drug development is still in its infancy. However, our early findings suggest that our approach can help this arduous process. What’s next for chemical cartography? There is a strong spatial component to many diseases that would benefit from chemical cartography approaches and the discovery of new interventions; these include both infectious and noncommunicable diseases, such as Giardia infection, influenza, and Takotsubo cardiomyopathy. Chemical cartography can also be integrated into

current drug development pipelines to assess tissue drug levels and drug clearance, and to explain treatment failure or success. For example, in 2017, Neha Garg (then at the University of California, San Diego) and colleagues showed that antibiotics don’t equally penetrate lung regions in patients with cystic fibrosis. Chemical cartography does require invasive tissue collection to build these spatial maps, so it is not amenable to direct monitoring of disease. Instead, we can use this technique to identify the specific metabolites perturbed at the site of disease in biopsies or in animal models, build a list of candidate molecules, and then monitor these targets noninva-

Laura-Isobel McCall is an assistant professor in the departments of chemistry and biochemistry and of microbiology and plant biology at the University of Oklahoma. Her work focuses on chemical cartography and host–microbe interactions. Email: [email protected]

parasite burden 12 days postinfection

parasite burden 89 days postinfection

These chemical cartography images show the abundance of parasites and the degree of metabolic disturbance in a mouse’s digestive tract 12 days and 89 days after a T. cruzi infection. Blue signals few to no parasites or metabolic changes, white signals some parasites or metabolic changes, and red signals a high level of parasites or metabolic changes. In the acute stage 12 days after the initial infection, there’s a medium to high parasite burden in the distal colon and small intestine and a higher metabolic disturbance in the small intestine. Over time, however, as the parasites all but disappear, metabolic disturbances increase in the esophagus and large intestine.

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Perspective

The Discovery of the Shark’s Electric Sense A half century ago, Ad Kalmijn proved that sharks can sense electromagnetic fields. His work is still reshaping our understanding of ocean ecosystems. David Shiffman

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little more than 50 years ago, Adrianus “Ad” Kalmijn conclusively proved that sharks and rays can sense electromagnetic fields and use them to locate hidden prey. The finding transformed our understanding of the ways in which animals respond to their environments. I spoke about this discovery with Steve Kajiura of Florida Atlantic University, who is one of only a few experts studying sensory physiology in sharks and rays. “We hadn’t discovered a whole new sensory system in centuries,” he told me. “Imagine discovering that animals can see or hear, just a few decades ago.” Kalmijn, who studied the intersection of biology and physics at Woods Hole Oceanographic Institution and Scripps Institution of Oceanography for more than 40 years, died this past December of leukemia. His work continues to influence recent discoveries about how sharks sense their world, and how the workings of their electrosense can be used to guide conservation and fisheries management. It’s difficult to summarize how influential Kalmijn’s greatest discovery continues to be to this day. It has changed the way that biologists (including me) think about ocean life. The fact that sharks sense electromagnetic fields has become such common

knowledge that it’s been mentioned in four of the last five children’s books about sharks that I’ve reviewed. Although I never knew Kalmijn, early in my career I developed a relationship with his work that deepened my respect for his contribution and the

“We hadn’t discovered a whole new sensory system in centuries.” subsequent research it spawned. Even though decades passed before biologists began studying the implications in earnest, recent and emerging areas of research have shown that exploring the electrosensory worlds of sharks and rays continues to lead to surprising and exciting discoveries. The Story of Kalmijn’s Discovery Biologists have long been aware that sharks and their relatives have a peculiar system of mucus-filled pores, called ampullae of Lorenzini, on and around their snouts. I’ve been a shark nerd my whole life, and for me (and

many other shark nerds I know) “ampullae of Lorenzini” was one of the first science-jargon terms I ever learned. This name comes from Italian ichthyologist Stefano Lorenzini, who formally described these anatomical features in the 17th century. What no one knew was what these pores were used for. There were many guesses, but no evidence. A key breakthrough came in the 1930s, although no one realized it for decades. In 1935, comparative physiologist Sven Dijkgraaf at the State University of Utrecht in the Netherlands was studying sharks for an unrelated project when he observed that a captive shark reacted when it approached a rusty wire in its tank. The shark retreated from the wire after encountering it, recoiling in apparent disgust or pain even though the fish had never touched it. Moreover, this escape reaction occurred even when the shark was blindfolded and could not see the wire. Clearly, the wire was providing a nonvisual stimulus that the shark could pick up. Dijkgraaf seems to have filed away this observation as a curiosity outside of his focus of study at the time. More than 30 years later, Kalmijn began working with Dijkgraaf and duplicated these results with a few other species of sharks and rays, showing that the ability to sense something

QUICK TAKE In 1971, Adrianus “Ad” Kalmijn published an exciting paper proving that sharks and rays have an additional sense that perceives electromagnetic fields. Kalmijn died last year.

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Decades passed before biologists studied sharks’ electrosenses in earnest. Even today, this fundamental discovery has received little followup, relative to research on other senses.

Now, research on the electrosensory worlds of sharks and rays has picked up, especially regarding the effects of offshore wind farms on sharks and preventing shark bycatch.

© David Fleetham/naturepl.com

Sharks and rays can sense electromagnetic fields given off by prey animals. This discovery, made 50 years ago, has received little follow-up since then. But several active and emerging areas of research show exciting potential.

near an electrical source is widespread in this group of fishes. Around the same time, chemist Royce Murray of the University of North Carolina at Chapel Hill documented that sensory cells in the ampullae of Lorenzini reacted to electromagnetic fields. This work was done in the lab with just the ampullae organs, not a living, swimming shark or ray. By this point, scientists knew that sharks reacted to some stimulus given off by an unshielded wire, and that the ampullae of Lorenzini reacted in the presence of electromagnetic fields. Kalmijn wanted to test whether sharks and rays could sense the electric field given off by living marine animals, such as prey. Kalmijn’s breakthrough came from asking the following questions, as reported in his seminal 1971 paper in the Journal of Experimental Biology: “Are there electric fields in the www.americanscientist.org

natural habitat of the sharks and rays that can be detected by these animals?” and “If so, do the sharks and rays make a significant use of these fields?” To answer these questions, Kalmijn performed a series of clever experiments, enclosing live prey animals in protective cases so that sharks couldn’t see, hear, or smell them but could still sense their bioelectric fields. The sharks reacted to their otherwise hidden prey, leading Kalmijn to conclude that “all criteria . . . have now been satisfied to accredit these animals with an electric sense, and to designate the ampullae of Lorenzini as electroreceptors [emphasis in the original]”! This new way of approaching the problem was revolutionary. At the time, physiologists tended to look at tissues and cells, as Murray had when studying the ampullae of Lorenzini, rather than the whole animal. “Kalmijn didn’t just look at tis-

sues in a petri dish, he looked at the whole animals, alive and interacting with their environment,” Kajiura told me. “That’s what we finally needed to learn that they’re using this as a way to detect electric fields.” Kalmijn’s 1971 paper documenting these experiments was the first scientific paper that I ever read in detail. That’s because my undergraduate honors thesis work at the Duke University Marine Lab was based on these experiments. Kalmijn’s research inspired the first scientific project I ever performed: I looked at whether smooth butterfly rays could tell the difference between the bioelectric fields of different prey animals. The 1971 paper is wonderfully written, with enthusiasm shining through in a way one rarely sees in scientific writing. Kajiura told me that when he first read it during his early career, he “marveled at such a wellwritten paper.” Kyle Newton, a research associate at Oregon State University who works on how electromagnetic fields given 2022

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Adrianus “Ad” Kalmijn (above and below) discovered in a 1971 experiment (right) that sharks can sense electromagnetic fields. Kalmijn enclosed live prey in protective cases so that sharks couldn’t see, hear, or smell them, but could sense their electromagnetic fields. The sharks reacted to the prey. In the figure on the right from Kalmijn’s 1971 discovery paper, the shark’s response was compared among several treatments: prey under sand (a), prey encased to block all sensory signals except bioelectric stimuli (b), encased pieces of fish (c), prey encased to block all sensory signals including bioelectric stimuli (d), buried electrodes (e), and an aboveground piece of fish and buried electrode (f). Solid arrows indicate shark responses. (Figure from A. J. Kalmijn. 1971. Journal of Experimental Biology 55:371–383.)

Courtesy of Scripps Institute of Oceanography

off by offshore energy facilities affect sharks and rays, told me that humans are “so visually dominant that the idea that other animals can detect a whole other type of stimulus is just totally

beyond our perception. What would it feel like? It’s beyond our comprehension.” Newton pointed out that some animals can see ultraviolet or infrared light (wavelengths humans cannot

see), but that’s a different range of a sense we have, rather than an entire sense we don’t have. Studying Electrosenses Today After Kalmijn’s discovery that sharks and their relatives can sense electromagnetic fields, researchers began exploring what exactly they do with that capability. Only a handful of researchers in the world study topics related to electrosenses and are equipped with the expertise to speak on Kalmijn’s legacy. Among them is Timothy Tricas, who studies animal electrosenses at the University of Hawai॒i. He told me that we now know that sharks can use their electrosense not just for finding prey buried under sand or mud, but Kalmijn (left) revolutionized what we know about sharks’ sensory perceptions, with implications we’re only beginning to understand decades later. Kalmijn was aware of and involved in the research his discovery later inspired. He died in December 2021.

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The ampullae of Lorenzini are pores around the snout and head of sharks and rays (c, f) that they use to sense electromagnetic fields. The pores (black dots in a, b, d, and e) lead to canals (blue lines) filled with conductive mucus. The top panels show the chain catshark (Scyliorhinus retifer) and the bottom panels show the little skate (Leucoraja erinacea). (From Bellono, N. W., D. B. Leitch, and D. Julius. 2018. Nature 558:122–126.)

also for hunting in the open ocean in the dark, as well as for locating mates and avoiding predators. In a 2013 paper poetically titled “Survival of the Stillest,” a team led by Ryan Kempster, a graduate student at the University of Western Australia at the time, found that shark embryos in eggs stop moving when they detect an electrical field, a powerful predator defense behavior for an animal that can’t yet swim away. Just last year, a team of scientists led by Bryan Keller of the U.S. National Oceanic and Atmospheric Administration showed conclusive evidence that sharks can use the Earth’s magnetic field for precise long-distance open-ocean migration. Even after five decades, the field of electroreception in sharks and their relatives remains wide open. Kajiura told me that the dearth of published studies on how sharks and rays use the electrosense is especially striking compared with research on other senses. And Newton said, “There aren’t a lot www.americanscientist.org

of behavioral studies happening with whole animals in wild environments. It’s been a while since people worked on this topic, and Dr. Kalmijn’s work was essentially a huge breakthrough

The dearth of published studies on how sharks and rays use the electrosense is especially striking compared with research on other senses. that’s seen relatively little follow-up.” But that’s changing. There are several areas of active or emerging research on shark electrosenses.

Sensory Traps and Wires in Seawater Knowing that sharks can sense electromagnetic fields, but most other fish cannot, gives us shark researchers the chance to create a sensory trap. “We can sucker [sharks] in or repel them, with their own biology,” Newton told me. This tactic has many uses, including one that could help turn the tide in the fight to conserve sharks, and one that may help protect people from sharks. Sharks are some of the most threatened vertebrate animals in the world. Given their ecological importance in structuring coastal and marine ecosystems that humans depend on for food, that’s bad news for everyone. One of the biggest threats to sharks occurs when commercial fisheries target one type of fish but accidentally catch something that is swimming near it— referred to as bycatch. In addition to animals such as sea turtles, seabirds, and marine mammals, sharks are commonly caught as bycatch, killed in the process, and often simply discarded. 2022

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The ampullae of Lorenzini are stained dark blue in this preserved little skate.

to bycatch. In the case of longline fishing for tuna, such magnets create a powerful electromagnetic field near the baited hook, which sharks can detect and tuna cannot. Ideally, this field would repel sharks without repelling tuna. Early trials have had mixed success, in some cases even increasing the number of sharks caught, but for some species of sharks, rare earth metal magnets significantly reduce bycatch. Given recent reports that open-ocean shark species commonly caught as bycatch in tuna fisheries have declined by 71 percent since Kalmijn’s paper

Courtesy of Fishtek Marine

The basic principle of bycatch reduction is that we want to reduce the number of animals caught accidentally without reducing the amount of target catch—for example, we want to catch fewer sharks but still bring in the same amount of tuna. Fishers are unlikely to adopt a solution to save sharks that makes it harder for them to catch what they’re trying to catch. They’re also unlikely to adopt a solution that’s expensive or difficult to use. Attaching magnets made from rare earth metals to fishing hooks may be effective at reducing the loss of sharks

was published in the 1970s, it’s certainly worth exploring the magneticrepellent approach further. Electromagnetic fields might also prove useful for keeping sharks away from swimmers. Although the odds of getting bitten by a shark are astronomically low, the risk has long captivated our imaginations and fears. There are several personal shark repellent devices on the market that aim to use electrosense of sharks to repel them. I am skeptical of the need for and utility of these devices—it’s worth noting that in 2016, a Florida teenager was wearing a Sharkbanz shark repellent when he was bitten—but clinical trials published by Charlie Huveneers’s lab at Flinders University in Australia indicate that some of these devices truly can repel some shark species under certain conditions. The initial breakthrough in the discovery of sharks’ electrosense came from the observation that sharks reacted to a wire in their tank. Over the next few years, humans are planning to put a lot more wires into seawater, in the form of high-voltage cables carrying energy generated by offshore wind farms. Sharks have a long history of disturbing submarine cables— the webcomic The Life of Sharks amusingly claimed that sharks were biting the underwater infrastructure of

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A shark swimming into an artificially generated electromagnetic field may respond by swimming away or attacking the source, depending on the type of shark and the field’s properties. This response might be used to protect sharks from traps meant for other fishes, such as this longline hook (right) intended for catching tuna and equipped with a magnet. But sharks’ electrosense also presents challenges. Cables carrying energy from offshore wind farms could have unintended consequences for sharks.

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the internet because “those photos CAN’T get shared” (see comic on the right). But the types, quantity, and location of cables about to be constructed are unprecedented. How will all these new electromagnetic fields in the ocean affect the sharks? Answering that question is the focus of Newton’s research at Oregon State University. “We really don’t know what, if anything, all these EMF’s [electromagnetic fields] in the water will do,” he told me. “Is this going to change their behavior or migrations, like beachfront resort light distracts sea turtle hatchlings? Make them forage where there’s no food, or avoid areas where there is food? Will the EMFs mask the signal of prey? We can’t even sense these fields, which means we can do all kinds of things to the environment without understanding the possible impacts.”

shore wind power. Kalmijn stayed involved with this research through his illness, and when he died he had two papers in preparation for peer review, to be submitted to journals posthumously by colleagues. Kalmijn’s research revolutionized what we know about how animals perceive the world around them, with implications we’re only beginning to understand decades later. He lived to see his revolutionary ideas not only become widely accepted enough to be included in textbooks and children’s books, but also shape the cutting edge of emerging fields. Kalmijn opened a door to a new field of research, and his contributions will continue into the future. Kalmijn was aware of and interested in these latest implications of his work and even attended a recent workshop on the environmental effects of off-

David Shiffman is a faculty research associate at Arizona State University. His career focuses on interdisciplinary marine conservation biology and science communication. Twitter: @WhySharksMatter

2022 Student Research Showcase Presentation judging and workshops for students April 25–May 9 People’s Choice Voting May 9–13 People’s Choice and Award winners announced May 16

For more information, visit:

sigmaxi.org/srs

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Engineering

Frozen Tomatoes and Other Construction Materials Plant matter and bridge building have a long history together. Henry Petroski A Quechua woman crosses the Queshuachaca rope bridge, one of the last standing Incan handwoven bridges in Peru. Ropes, vines, and other plant-based materials have long been used in bridges. Keren Su/China Span/Alamy Stock Photo

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any readers have suggested topics for this column. I try to keep a file of these recommendations so I can acknowledge whoever was responsible for an idea I might pursue. Unfortunately, I cannot find the original correspondence that first sowed the seed for the present column, but I was reminded of it when I received a more recent email from Virginia Trimble, a professor of physics and astronomy at the University of California, Irvine, who wanted to know if I had ever written on “bridges made of highly unconventional materials.” I replied to her that I had not, at least not about bridges made of what she suggested as a suitable material: “hard-frozen tomatoes.” The mere mention of the word tomato, no matter how it is pronounced, often elicits a quip, from the diplo-

matic “You say tomaˉto, I say toma˘to” to the quizzical “Is it a fruit or a vegetable?” Neither cliché absolutely demands a response, but a polite and appropriate one to the first might be “de gustibus,” and to the second, “It depends.” According to the dictionary website Lexico.com:

Henry Petroski is the A. S. Vesic Distinguished Professor Emeritus of Civil Engineering at Duke University. Email: [email protected]

In her message, Dr. Trimble credited the idea of a tomato bridge to a joke, one I had first heard on an episode

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The  confusion  about “fruit” and “vegetable” arises because of the differences in usage between scientists and cooks. Scientifically speaking, a tomato is definitely a fruit. True fruits are developed from the  ovary in the base of the flower, and contain the  seeds of the plant. . . . As far as cooking is concerned, some things which are strictly fruits, such as tomatoes or bean pods, may be called “vegetables” because they are used in savory rather than sweet cooking.

of The Big Bang Theory, when Sheldon criticizes Stuart for using the phrase “more wrong,” arguing: “Wrong is an absolute state and not subject to gradation.” Stuart retorts by stating, “To call a tomato a vegetable is wrong; to call a tomato a suspension bridge is much more wrong.” Joking aside, it should be possible to make a small arch bridge out of tomatoes if they were frozen in molds shaped like voussoirs, the wedge-shaped stones used in arch bridges. Even plain water frozen in an ice cube tray with appropriately shaped inserts could be used. An arch assembled out of such materials obviously would have a limited lifetime, although that could be extended by adding antifreeze beforehand. Indeed, under the right conditions, ice as a bridge is a tried-and-true building material. When it grows thick enough over a pond or river, it can be walked on, skated upon, and even driven over. In climates where winter temperatures remain predictably low,

such as in northwest Canada and Alaska, ice roads and bridges are an annual occurrence. With the ice about 40 inches (100 centimeters) thick, 18-wheeler tractor trailers can transport equipment, supplies, and construction materials across frozen lakes along the 370-mile (600-kilometer) road from Yellowknife, the capital of the Northwest Territories, to the arctic regions where De Beers and other diamond companies maintain mines. It is much more economical to run trucks only during winter months rather than trucks and cargo planes year-round. Ice roads are wide, level, straight, and safe compared to the narrow, rolling, curving, and dangerous portage lanes across the strips of land that separate the lakes along the route. The human and technical drama involved in driving under wintry conditions was the basis for the History Channel’s reality-show series Ice Road Truckers, which ran for 11 seasons from 2007–2017, although it received mixed reviews on the website Rotten Tomatoes. Woven Together In her message, Dr. Trimble noted that there are bridges made of tropical climbing vines called liana. Indeed, there are plenty of examples of suspension bridges whose principal structural elements are vines, some of which can resist a substantial amount of force. I once lived in a house whose entire backyard was paved with ivy. It looked nice, except where it climbed up trees, fences, and brick walls, adhering to them so tenaciously that when I pulled strands of it away from those surfaces, the sticky pods damaged bark, paint, and mortar. At the base of a tree, for example, a high-climbing vine could be as thick as a finger and so woody and strong that I could separate it from its roots only by using heavyduty garden shears. Having severed it, I peeled it from the bark by pulling at an angle away from the tree. As the vine climbed, its newer growth was thinner and less strong, so there came a point at which it broke, something a bridge builder would not want to see happen. Nor would Tarzan want to swing from such puny vines. I was living at about a 36-degree latitude at the time of my tug-of-war with ivy, but it is easy to imagine how much larger, stronger, and faster-growing vines could thrive in a tropical rain forest. Harvesting such vines and twisting or braiding them together naturally multiplies the strength of the individual www.americanscientist.org

ones and results in a robust construction material. Indeed, making rope from even relatively short and individually weak vegetable fibers has been practiced for millennia. The Egyptians used palm and reed fibers to make ropes capable of hauling sleds bearing stones weighing tons. But, as with much of technology, knowing how to do something does not imply that there is a full understanding of why it works—or does not. Thus, one of the first questions asked in Galileo’s 17th-century Dialogues Concerning Two New Sciences was, “How are fibres, each not more than two or three cubits in length, so tightly bound together in the case of a rope one hundred cubits long that great force is required to break it?” Indigenous peoples did not have to ask or wait for an answer. Cultures around the world had long relied on

The roots do not grow naturally into a bridge; rather, human ingenuity and patience train them to do so. experience, custom, and oral tradition to build substantial bridges out of vegetable materials. Some can be found today on the Japanese island of Shikoku, whose name is most familiar to me because it was part of the Honshu-Shikoku Bridge Project of the late 20th century that linked two of the country’s five main islands. I followed closely the progress of its centerpiece, the Akashi Kaikyo Bridge, which at the time of its opening in 1998 was the longest suspension bridge in the world, spanning about a mile-and-aquarter (2 kilometers) between its steel towers. Although the longest of vine bridges may span only a couple hundred feet (or about 50 meters), they are equally outstanding projects in the context of their techno-ecology. The Inca built an extensive system of roads throughout pre-Columbian South America, even in remote areas of the high Andes such as where Machu Picchu is located. Suspension bridges across gorges have typically been made of woven ichu grass, a mountain cover also known as Peruvian feathergrass. Queshuachaca, the last such bridge ex-

tant, is located in southern Peru, in the vicinity of Cuzco, the capital of the Inca Empire, and is now a World Heritage Site. Because vegetable matter deteriorates over time, these bridges had to be carefully maintained, which in many cases meant being replaced annually in a ritualized rebuilding. There is a kind of vegetable bridge that does in fact grows stronger with age—something even a modern steel or concrete structure is not expected to do. It is the root bridge, which can be encountered in the subtropical region of northeast India. This kind of span is typically an extension of the root system of a large fig tree (Ficus elastica) growing beside a river. The roots do not grow naturally into a bridge; rather, human ingenuity and patience train them to do so. About a decade after the tree has become rooted securely in the soil, it puts out secondary roots a distance up its trunk. These aerial roots are very flexible and can be woven together and “weedled” across the river, where they are secured to another fig tree. As they continue to grow, the woven roots put out their own secondary ones, known as daughter roots, and over time these offshoots get entangled with branches, tendrils, and other parts of the tree until the whole intertwined system becomes a load-bearing structure capable of being used as a fixed crossing. A root bridge can grow stronger over time because any nicks and cuts it might suffer will be self-healing and, unlike steel that must be kept painted to prevent it from rusting, or concrete that must be kept from cracking and spalling, a living bridge thrives in a moist environment and welcomes rain, which in this part of India can amount to about five feet (1.5 meters) annually. Some tree root bridges are believed to be 500 years old. Shoots and Planks Of course, harvested trees themselves, in the form of timber piles and boards, have provided construction material since ancient times. Julius Caesar wrote in some detail in The Gallic Wars of a timber bridge built across the Rhine in the 1st century BCE. Up until the late 18th century, when iron became a viable alternative, the choice for bridge building was between stone and timber. For a given crossing, the former took longer to build and hence was more expensive, but it could be expected to last for centuries; the latter was more quickly erected, 2022

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ephotocorp/Alamy Stock Photo

A living root bridge has been handmade over decades from the aerial roots of rubber fig trees (Ficus elastica) by the Khasi and Jaintia peoples of Meghalaya, India.

which kept its cost down, but it was vulnerable to rot and fire. As with so many engineering decisions, which alternative to choose was often a judgment call. In the young United States, where impatience was a virtue and forests were old and abundant, timber was the material of choice. To extend the life of a wooden bridge, it was encased in a house-like structure but still had to be replaced over a time measured in decades rather than centuries. Covered bridges may have sufficed for wagon and livestock traffic, but they did not for railroads. Speed was such a driving force in the development of rail transportation that enormous timber trestles were built to maintain a level track and save the time and operating expense of having trains snaking down one side of a valley and up the other. As locomotives and rolling stock grew increasingly large and heavy, old timber bridges had to be strengthened or rebuilt from scratch. Iron and later steel bridges, even though they also had to be maintained and upgraded, all but drove the timber bridge to extinction. Yet quaint and historically significant covered bridges can still be found servicing remote rural areas. Although bamboo is botanically a member of the grass family, its stalks have long been used throughout the world as if they are pieces of timber. Unlike fibers of hemp or blades of grass that need to be woven or braided to provide substantial structural strength, bamboo can simply be cut down and assembled directly into a structure, including the kind of bridge known as scaf160

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folding. Examples are commonly found as the structures upon which masons stand as they lay bricks to form the facade of a new building, or protecting pedestrians walking beside an older building whose facade is shedding bricks loosened by some form of damage or deterioration. Although in the United States, scaffolding most commonly consists of metal modules fitted together like the parts of a child’s construction toy set, throughout much of the world,

Iron and later steel bridges, even though they also had to be maintained and upgraded, all but drove the timber bridge to extinction. lengths of bamboo can be found lashed or coupled together into structures resembling frameworks or jungle gyms. Plant Fuel It was vegetable material in a vastly different form that eventually revolutionized bridge building. Whereas tropical climates may have yielded sufficiently large quantities of robust vines and roots for bridge-building purposes, such supplies were not available in more northerly areas, such as

England’s West Midlands region. It was there, specifically in the county of Shropshire, that the Industrial Revolution is said to have originated. Among the most significant individuals in that transition was Abraham Darby, an iron founder who in the early 18th century began to use coke (which is derived from coal) rather than charcoal (which comes from wood) as fuel for the blast furnace in which he smelted ore, which allowed him to produce cast iron in greater quantities and of better quality. In 1779 his grandson, Abraham Darby III, used such iron in casting the components of a bridge. When the large castings were assembled to cross the Severn River at Coalbrookdale, they formed an arch of 100-foot (30-meter) span. It was the world’s first iron bridge, and is appropriately known as Ironbridge. Although dependent upon decayed and pressurized vegetable material for its very existence, iron as a bridgebuilding material had numerous advantages over grasses, vines, wood, timber, and even stone. It was much more durable than the plant-based ones and could be erected in a fraction of the time it took to build a bridge stone-by-stone. This latter advantage was a result of the voussoirs effectively being cast in one step into an arch form, a time-saving process even when taking into account the need to prepare a sand mold into which the molten iron was poured. All materials do have their limitations, of course, but the brittleness of cast iron was for all practical purposes irrelevant when it was used in compression, which is what occurs in the form of an arch. For other types, such as the suspension bridges traditionally made of vines and roots, cast iron’s relative weakness in tension—by a factor of five or six compared to its strength in compression—called for a different kind of iron. Wrought iron, the kind that results from being repeatedly heated and hammered into a desired shape, was needed. By working wrought iron into bars and links, suspension chains could be forged. Among the earliest chain suspension bridges was the Union Chain Bridge across the River Tweed, whose bicentenary was the subject of this column in January–February 2021. The coexistence of cast iron, wrought iron, and timber enabled engineers to design hybrid bridges using the different materials selectively to take advantage of each one’s relative strength, such as by using cast iron for

of some form of temporary structure onto which the individual parts can be assembled until the ensemble becomes self-supporting. This need to build a temporary bridge in order to build a permanent one has always put stone at a disadvantage. Even the first iron bridge needed a mold into which to be cast—as do plastic bridges. Some early suspension bridges, whose main cables comprised distinct links of iron bars formed into a chain, required scaffolding for assembly. The development of cables made of continuous lengths of iron formed into wire rope relaxed this requirement somewhat, but as spans grew longer and cables larger, steel wires had to be laid parallel to each other, which required the construction of temporary bridges in the form of catwalks to ensure the wires were installed correctly. It is as if the incremental history of bridge building is replayed in the construction of each new structure, no matter what the material employed. Selected Bibliography

World History Archive/Alamy Stock Photo

Timber was plentiful in the early days of railroads in the United States, and it was more efficient operationally to have trains use a level trestle bridge than to follow switchback tracks down into and then up out of a valley. This 1869 woodcut shows the Union Pacific Railroad’s wooden trestle bridge at Dale Creek in Wyoming, which used timber hauled 1,600 kilometers from Chicago.

the parts in compression and wrought iron for the parts in tension. Stone long continued to be the preferred material for the foundations and piers that supported the bridge proper. Concrete, which is sometimes referred to as artificial stone, has also been used for the sub- and superstructure of bridges. Although concrete, like cast iron and stone, is much weaker in tension than in compression, it can be reinforced with steel, which pound-forpound is stronger than wrought iron. It was the Bessemer process, which was developed in the latter half of the 19th century, that enabled the mass production of steel (see Technologue, January– February 2016). The first great engineering structures to use steel were two historic bridges: the Eads (1874), which used steel castings for its segmental arch ribs to cross in three 500-foot (150-meter) spans the Mississippi River at St. Louis, and the Brooklyn (1883), which used continuous lengths of steel wire laid into cables to span just short of 1,600 feet (488 meters) between its East River towers. The last great wroughtwww.americanscientist.org

iron structure was the 300-meter (almost 1,000-foot) Eiffel Tower (1889). Today, plastic is increasingly being used as a structural material, and it much resembles the composite boards that now commonly replace wood planks for outdoor decks. In 1998, the first plastic vehicular bridge was installed at Fort Leonard Wood, Missouri. A decade later, Rotterdam, the Netherlands, a city of canals and 850 pedestrian bridges, began replacing deteriorating wood, concrete, and steel bridges with ones made from a lightweight fiberreinforced polymer expected to last a century. A bridge made from recycled plastic installed at Fort Bragg, North Carolina, in 2009 proved capable of supporting a 71-ton Abrams tank. In 2011, a 90-foot-long (27-meter-long) bridge across the River Tweed became Europe’s first made from recycled plastic—in this case, high-density polyethylene. Regardless of their material, bridges are built on the backs of bridges. The erection of an arch bridge out of voussoirs, whether of stone or frozen tomatoes, always requires the construction

Chandra, V., et al. 2010. World’s first thermoplastic bridges. The Infrastructure Show, June 22. theinfrastructureshow.com/audio /downloads/Worlds-First-Thermoplastic -Bridge.pdf French, C. 2008. Driving the ice road to Canada’s diamond mines. Reuters (March 11). www.reuters.com/article/us-diamonds -iceroad/driving-the-ice-road-to-canadas -diamond-mines-idUSN1451326320080312 Kim, S. 2011. Europe's first bridge made from recycled plastic. ZDNet (October 31). https://www.zdnet.com/article/europes -first-bridge-made-from-recycled-plastic Morton, E. 2013. The vine bridges of Iya Valley, Japan. Slate (December 6). www.slate .com/blogs/atlas_obscura/2013/12/06 /the_vine_bridges_of_iya_valley_in_shikoku _japan.html Peters, A. 2016. Why Rotterdam is building hundreds of bridges from plastic. Fast Company (March 22). www.fastcompany .com/3058035/why-rotterdam-is-building -hundreds-of-bridges-from-plastic Rathnayake, Z. 2021. The ingenious living bridges of India. BBC.com (November 17). www.bbc.com/future/article/20211117 -how-indias-living-bridges-could-transform -architecture Rosenthal, S. 2019. Clingers and twiners: Vines have tangled relationship with trees and buildings. Tallahassee Democrat (July 25). https://www.tallahassee.com/story/life /home-garden/2019/07/25/vines-have -tangled-relationship-trees-wildlife-and -buildings/1819862001 Zorn, A. 2017. Bamboo bridge in Indonesia demonstrates sustainable alternatives for infrastructure. ArchDaily (June 18). www .archdaily.com/873588/bamboo-bridge-in -indonesia-demonstrates-sustainable -alternatives-for-infrastructure 2022

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How Bacterial Pathogens Emerge Can scientists predict where disease-causing microbes will arise before they cause the next pandemic? Salvador Almagro-Moreno

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n the blink of an eye, our world can be turned upside down by the appearance of a new pathogen such as SARS-CoV-2, the virus that causes COVID-19. These devastating events are not something new to humanity, and, unfortunately for those of us trying to forecast them, they do not typically occur in a slow and predictable fashion: Harmless organisms can undergo quantum leaps in evolution to become deadly and then spread like wildfire. The plague and cholera have killed millions over the past centuries and are ominous examples of this phenomenon. Both diseases are caused by bacteria that began with an innocuous ancestor but evolved to become some of humanity’s worst scourges. We cannot predict the future, but we can learn many critical lessons from studying the past of pathogenic disease. Black death reached pandemic status after Yersinia pestis, the bacterium that causes bubonic plague, experienced two major sequential changes. Y. pestis emerged from its ancestor, Yersinia pseudotuberculosis, about 5,000 years ago somewhere in the Eurasian continent, leading to a drastic change in its disease profile from a relatively benign intestinal pathogen to a deadly systemic one capable of causing pandemics. After Y. pestis acquired one cluster of genes, it gained the ability to cause the respiratory form of the disease. Another leap, the acquisition

of a gene called ymt, gave rise to transmission via fleas. This seemingly minor change gave the bacteria the ability to cause bubonic plague and spread both within a human body and among humans in a way that changed human history: The Black Death devastated the Eurasian continent from 1347 to 1351, leading to Europe losing over a third of its population. Vibrio cholerae, the agent of the severe diarrheal disease cholera, experienced a similar transition from a harmless ancestor to one of humanity’s worst curses. The evolutionary history of this aquatic bacterium involves a few more players than Y. pestis, most of them clusters of genes acquired from the environment. The events that can lead microorganisms such as these to turn from benign to bad are as diverse and numerous as the pathogens themselves. Over the past several decades, scientists have uncovered myriad mechanisms and factors that mediate this critical transition. These findings are helping us develop more sophisticated frameworks to address emerging pathogens before they become serious problems for public health. The process by which a biological agent that poses no threat to human well-being gains the ability to colonize and harm us is called pathogen emergence. Typically, this process happens when a microorganism with an environmental lifestyle that does not need

people to exist, or a commensal one that harmlessly grows on or within us, becomes capable of harming us. The emergence of novel human pathogens is without a doubt one of the most pressing problems that we face. I have been working for almost two decades trying to understand what the biological rules and evolutionary forces are that make a microorganism transition to causing disease in humans. It all started when I was a graduate student at the National University of Ireland working to identify large pieces of DNA called pathogenicity islands that differentiate pathogenic V. cholerae from its more innocuous cousins. Between genomic comparisons, DNA extractions, and pints of Murphy’s, my curiosity to understand pathogen emergence grew, and I have dedicated my career ever since to investigating this complex phenomenon. When I started studying pathogen emergence, the field was still relatively in its infancy. The leading view at the time was that harmless organisms acquired discrete pieces of DNA that conferred univocal properties such as the production of a toxin or the expression of a critical factor that allowed bacteria to colonize the human host. Over the years, novel findings have provided a larger context for these entities, unearthing previously unrecognized relationships between these elements and the bacterial genome. Furthermore, my group and others

QUICK TAKE The plague and cholera are two major pandemic diseases that evolved from harmless bacteria to eventually sicken and kill millions of people.

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A variety of mechanisms allow bacteria to acquire new traits from the environment, helping them achieve the quantum leap required to emerge as pathogens.

New insights into pathogens could enable scientists to forecast the events that lead to the emergence of novel infectious agents, which is pivotal for disease management and control.

Science History Images/Alamy Stock Photo

Pandemic infectious diseases have been a recurrent blight throughout the history of humanity. The severe diarrheal disease cholera is caused by the bacterial species Vibrio cholerae, which evolved in quantum leaps from a harmless ancestor to a dangerous pathogen. This cartoon published in 1866 during the London cholera epidemic depicts cholera as a deadly threat lurking in drinking water.

are identifying the ecological drivers that lead to the selection of pathogenic traits and virulent strains. The connections exposed by these discoveries www.americanscientist.org

are beginning to provide the tools we need to potentially forecast the events and drivers that lead to the emergence of novel infectious agents, which is

pivotal for successful disease management and control. Genetic Paths to Disease Pathogen emergence is a dynamic, complex, and multifactorial phenomenon that involves an interplay of various genetic adaptations and ecological drivers. Microorganisms are built to evolve. Bacteria in particular, 2022

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mechanisms of horizontal gene transfer

a transformation

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Bacteria use a variety of mechanisms to acquire pathogenic DNA (a). Transformation involves the acquisition of naked DNA directly from the environment. Conjugation occurs when organisms exchange genetic information via specialized tubelike appendages called conjugative pili. Transduction is mediated by bacteriophages, viruses that infect bacteria and carry their DNA with them. Numerous mobile genetic elements can also confer virulence traits to recipient cells (b). Transposons are “jumping” genes that lead to genomic rearrangements and sometimes carry antibiotic resistance. Pathogenicity islands (PAIs) are large chunks of DNA that can encode colonization factors and are present in clinical strains of bacterial pathogens. Bacteriophages can also carry virulence genes encoding toxins or other factors necessary for pathogenesis. Integrative and conjugative elements (ICEs) are elements that are transferred through the process of conjugation and can integrate into the host genome. Membrane vesicles are extrusions of the cell membrane resembling little spheres that get secreted into the environment, carrying cell content and sometimes virulence genes. 164 American AmericanScientist, Scientist,Volume Volume110 110

such as the agents of cholera and the plague, possess incredibly sophisticated mechanisms that render them capable of acquiring pieces of DNA from the environment or accumulating mutations that allow them to adapt to new environments in a way that multicellular organisms such as humans never could. They are essentially “evolution machines.” One process that has vastly influenced pathogen emergence is the acquisition of new genes via horizontal gene transfer. Humans can only pass genes vertically through generations, that is, from parents to offspring. In contrast, bacteria can pass on genes vertically and also horizontally, trading chunks of genetic information among one another in ways that can accelerate evolution. Through this type of gene transfer, some virulence traits emerge when a cell acquires genetic material from other microorganisms or from its surrounding environment. These traits are often encoded in mobile genetic elements, such as plasmids, pathogenicity islands, or bacteriophages, which are horizontally acquired factors that move around in the environment and play a critical role in the emergence of pathogens. Understanding the complexity and wealth of these mechanisms will help reveal the potential ways we can detect emerging pathogens and develop surveillance platforms. For instance, plasmids are circular pieces of DNA that can be acquired from the environment via a process of gene uptake called transformation and have long been associated with the attainment of pathogenic traits such as toxins and antibiotic resistance. Plasmid acquisition has even led to events where new species of pathogens emerge, including the emergence and speciation of the pathogenic Yersinia species from environmental strains. Acquisition of the virulence plasmid pYV by environmental Yersinia results in a virulent ancestral strain that can overcome host defense mechanisms and colonize lymph tissues. Pathogenicity islands are large clusters of genes that are confined to pathogenic strains within a species and typically encode important genes that are critical for host colonization. For instance, the pandemic strains of V. cholerae harbor several major pathogenicity islands; one encodes an essential intestinal colonization factor called toxin-coregulated pilus. Bacteriophages are viruses that

aquatic reservoir

small intestine V. cholerae toxin-coregulated pilus

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cholera toxin

V. cholerae

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Vibrio cholerae, the causative agent of cholera, exists naturally in aquatic ecosystems. It is contracted by ingesting food or water contaminated with pathogenic strains of the bacteria. Once in the small intestine, V. cholerae produces the toxin-coregulated pilus and the cholera toxin. Cholera toxin leads to increased concentrations of fatty acids, which serve as food for the bacterium, and causes an electrolyte imbalance that results in the diarrhea associated with the disease.

can infect bacteria and in certain cases can integrate within the genome and confer new traits to the host cell. Bacteriophages are a major vehicle for the acquisition of bacterial toxins in several pathogens. Bacteriophages led to the emergence of new virulent and epidemic clones of Escherichia coli 0157:H7, a foodborne pathogen that causes hemorrhagic diarrhea, and these viruses also conferred the cholera toxin to pathogenic strains of V. cholerae, the source of the diarrhea associated with cholera. Not all of these elements are acquired directly from the surrounding

“jumping” elements that can “jump” within the genome and insert in different locations. Transposons primarily move around genes associated with antibiotic resistance. Interestingly, unlike pathogenicity islands or plasmids that physically carry and transfer virulence-associated genes, insertion sequence elements primarily disrupt genes by inserting in them. This literal movement of DNA leads to genome rearrangements that alter gene expression. Integrons are genetic elements encoded within the ancestral bacterial chromosome that facilitate the efficient capture and expression of genes that

The emergence of novel human pathogens is without a doubt one of the biggest problems that we face. environment. For instance, integrative and conjugative elements are transferred via conjugation, a process that requires the production of an extracellular appendage (called a conjugative pilus) that connects two bacterial cells and allows them to exchange genetic material. Integrative and conjugative elements typically encode genes that provide resistance to antibiotics, help outcompete other bacteria during colonization, and enhance survival of the bacterium within the host. Insertion sequences and transposons are small www.americanscientist.org

have been acquired from the environment. Integrons primarily capture genes associated with antibiotic resistance, but some of the genes they contain can also drive host colonization and virulence. In addition to these canonical modes of horizontal gene transfer, other gene transfer mechanisms have been identified that might play significant roles in the emergence of bacterial pathogens. Membrane vesicles are extrusions of the cell membrane resembling little spheres that get secreted into the environment,

carrying cell content and, importantly, DNA. It was recently found that membrane vesicles from pathogenic E. coli can harbor genes encoding virulence factors that result in increased cytotoxicity of nonpathogenic E. coli strains. Recently discovered gene transfer agents also encompass another potential mode of horizontal gene transfer. These elements exclusively package random segments of bacterial DNA and inject them into recipient cells. Future research will uncover the impact of these novel transfer mechanisms in shaping the emergence of bacterial pathogens and potentially reveal novel emergence mechanisms, which will undoubtedly enrich and likely reshape our picture of what it takes to become a pathogen. Avoiding Self-Sabotage Clearly, a plethora of mechanisms and vehicles exist that allow bacteria to acquire new traits from the environment, helping them achieve the quantum leap that can lead to their emergence as pathogens. But evolution does not follow an intentional course, so the quantum leap can also take bacteria in the wrong direction: Acquiring foreign genetic fragments can cause substantial wreckage and disrupt an organism’s well-ingrained physiology. Identifying the environments and conditions that favor microbial risk-taking is an active area of research. It turns out that bacteria are very picky about the genes that they acquire and express. This genetic shuffling is held in check by a variety of intricate cellular processes. Pathogens must carefully balance the acquisition and expression of the genes that could potentially help them colonize the human host against the indiscriminate uptake and assimilation of detrimental 2022

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Yersinia pestis pYV environmental Yersinia

Hms Yersinia pseudotuberculosis

virulent ancestor HPI

pCP1 pMT1 pPIa

Barbara Aulicino; Cultura Creative Ltd/Alamy Stock Photo; Dennis Kunkel Microscopy/Science Source

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Vibrio cholerae VPI-1 pandemic Vibrio cholerae

environmental Vibrio cholerae

as they naturally prevent the acquisition of foreign genes. Gene silencing is another widespread approach for bacteria to control the expression of new genes potentially associated with virulence. For this mechanism, bacteria use xenogeneic silencing proteins that bind to and suppress the expression of these acquired genes. This mechanism minimizes the potentially negative effects associated with unregulated expression of foreign DNA. Proteins such as HN-S in E. coli are critical regulators of acquired virulence genes, and proteins with similar function and evolutionary origin can be found in a wide range of important human pathogens such as Mycobacterium tuberculosis or Pseudomonas aeruginosa.

CTXФ VPI-2

Shigella-EIEC SHI-1

noninvasive Escherichia coli

SHI-3 ShigellaEIEC

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SHI-2

Some bacterial pathogens have evolved in quantum leaps from harmless ancestors. Examples of this pattern of pathogen emergence include Yersinia pestis, the agent of bubonic plague, which evolved by acquiring the three plasmids pCP1, pMT1, and pPla and numerous insertion sequences; Vibrio cholerae, the agent of cholera, which acquired the CTXphi bacteriophage that encodes the cholera toxin and two pathogenicity islands, VPI-1 and VPI-2; and Shigella flexneri, which acquired the pINV virulence plasmid that encodes the molecular machinery essential for invasion, survival, and dissemination in the host, and three pathogenicity islands, SHI-1, SHI-2, and SHI-3.

genes that would compromise their survival. To do so, they have devised complex ways to modulate DNA acquisition and gene expression. In contrast to integrons, which favor the successful maintenance and expression of acquired genes, DNA assimilation is inhibited by either degrading incoming DNA via CRISPR-Cas systems, or by preventing gene expression via xenogeneic silencers (“xenogeneic” means obtained from an organism of a different species). CRISPR-Cas systems have gotten substantial media attention as a new technology to edit genomes; however, their original function is as a bacterial defense mecha166

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nism that can degrade incoming pieces of foreign DNA. (See “Interview with a Gene Editor,” July–August 2015.) Interestingly, CRISPR-Cas systems have recently been found to prevent the establishment of specific gene clusters associated with pathogen emergence. For instance, during mice infections with Streptococcus pneumoniae, CRISPR-Cas sequences that target the capsule genes prevent this respiratory pathogen’s cells from becoming encapsulated, eventually blocking establishment of a successful infection. These findings could help explain why many strains of major human pathogens lack CRISPR-Cas systems in their genomes,

Virulence Genes If all it takes to emerge as a pathogen is to acquire some mobile genetic elements, why do only a small number of species and strains cause disease in humans? For instance, the mobile genetic elements that confer pathogenic traits to V. cholerae can be easily exchanged and are widespread in cholera endemic areas. In fact, numerous environmental nonpathogenic strains of V. cholerae encode these islands and the bacteriophages required to develop the disease but are totally harmless. However, only one group, the aptly named pandemic group, can cause cholera in humans. What is so special about them? This question puzzled me throughout graduate school, where I was investigating the role of horizontally acquired DNA in V. cholerae, but it wasn’t until my time as the Ernest Everett Just Postdoctoral Fellow at Dartmouth College that I started to explore it fully. The only way I could make sense of the data was under a scenario in which those strains that emerged as pathogenic had a unique genetic makeup that provided “fertile ground” for these mobile genetic elements to land on. A few years later when I started my own lab, we discovered that strains that cause cholera encode what we call “virulence-adaptive polymorphisms,” which are variations that provide them with preadaptations to virulence. These preadaptations are independent from the horizontal acquisition of genetic material and occur in the environment prior to the bacterium acquiring the ability to colonize the human host.

This behavior is not unique to pathogenic strains of V. cholerae. Other studies have explored the relationship between the genomic background of E. coli strains and the retention and expression of acquired virulence factors. These analyses have identified two distinct genomic profiles in pathogenic strains: first, an ancestral background that allows expression of factors associated with mild, chronic diarrhea and is found in most E. coli, and second, a derived background that favors expression of factors with more severe pathologies and that is found in pathogenic strains such as enterotoxigenic or enterohemorrhagic E. coli. It is becoming increasingly clear that the specific genomic makeup of a given strain is essential for the emergence of pathogenic traits and its ability to colonize the host, which might explain the uneven distribution of virulent clones in numerous pathogenic species.

and adapt to new niches. For instance, more than 90 percent of commensal E. coli express a gene called mannosesensitive type 1 fimbriae that helps them colonize the intestine. Pathoadaptive mutations in this gene help the bacteria adhere more tightly to the lining of the urinary tract, allowing a change in the type of tissue that E. coli can colonize. This change ultimately leads to a major evolutionary transition from an intestinal commensal to a pathogen that causes urinary tract infections. The emergence of other major virulence phenotypes such as resistance to host defense mechanisms is also associated with pathoadaptive mutations. For instance, commensal Mycobacterium abscessus strains that are adapted to the lungs of cystic fibrosis patients possess a large number of mutations in genes that lead to enhanced survival within macrophages.

A plethora of mechanisms allow bacteria to achieve the quantum leap that can lead to their emergence as pathogens. Besides a particular set of preadaptations in the genomic background of pathogens, there are mutations that arise within the host that also confer virulence-adaptive traits, also known as pathoadaptive mutations. These mutations are typically associated with the colonization of different tissues, adaptation to new metabolic conditions, or evasion of the immune system. A quintessential example of the significant role of pathoadaptive mutations in pathogen emergence is the rise of pathogenic Shigella species, water and foodborne pathogens that cause severe diarrhea, from their closely related nonpathogenic commensal E. coli. The latter require the activity of an enzyme called CadA-mediated lysine decarboxylase for growth in the intestine; however, CadA blocks the activity of the Shigella toxins. Pathoadaptive mutations in the cadA gene occurred independently in various Shigella species, allowing for toxin activity and contributing to the emergence of pathogenic Shigella from commensal E. coli. These mutations also allow pathogenic E. coli to colonize new tissues www.americanscientist.org

All these examples highlight the relevance of unique genomic adaptations in the process of pathogen emergence. These, together with horizontally acquired DNA, appear to be main molecular drivers of this complex phenomenon. Much of my research has revolved around a key question: What evolutionary forces select for these disease-causing traits? Accidental Pathogenicity A major driver of the evolution of pathogenic bacteria is predation. In the wild, bacteria must survive assaults by bacteriophages, protozoa such as amoeba, and predatory bacteria such as Bdellovibrio. The evolution of a variety of defense mechanisms against these threats has been accompanied by the incidental development of virulence traits that aid in the colonization of humans. For example, some of the defense mechanisms in Legionella pneumophila, E. coli, and P. aeruginosa that are critical for evading predation by protists in their natural environment are also fundamental for the ability to colonize and survive within human hosts.

L. pneumophila, which causes the severe respiratory syndrome Legionnaires’ disease, represents a fascinating case of accidental evolution of virulence. Survival and spread of the bacterium in freshwater reservoirs and moist soil are contingent upon replication in free-living protozoa such as Acanthamoeba castellani. The pool of virulence traits in this pathogen evolved as a result of its interaction with aquatic protozoa, which in turn enabled its ability to survive within human alveolar macrophages. This relationship is so well established that the bacterium has acquired a large number of genes from its eukaryotic host. For instance, the enzyme in L. pneumophila sphingosine-1 phosphate lyase (LpSpi) plays a role in sphingolipid biosynthesis, a pathway that is conserved in protozoa but is hardly ever found in bacteria. LpSpi modulates the metabolism of the protozoa to aid L. pneumophila growth by preventing cell-death processes that naturally occur upon infection. Interestingly, the gene is related to their eukaryotic counterparts, suggesting horizontal gene transfer from A. castellani to L. pneumophila. Legionella species are not the exception, but rather some of the many examples in the bacterial world of acquiring genes from eukaryotes. Amoebae may be training grounds for future bacterial pathogens as the ecologically and phylogenetically diverse bacteria thrive inside amoebae, acquiring traits that also allow for survival and pathogenesis in the human host. Therefore, it is evident that the environment and its dwellers can serve as selective agents that ultimately lead to the emergence of bacterial pathogens. As humans alter that environment, we may be easing their path toward colonizing us. From Disruptions to Disease Human-made ecological perturbations, such as climate change or pollution of our ecosystems, are drastically affecting the spread and proliferation of disease-causing bacteria, accelerating their rampant acquisition of antibiotic resistance, and increasing the likelihood of the emergence of novel pathogens. The warming of the oceans is leading to a measurable increase in the overall number of Vibrio bacteria and their associated infections over the past few decades. Antibiotic resistance is drastically increasing among 2022

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a

global warming

b

antibiotics

antibiotics increase in water temperature waterborne pathogens

antibiotic sensitive

c

fertilizers

d

antibiotic resistant

deforestation

vibrio

cyanobacteria

Stephanie Freese

The spread and proliferation of pathogens are being driven by numerous human-made environmental perturbations, such as climate change, the overuse of antibiotics and fertilizers, and deforestation.

environmental bacteria, in large part because of the addition of antibiotics to farm feed and treating orchards with antibiotics to prevent blights. The runoff of fertilizers due to heavy rains leads to cyanobacterial blooms in estuaries and lakes. We recently found that

Land-use changes, such as deforestation, urbanization, and agricultural expansion, disrupt biodiversity and the food-web structure, and cause habitat fragmentation. The resulting loss of habitat introduces non-native species, including pathogens, into the human

Effective prediction of emergence events is now a possibility and will benefit disease management and public health measures. those blooms lead to the proliferation and fast growth of vibrios. Interestingly, some studies have shown a direct correlation between cholera cases and the presence of these blooms in the Bay of Bengal. 168

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matrix, thus increasing host-pathogen interactions, ultimately leading to the emergence of new diseases in humans, domestic animals, and wildlife. For instance, deforestation and land disturbances in the southern Amazon basin

of Peru have been correlated with the growing prevalence of rodent-borne Leptospira and Bartonella species. Forest fragmentation in the northeastern United States has led to an increased risk of Lyme disease due to an abundance of white-footed mice, considered “superspreaders” of the tick-borne pathogen Borrelia burgdorferi. Deforestation activities in Brazil have been shown to influence the risk of Brazilian spotted fever caused by the vector-borne bacterium Rickettsia rickettsii. Spillover of zoonotic pathogens from animals to human hosts, such as the transition of SARS-CoV-2 from bats to humans, accounts for the majority of the emerging infectious disease events in the past 80 years, more than half of which were of bacterial origin. However, besides research on how environmental perturbations affect the spread or antimicrobial resistance of pathogens, there have been very few studies investigating how these changes affect the likelihood of a bacterium becoming pathogenic or drive the acquisition of novel pathogenic traits. This is a major gap in our current knowledge that, once addressed, will

lead to unprecedented advances in our ability to predict and identify sources of potential pathogens. Lessons of Pathogen Emergence Pathogen emergence is a dynamic and complex phenomenon, which makes it enormously challenging to study. For instance, which variables do we study to attempt to find associations? If we find one variable, how do we switch from correlation to causation? How often and how many samples do we need to generate accurate predictive models? Most importantly, is it possible to build a realistic and costeffective surveillance framework? My lab members and I recently aimed to answer some of these questions by implementing a holistic approach where we mixed ecology, computational biology, and molecular genetics to dissect the drivers that foster the selection of virulence traits and pathogenic clones within environmental populations. We focused on Vibrio vulnificus, an aquatic bacterium that can cause a deadly flesh-eating infection in humans, as a model system. Our findings, which were published in the Proceedings of the National Academy of Sciences of the U.S.A., suggest how ecosystems generate selective pressures that facilitate the emergence of specific strains with pathogenic potential in a natural population. These insights can be applied toward predictive frameworks to assess the risk of pathogen emergence from environmental sources. Effective prediction of emergence events is now a possibility and will benefit disease management and public health measures. Sequencing technologies are becoming more affordable, and their widespread implementation is helping address the roots of pathogen emergence. For instance, techniques that allow us to examine the microbial communities in a given environment and their evolution can be used to determine the impact of natural and anthropogenicinduced effects on ecosystems. These approaches can also identify risk factors such as the increased prevalence of bacterial strains with pathogenic potential in a population, or the availability of known virulence factors in environmental reservoirs. The data obtained using these techniques can provide valuable insights into the likelihood of new emergence events. Furthermore, the integration of this genomic information paired with the www.americanscientist.org

Courtesy of Salvador Almagro-Moreno

Scientists are currently working on developing surveillance networks to investigate how bacteria evolve pathogenic properties in order to predict the next pandemic. Here, members of the author’s lab sample the waters of the Indian River Lagoon in eastern Florida to assess the ecological dynamics of endemic populations of Vibrio vulnificus and Vibrio cholerae.

currently used culture- or PCR-based monitoring of natural habitats will significantly strengthen surveillance platforms to detect pathogen emergence by providing an in-depth yet affordable means of monitoring potential pathogen sources. Such informed surveillance networks and subsequent risk factor analyses will help us identify and categorize high-risk habitats, such as prioritizing specific sites and seasons for sampling rivers and lakes, identifying certain animals and meat that are of concern in markets, and monitoring specific rodent or insect populations. As a result, these efforts can lead to appropriate interventions and public health advisories for effective outbreak prevention and control. In addition to potentially helping forecast pathogen emergence events, these approaches can also be useful after an emergence event or outbreak. For instance, retroactive outbreak analyses on the contributing environmental and genetic factors can be informative in preventing future emergence events. We recently applied this approach to the catastrophic cholera epidemic that killed thousands of people in Latin America in the 1990s, gleaning important lessons, including the role of weather patterns such as El Niño and the importance of specific food

preparations, which can be applied to future outbreaks. Despite the numerous dark events in human history caused by emerging pathogens, we and other scientists are gathering the knowledge, tools, and approaches we need to help us detect the next quantum leap in pathogenicity, and potentially avert the next pandemic. Bibliography Balasubramanian, D., T. A. Grant, M. LópezPérez, C. B. Ogbunugafor, and S. AlmagroMoreno. 2022. Molecular mechanisms and drivers of pathogen emergence. Trends in Microbiology doi:10.1016/j.tim.2022.02.003. Balasubramanian, D., S. Murcia, C. B. Ogbunugafor, R. Gavilan, and S. AlmagroMoreno. 2021. Cholera dynamics: Lessons from an epidemic. Journal of Medical Microbiology doi:10.1099/jmm.0.001298. López-Pérez, M., et al. 2021. Ecological diversification reveals routes of pathogen emergence in endemic Vibrio vulnificus populations. Proceedings of the National Academy of Sciences of the U.S.A. 118:e2103470118. Shapiro, B. J., I. Levade, G. Kovacikova, R. K. Taylor, and S. Almagro-Moreno. 2016. Origins of pandemic Vibrio cholerae from environmental gene pools. Nature Microbiology 2:16240. Salvador Almagro-Moreno is an assistant professor of medicine at the Burnett School of Biomedical Sciences at the University of Central Florida. His research focuses on the emergence and evolution of bacterial pathogens. Email: [email protected] Twitter: @bioetry 2022

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How Glyphosate Cropped The controversial herbicide, originally developed in a quest for improved water softeners, became ubiquitous in modern agriculture long before its mode of action was understood.

Philip A. Rea

Westend61 GmbH/Alamy Stock Photo

W

eeds are a major, expensive threat to crop yields and quality. The weed killer that has transformed global agriculture is glyphosate, which you likely know as Roundup. This herbicide had a fascinating scientific and industrial journey to its eventual market dominance. Since its introduction in 1974, more than 2.2 billion kilograms of glyphosate have been applied in the United States, and more than 10 billion kilograms globally. Initially it was applied carefully to kill only weeds and not crop plants, but use of glyphosate increased explosively after the introduction in 1996 of genetically engineered

To plant scientists, weeds have the same dignity and beauty as all other plants, but to cultivators of gardens and croplands, weeds are cursed for growing in the wrong places. Glyphosate, commercially known as Roundup, is a harrow for weeds and a liberator of crop yields. Its emergence is a winding tale of serendipity, painstaking research, and a seemingly “perfect” small molecule.

crops that resist glyphosate’s killing action, allowing freer application of the weed killer among resistant crop plants. As of 2019, glyphosate was applied to an average of 121 million hectares (1.2 million square kilometers) of cropland annually in the United States alone, which amounts to about five times the total land area of the United Kingdom. Glyphosate has received media coverage about human health concerns. It was recently classified as a

Group 2A probable human carcinogen by the International Agency for Research on Cancer (IARC), linking exposure to an increased risk of non-Hodgkin’s lymphoma, and three court trials in 2018 and 2019 awarded damages to plaintiffs who attributed their non-Hodgkin’s lymphoma to glyphosate exposure. In 2018, Monsanto, the patent holder for Roundup, was acquired by Bayer AG for a staggering $63 billion. The purchase was soon followed by

QUICK TAKE Glyphosate, trade name Roundup, is the most important herbicide of all time, based on the billions of kilograms that have been applied to croplands worldwide.

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First came the molecule with peak herbicidal activity against weeds and other plants. Then agriculture was transformed by the development of crops the herbicide couldn’t harm.

The emergence of glyphosate is a story of diligent research and serendipitous discovery, followed by years of unraveling how the chemical works.

Up

ly designed—anything but. Its Monsanto beginnings date to 1960, when chemists in the company’s Inorganic Chemicals Division in St. Louis developed a new process for the synthesis of compounds called aminomethylphosphonates (AMPs) as candidate water softeners, which bind and sequester

Amines are derivatives of ammonia, with a central nitrogen atom attached to various hydrocarbon groups. These were compounds that no one at Monsanto had made before. The search was on for that secondary AMP, and it soon paid a dividend. Of the new AMPs Franz

Rational design of biologically active chemicals involves studying compounds and synthesizing subtle variants to refine those activities. Glyphosate was not rationally designed—anything but.

Bayer agreeing to pay $10 billion to address tens of thousands of lawsuits implicating the herbicide in non-Hodgkin’s lymphoma. Looking beyond these emotionally charged social and legal concerns, how did Roundup become so ubiquitous? An extraordinary convergence of factors and serendipitous science behind glyphosate’s discovery enabled this simple compound to transform global agriculture. What makes it so effective? How can it target plants but not animals? How were some crop species made immune to Roundup, and how do those plants dodge glyphosate’s killing action? Born of Serendipity Rational design of biologically active chemicals involves studying compounds with known biological activities and shrewdly synthesizing subtle variants to refine and enhance those activities. Glyphosate was not rationalwww.americanscientist.org

minerals that cause limescale formation (calcium or magnesium carbonate deposits) in pipes, on water heating elements, and the like. The company already had a few such water softeners on the market, but when their chemists developed a simple procedure for producing these products in high yield, the hunt began for variations with enhanced water-softening properties and lower production costs. In a different department at Monsanto, Philip C. Hamm, then head of the company’s herbicide screening program, advocated screening all new in-house compounds regardless of source for herbicidal activity in a wideranging search for new products. This search identified two compounds with weak herbicidal capabilities. Catching Hamm’s attention, though, was that the herbicidal activity was not limited to annual plants but was also active against perennials, at a time when herbicides for perennials had not yet entered the market. Over the next nine years, from 1960 to 1969, Monsanto researchers searched for AMP compounds with herbicidal activity at least 10 times that of the first two lead compounds. Those efforts met with failure. Then John E. Franz, newly transferred from the company’s Organic Chemicals Division to the Agricultural Products Division, switched the research attention from AMPs in which the amine nitrogen was bonded to three carbon atoms (tertiary amines) to those in which the amine nitrogen was bonded with two (secondary amines).

synthesized, two or three were what he termed “deader than doornails,” but there was one that was at least 10 times more effective as an herbicide than the AMPs they had started with. The compound in question was N-(phosphonomethyl)glycine, which we now know as glyphosate. Franz first synthesized glyphosate in May 1970. Monsanto’s patent application was filed in May 1971 and issued in March 1974. Franz, the sole named inventor on the patent, was awarded the princely sum of five dollars when the patent was first issued. Promotions and accolades followed, but not for many years. Discovery requires both knowing what has been discovered and knowing what is new. Monsanto’s 1974 patent was not for the discovery of glyphosate but for establishing its herbicidal properties. Credit for glyphosate’s original discovery goes to the Swiss chemist Henri Martin, who first synthesized the molecule in 1950 while working for the pharmaceutical company Cilag (now a subsidiary of Johnson & Johnson). The molecule had no obvious pharmaceutical applications and Cilag had no portfolio in herbicides, so glyphosate was relegated to the chemical archives until 1964, when it cropped up in another patent, this time issued to Stauffer Chemical Company (now part of Sanofi-Aventis). Although it was an agricultural company, Stauffer’s patent had nothing to do with herbicides. Rather, it was concerned with the synthesis of 2022

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estimated use on agricultural land, in kilograms per square kilometer

estimated agricultural use for glyphosate in 2019

< 1.00

no estimate

4.95 to 20.25 > 20.25

1.00 to 4.94

U.S. Geological Survey

Estimates of glyphosate use and its geographic distribution in the United States jumped from 1996 (left), when glyphosate-resistant crops were first commercialized, to much higher levels 23 years later in 2019 (right).

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solubility, packaging, storage, and use in the field. Blind Targeting Even as it was becoming a huge commercial success, glyphosate remained something of a biochemi-

chelating agent

– –

M 2+

Morgan Ryan

phosphinic acids as water-softening agents, in which glyphosate got a mention as one of several oxidation products of this class of phosphorus oxyacids. Some commentators have insinuated that Monsanto acquired its original glyphosate samples from Stauffer. It didn’t. The glyphosate Monsanto had in hand was independently synthesized in-house. Glyphosate’s commercial success spurred Monsanto and other agrochemical companies to try to develop a chemically modified form with improved action—no surprise there. What is surprising, given that glyphosate was not rationally designed, is how close to accidental perfection its “design” was. As chemists systematically made substitutions to each and every atom or functional group of the molecule, the result was always the same—partial or complete loss of herbicidal activity. Whereas most drugs and pesticides contain solitary or clustered functional groups responsible for the compound’s toxicity, called toxophores, glyphosate in its entirety is the toxophore. Any change to the molecule reduces its effectiveness. It was as if a market had been cornered—no modifications of the original could compete—until the initial patent expired in 1991. Even then, Monsanto retained exclusive rights in the United States until the expiration in 2000 of their patent protecting the isopropylamine salt formulation of the product, which offers improved

Water softeners combat limescale (calcium or magnesium carbonate deposits), often working by chelation—capturing ions based on structure and attraction (above). Glyphosate was one of many compounds investigated in the search for a water softener that would minimize the formation of limescale in plumbing components (right).

cal mystery. When glyphosate first came to market in 1974 as a broadspectrum herbicide, not much was understood about its mechanism of action other than that it killed plants after they emerged from the ground and did so relatively indiscriminately. About all that was known were the results published in 1972 by Ernest Jaworski and his colleagues at Monsanto indicating that glyphosate somehow inhibits the pathway responsible for synthesis of the amino acids phenylalanine and tyrosine. It was not until 1979–1980, five years after its market entry, that glyphosate’s precise target was identified as the enzyme 5-enoylpyruvylshikimate-3-phosphate (EPSP) synthase. And it was not Monsanto scientists, or academic scientists sponsored by Monsanto, or even U.S. scientists who made the discovery, but instead a German group headed by biochemist Nikolaus Amrhein of ETH Zurich. Jaworski had

Olga Traskevych /Alamy Stock Photo

estimated agricultural use for glyphosate in 1996

A Biosynthetic Cornucopia The shikimate pathway owes its name to the iconic shikimi plant (Japanese star anise, Illicium anisatum). The shikimi plant is one of the sources of aniseed, from which the organic acid shikimic acid (or shikimate) was first isolated by the Dutch chemist Johann Frederik Eijkman in 1885. Several things make the shikimate pathway special. It is ubiquitous in plants and is widely distributed in bacteria and fungi, but crucially, animals completely lack the shikimate pathway. The enzyme targeted by glyphosate is simply not present in animals. However, the products of the shikimate pathway are essential for our survival, and we acquire them without making them by eating plants and eating animals that eat plants. The shikimate pathway consists of a sequence of enzyme-catalyzed reactions that yield the amino acids phenylalanine, tyrosine, and tryptophan. These molecules and some other intermediates both up- and downstream in the pathway serve as precursors for the synthesis of an incredible array of natural products— vitamins, pigments, flavor agents, structural molecules, and many other compounds. How important is the shikimate pathway in nature? The biosphere would be hardly recognizable if not for the biosynthetic bounty it produces. In sheer scale, it accounts for roughly one-third of the carbon fixed by photosynthesis in green plants, and for many essential nutrients, vitamins, and vitamin precursors upon which all life depends. Small wonder that an agent that slams the brakes on the shikimate pathway should be so devastating for plants. And that is what glyphosate does: By inhibiting EPSP synthase, it stalls the synthesis of EPSP from phosphoenolpyruvate (PEP) and shikimate-3-phosphate (S3P), thereby preventing the synthesis of phenylwww.americanscientist.org

glyphosate

PEP

Morgan Ryan

The chemical structure of glyphosate (left) resembles that of phosphoenolpyruvate (PEP) (right), one of the two substrates of the enzyme EPSP synthase, which is the target of glyphosate. The structures of glyphosate and PEP are similar enough that they compete to bind in the enzyme’s active site, where catalytic activity occurs.

alanine, tyrosine, tryptophan, and the many other vital compounds that are ultimately derived from EPSP. There is something else significant and rather special about glyphosate’s action—not just the centrality of the enzyme it shuts down, but

although the inhibition of EPSP synthase by glyphosate is competitive with respect to one of the enzyme’s substrates (a substance that reacts to the active site of the enzyme), PEP, which was not surprising, it is uncompetitive with respect to the other

Whereas most pesticides contain functional groups responsible for the compound’s toxicity, called toxophores, glyphosate in its entirety is the toxophore. how it does so. In the 1980s, nearly a decade after glyphosate reached the market, a Scottish group under the leadership of University of Glasgow biochemist John R. Coggins made an unlooked-for and unexpected discovery. They found that

substrate, S3P, which was very surprising and has profound implications. (See box on page 175.) Uncompetitive inhibition is an aspect of enzyme activity that is always described in biochemistry textbooks but is actually very rare. Competitive

The Japanese star anise (Illicium anisatum) is one of the sources of aniseed, as well as the plant from which the organic acid shikimic acid (or shikimate), a major intermediate of the shikimate pathway, was first isolated.

Wikimedia Commons

been on the right track, finding that glyphosate acted on the biosynthetic pathway leading to, among other things, aromatic amino acids. What the German group did was place front and center stage the enzyme that acted on a chemical called shikimate-3-phosphate, the precursor for a highly active, branched array of enzyme-catalyzed reactions of extraordinary importance for plants.

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inhibitors are compounds that resemble the true substrate of an enzyme and bind directly to the enzyme’s active site—they compete for binding sites, and only one or the other can be bound in a given active site, so the presence of the inhibitor slows the catalytic activity of the enzyme. Another type of inhibitor, referred to as noncompetitive, binds at a site distinct from the active site of the target enzyme and generally bears little resemblance to the true substrate.

Either or both may be bound to the enzyme at the same time. Now contrast these two modes of inhibition (both common) with uncompetitive inhibition (rare). Uncompetitive inhibitors bind to the enzyme only after it has a substrate bound to it. Substrate binding changes the shape of the enzyme so that it can bind the uncompetitive inhibitor. This property means that an increase in substrate concentration actually enhances the action of an uncompeti-

Morgan Ryan; Wikimedia Commons; Shutterstock/Jantana Phattha; spline_x; Wikimedia Commons; Shutterstock/capture and compose; clipartmax.com

shikimate

shikimate-3-phosphate PEP glyphosate EPSP synthase

folate (vitamin B9)

Folate is abundant in green vegetables and crucial for DNA and RNA metabolism. L-tryptophan

phylloquinone (vitamin K1)

Vitamin K1 is a key cofactor for several of the enzymes involved in blood clotting.

chorismate

tyrosine

phenylalanine Lignins give bark and wood their rigidity.

Glucosinolates give mustard its pungency.

Betanins give beetroot its rich red color.

Anthocyanins formed from tyrosine and d phenylalanine give flowers their vibrant red, yellow, and blue hues. This metabolic pathway from shikimate shows the location of the enzyme EPSP synthase, the target of glyphosate. The reaction catalyzed by EPSP synthase is found in all plants and many bacterial and fungal species, and is responsible for synthesis of the amino acids tryptophan, tyrosine, and phenylalanine, and the precursors for countless vital natural products, only a few of which are shown here. 174

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tive inhibitor. When the enzyme is inhibited, substrate piles up from reactions upstream. A higher concentration of substrate allows more of the available enzyme to be converted to its inhibitor-binding state. The enzyme acted on by glyphosate, EPSP synthase, has two substrates, S3P and PEP. Binding of S3P must come first because that event changes the shape of the enzyme. The conformational change that follows forms the binding site for PEP (or glyphosate). The binding of S3P, by creating a binding site for glyphosate, therefore reinforces the inhibitory action of glyphosate. Sustained activity of the reactions upstream in the pathway produces S3P that has nowhere to go because the next step is blocked by inactive, dead-end EPSP synthase complexes with substrate and glyphosate bound. The upshot is that the indispensable shikimate pathway crashes because the inhibitory action of glyphosate gets amplified. Catastrophic shutdown of the shikimate pathway annihilates the plant containing it. The sheer disruption caused by uncompetitive inhibitors may explain why they are extremely rare. Only a few examples are known, and two of those are not natural but based on experimental introduction of compounds with inhibitory properties. The rarity of this type of inhibition leaves one wondering whether, as clearly stated by the enzyme kineticist Athel Cornish-Bowden, “the severely toxic effects that an uncompetitive inhibitor might be expected to have may have caused enzymes to have evolved in such a way that there has been selection against structures that might favor uncompetitive inhibition.” In short, the property that might make uncompetitive inhibition a device for maximizing toxicological or pharmacological effect, as exemplified by glyphosate, is a property that has prevented, or at least limited, its evolutionary emergence as a regulatory device. Structural studies of EPSP synthase published in 2001, a quarter century after the herbicide’s commercialization, revealed another secret in the glyphosate story. How exactly does the shape of the EPSP synthase enzyme change to make it susceptible to uncompetitive inhibition by glyphosate?

EPSP synthase is a modestly sized single-subunit protein consisting of two similar lobes that can be in either an “open” or “closed” conformation. In its free form, when not associated with substrate molecules (the enzyme’s natural substrates or glyphosate), the two domains of the enzyme are in the “open” conformation. But on interaction with one of the substrates, S3P, the only substrate that binds with the open form of the enzyme, the two domains close on each other, forming a binding site inside the enzyme. With the trap now set, glyphosate can occupy the active site ordinarily occupied by the other substrate, PEP. Roundup Revolution The foundation of glyphosate’s commercial value—the ubiquity of the shikimate pathway in plants—also played a big part in initially restricting its use. Because plants to be cultivated and weeds to be eliminated both rely on the shikimate pathway for survival, glyphosate was largely restricted to weed control before crop planting. Mechanical innovations such as shielded sprayers, designed to minimize contact of the crop’s foliage with the herbicide, helped moderate this restriction, but it was not until the development of glyphosate-resistant plants, as exemplified by Monsanto’s Roundup Ready crops, that agricultural practice was to undergo a radical transition. Glyphosate had been on the market for 20 years before Roundup Ready crops catapulted to market dominance with the advent of the transgenic era in the mid-1990s. In 1996, glyphosate-resistant (GR) soybeans were released, starting the rise of glyphosate to preeminence as the most widely used herbicide ever. By 2006, more than 90 percent of the soybeans cultivated in the United States were GR, and by 2014 more than 90 percent of U.S. cotton and corn was also GR, soon to be followed by alfalfa, canola, and sugar beet. Waiting in a Waste Pipe If the discovery of glyphosate epitomizes serendipitous small-molecule discovery, then the discovery of the first glyphosate-resistant variant of the target enzyme must rank high among serendipitous gene discoveries. In a twist, glyphosate resistance was first found not in a crop or even www.americanscientist.org

substrate and inhibitor compete to bind at same site substrate

substrate:

inhibitor

inhibitor binds only after substrate binds

substrate and inhibitor bind to different sites

substrate binding interferes with inhibitor binding and vice versa

substrate binding is unaffected by inhibitor binding and vice versa

substrate binding is necessary for inhibitor binding

decreases inhibition

neither increases nor decreases inhibition

increases inhibition

competitive

noncompetitive

uncompetitive Morgan Ryan

Enzyme activity can be inhibited by three mechanisms, two that are commonplace and one that is rarely encountered. In the outlier, called uncompetitive inhibition, which is exemplified by how glyphosate works, the inhibitor has nowhere to bind the enzyme until the substrate binds first. Compare that with competitive inhibition, in which an increase in the concentration of substrate makes binding of the inhibitor less likely because the binding sites are taken by the substrate, and with noncompetitive inhibition, in which an increase in substrate concentration does not have an effect on inhibitor binding because the substrate and inhibitor bind to different sites. In uncompetitive inhibition, an increase in substrate concentration makes the binding of the inhibitor (such as glyphosate) more likely by opening up the site to which the inhibitor can bind. Natural selection has almost always avoided this inhibitory mechanism.

a plant species, but in a bacterium lurking in a waste pipe at a Monsanto glyphosate production facility. Many genetic engineering experiments had been explored in the quest

surrounds of a glyphosate production facility. It was through the introduction of the bacterium’s gene into crop species that Roundup Ready crops first became available to farmers in 1996. In-

Instead of spraying glyphosate on fields just before planting, farmers could now spray it over growing glyphosateresistant crops to eliminate the weeds while leaving the crop plants unaffected. for Roundup Ready crops, but things didn’t take off until the discovery of Agrobacterium sp. strain CP4, a member of the genus that causes crown gall disease. The CP4 gene of Agrobacterium encodes a glyphosate-resistant version of EPSP synthase—surely the reason the bacterium was able to survive in the

stead of spraying glyphosate on fields just before planting, farmers could now spray it over growing glyphosateresistant crops to eliminate the weeds while leaving the crop plants unaffected. After the introduction of Roundup Ready crops, global use of glyphosate increased 15-fold. 2022

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Morgan Ryan

open, no ligands

closed, with shikimate-3-phosphate and glyphosate bound in the active site formed when the enzyme changes shape

University of Minnesota Extension; Wikimedia Commons; www.maxpixel.net, CC0

The structure of EPSP synthase has two major conformations. The enzyme is in its open conformation (left) before binding the first substrate, shikimate-3-phosphate (S3P). Binding S3P causes the enzyme to change shape (right), which is required before either PEP, its natural cosubstrate, or glyphosate can bind.

We now know that EPSP synthases in nature fall into two classes: Class I enzymes, found in plants and most bacteria and fungi, are sensitive to glyphosate; class II enzymes, as exemplified by the version found in Agrobacterium sp. strain CP4, are relatively resistant to glyphosate. What is the difference between glyphosate-resistant and nonresistant EPSP synthase? Remarkably, it comes down to the difference in size between the two smallest amino acids, alanine and glycine, and whether one or the other is present at one position in the enzyme’s active site (position 100 in the chain of amino acids). Alanine has a small methyl group (CH3) side chain; glycine has an even smaller hydrogen atom as its side chain. The alanine in the glyphosate-resistant enzyme interferes with the binding and positioning of the herbicide, whereas glycine in position 100 leaves room for glyphosate to bind in the conformation that stalls the enzyme’s activity. That’s one part of the Roundup Ready enzyme’s active-site magic. But how is the resistant enzyme able to continue reacting with its natural substrate (PEP), which competes with glyphosate for the same altered binding site? Simply enough, PEP is shorter than the inhibitory long form of glyphosate. PEP doesn’t clash with the interfering group of the alanine, so the enzyme retains catalytic activity comparable to that of most of the uninhibited natural forms of the plant and bacterial enzymes. Thus, Roundup Ready crops owe their prowess to a mere 0.6-angstrom difference in the length of a small molecule. An Improbable Scenario Glyphosate has been the most commercially successful herbicide in history. In the United States alone, it is featured in more than 750 products. It’s used in agriculture, forestry, and horticulture, and in products used to control aquatic plants; it has even found use in controversial programs aimed at the eradication of drugproducing plants such as coca, opium poppies, and marijuana. Yet what could be a more improbable scenario than the accidental disExamples of glyphosate-resistant (Roundup Ready) crops include (clockwise from top right) soybeans, corn, sugar beets, and alfalfa.

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Photograph by B. Kuwana/Wikimedia Commons

Agrobacterium tumefaciens, which is closely related to Agrobacterium sp. strain CP4, is responsible for crown gall disease in plants, such as this gall on a mango tree. The bacterium induces tumors in dicotyledonous plants by transferring part of its large Ti (tumor-inducing) plasmid into host cells. Glyphosate-resistant crop species were first generated through the deployment of disarmed (non-tumorigenic) Ti plasmids from A. tumefaciens that had been engineered to contain the CP4 gene.

Ala-100

Gly-100

covery of a potent herbicide smaller than glucose, with a structure so refined that none of its substituents are superfluous, which targets with catastrophic consequences an enzyme in a crucial pathway that is indispensable for plant function, but which in humans is lacking and therefore unsusceptible to attack. All of which was followed by the equally accidental discovery of a bacterium harboring a version of the target enzyme which, by virtue of a single methyl group, is resistant to the herbicide. At just about every step along the way, these scientifically and commercially significant discoveries were separated by years from an understanding of their mechanisms. As mentioned at the beginning of this article, there is also a new storyline emerging regarding the safety of glyphosate, a story that may follow the pattern seen repeatedly here of the product having been deployed before its mechanisms were understood. The benefits of glyphosate over decades are widely recognized. Vanquishing weeds led to an explosion in crop yields worldwide and a huge increase in food production. But the human health effects are unsettled, and controls on glyphosate use are being considered and in some places implemented. The story of this aspect of glyphosate’s reign will be told in the coming months and years in scientific journals, legal filings, and newspapers. Bibliography

6.7 angstroms

7.3 angstroms

Boocock, M. R., and J. R. Coggins. 1983. Kinetics of 5-enolpyruvylshikimate-3-phosphate synthase inhibition by glyphosate. FEBS Letters 154:127–133. Cornish-Bowden, A. 1986. Why is uncompetitive inhibition so rare? A possible explanation, with implications for the design of drugs and pesticides. FEBS Letters 203:3–6. Duke, S. O. 2017. The history and current status of glyphosate. Pesticide Management Science 75:1027–1034. Schönbrunn, E., et al. 2001. Interaction of the herbicide glyphosate with its target enzyme 5-enolpyruvylshikimate 3-phosphate synthase in atomic detail. Proceedings of the National Academy of Sciences of the U.S.A. 98:1376–1380.

© 2006 National Academy of Sciences, U.S.A.

Glyphosate has two alternate conformations. It can only bind to the active site of glyphosateresistant wild-type (Ala-100) CP4 EPSP synthase by assuming a condensed noninhibitory conformation (short form; left). When this alanine (Ala) residue is substituted by glycine (Gly), the enzyme can bind glyphosate in its extended, inhibitory conformation (long form; right). The form on the left is approximately 0.6 angstroms shorter because of rotation about the C–N bond, indicated by the dashed lines. www.americanscientist.org

Philip A. Rea is professor of biology and the Rebecka and Arie Belldegrun Distinguished Director of the Roy and Diana Vagelos Program in Life Sciences and Management at the University of Pennsylvania. Email: [email protected] 2022

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The Chemical History of Superior Glass A glassmaker and a physicist teamed up to improve scientific lenses. Their developments revolutionized both laboratory equipment and domestic cookware. Ainissa Ramirez

O

tto Schott had dreams of discovering new things in the tidy and clean space of a chemical laboratory. Unfortunately, he was born into a family of glassmakers in Witten, Germany, in 1851, who worked in the heat, sweat, and dust of workshops. For generations, both sides of his family toiled in this strenuous and stagnant trade, and there was the expectation—spoken and unspoken—that he would join his father in the windowpane factory. Young Schott had other plans. He took every chemistry class he could, starting from high school, to prepare for a doctorate in organic chemistry. Schott, a short and slight man with a handlebar mustache, wanted to leave his mark by using his brain to understand materials, not his brawn to fashion them. Chemistry in the 1870s was the route to many exciting innovations, particularly in the making of drugs, fertilizers, and explosives. Organic chemists were enchanted with the ability to copy substances made in nature, such as the flavor of vanilla, and artificially duplicate them in the laboratory. Nature did not give up her secrets easily, but when her methods were decoded, these molecules became new products, manufactured by the ton. The world was smitten with what organic chemists could do. With visions of molecules dancing in his head, Schott applied for a graduate research position at the University of Leipzig. There was no space for him,

though. Disappointed but undeterred, he tried to enter organic chemistry sideways, by taking graduate classes in agricultural chemistry. But he soon found this new topic uninteresting and dropped out. With his dream thwarted,

Ainissa Ramirez

Microscopes labeled “Jena,” such as this 1924 Carl Zeiss Jena microscope from the author’s collection, were highly desirable scientific instruments in the late 19th and early 20th centuries due to the clarity of their borosilicate glass lenses.

he returned to glass, but this time for his doctoral studies, completing them in 1875 at the University of Jena. The title of Schott’s dissertation was “Contributions to the Theory and Practice of Glass Fabrication,” a subject he knew well from the time he was a boy.

After his graduate studies, Schott went on to work in a glass factory, publishing papers on the melting of glass, the strengthening of glass, and the chemical elements in glass. Schott returned to his hometown of Witten in 1878, steadily experimenting in glass on the factory floor. His work did not set the world on fire, but by using fire and chemical ingredients he hoped to unlock the workings of this old material and make it new. About 400 kilometers west from a wistful Schott was a disgruntled Ernst Abbe in a laboratory in the college town of Jena. An esteemed professor of physics and the director of a telescope observatory, Abbe had grown frustrated with the glass lenses in his microscopes and telescopes. The professor, with his mathematician’s unkemptness of finger-combed hair, a scruffy graying beard, and spectacles perched at the end of his nose, noticed there were multitudes of flaws in his scientific lenses, making it difficult to see anything clearly. Sometimes the glass had bubbles, streaks, or lines— called straie—that looked like a ship’s narrow wake. Sometimes the glass was cloudy, hazy, or swirled, with unblended parts like a marble cake. Above all, the glass was faulty because colors, such as blue and red, separated within an image, as if seen through modern 3D glasses. With such horrible materials, the chance of scientific breakthroughs was nearly impossible. Without good glass, science was blind.

QUICK TAKE In the 19th century, flawed glass equipment stymied scientific progress. Foggy lenses and thermometers that expanded when hot made it impossible to obtain accurate results.

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The invention of borosilicate glass solved the problem of faulty tools. Equipment made using the proprietary method developed in Jena, Germany, was prized by scientists.

While trying to replicate Jena glass, American manufacturer Corning Glass Works discovered other uses for the product, including bakeware they sold under the name Pyrex.

know-how. And without that knowhow, science was going nowhere. Schott got hold of this report three years later, and wrote a letter to the professor in 1879 volunteering to supply a range of different types of glasses, with the hopes of escaping the sweltering heat and silt of the factory floor. Schott had been working on systematically creating glasses of different chemical ingredients, but he didn’t have access to a laboratory to do the scientific measurements to see what his glasses could make. Abbe had access to those instruments, but didn’t have the ability to make new glasses. Together, these men were each other’s yin and yang. Abbe was willing to collaborate with a person unknown in the sciences, because he had nothing to lose. Schott was keen on doing extra work, because he had everything to gain. This opportunity was Schott’s shot. The Elements of Laboratory Glass Schott sent glass samples to Abbe, but they did not have the optical properties that Abbe desired. Nevertheless, the two struck up a correspondence, and Schott continued to make glasses of different combinations of chemicals. He was able to make better choices than scientists of the past Everett Collection because 20 years earlier a Siberian sciIn this 1950s publicity photograph, Lucille Ball (in character as Lucy Ricardo from I Love Lucy) holds entist, Dmitri Mendeleev, had turned a mid-century symbol of American domesticity: a Pyrex bowl. At the time, Pyrex bakeware was the field of chemistry upside down made by Corning Glass Works from borosilicate glass. Adding boric acid to glass resulted in a more with his breakthrough of the periodic durable product, which was ideal for both scientific equipment and cookware. table, in which all of the known ingredients of the world—the elements— To vent his frustration about the lack of new types of optical glass with uniwere found to systematically relate of research on glass, Abbe did what any form, calculable, and predictable prop- to each other on a chart, where elements man of science would do. He wrote a re- erties was required.” Abbe wanted the near each other on this chart acted like port in 1876 stating that the future of the manner of how a glass interacts with cousins. (See “The Grammar of the Eletweed-wearing scientists’ fine optical in- light to be cooked into it. Just as a baker ments,” November–December 2019.) Using struments such as microscopes and tele- changes the amount of flour, water, and the new periodic table, Schott began to scopes were in the thick and calloused yeast to modify a bread’s texture and take a methodical approach to explorhands of apron-wearing glassmakers. chewiness, Abbe wanted to know how ing how different concoctions of glasses The earliest glasses entailed heating the chemical ingredients changed the behaved. New formulations under the and mixing the ingredients of sodium glass’s ability to fan out white light into guidance of this table allowed Schott to carbonate (or soda), limestone (chalk), colors of the rainbow, or its ability to make better educated guesses. and silica (sand), creating crown glass, bend light, the way it makes a straw Schott set plans in 1880 to make new which was used for windowpanes seem broken in a beverage. Abbe want- glass mixes, treating the periodic table and bottles. Replacing the chalk with ed these traits to be turned up or down like a restaurant menu, selecting options lead compounds created the more or- in a regular and repeatable way, with from different columns, and sometimes nate flint glass, also called lead crystal. the knob being the chemical elements from the same column, to see what These two families of glasses had been that make up the glass. His report went worked best. He began his efforts by the only ones for centuries, and Abbe on to say how little had been done in adding the elements of phosphorus and declared there was a scarcity of studies the study of glass for decades, and he boron. In the fall of 1881 he focused on that explored new additives to make stated openly what many knew but boron, which comes from borax (a deglass with improved optical properties. were too polite to mention, particularly tergent additive), and discovered someIn his report, Abbe set a new research that the making of glass was based on thing very promising: Adding the redirection, stating that “the development traditional recipes and not on technical lated compound boric acid made a new www.americanscientist.org

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Everett Collection Historical/Alamy Stock Photo

Reliable glass equipment is crucial to many experiments, such as those conducted by this industrial chemist in a DuPont laboratory in 1943. Borosilicate glass could be tailored to fit specific needs, such as clarity for a microscope, durability to withstand damage from acids, and stability to maintain its shape in hot and cold environments. Glass instruments remain important in laboratories today and have become linked to the image of a scientist.

type of glass, borosilicate glass, which seemed free from defects. Schott sent these new glasses to Abbe for testing, looking forward to the results. In a letter dated October 7, 1881, Abbe wrote, “The problem [of flaws in optical glass] has been solved.” The professor followed

with Abbe and microscope-maker Carl Zeiss, with whom Abbe had a longstanding business relationship. No longer were Schott’s experiments confined to small furnaces where he could create samples no bigger than a cup of sugar. His specimens were now huge icicles

The glass was inferior, and with such horrible materials, the chance of scientific breakthroughs was nearly impossible. Without good glass, science was blind. up on that note by inviting Schott to visit Jena to demonstrate his new glass. With continual improvements over the next year, Schott got his secret wish. Abbe wrote that he thought it best for Schott not to continue his work in a glass factory, but insisted that it be done in a chemical laboratory in Jena. Schott made arrangements to leave Witten. In 1882, Schott moved to Jena to run a small-scale operation in partnership 180

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the diameter of bowling balls. Schott started a company in 1884, Schott & Associates Glass Technology Laboratory, to make and sell specialized glass. Their first catalog, published by the company in 1886, had 44 different glasses; by 1892, there were 76. Schott devised new formulations for better optical lenses, and later for thermometers, too. In the late 1800s, thermometers were one of the few tools

that scientists had to probe a chemical reaction. At the time, chemistry was limited to knowing how hot things got (the temperature), how much they weighed (the mass), how much space they took up (the volume), and how much they pushed the container walls (the pressure). Many scientists noticed that their temperature readings were higher than they should be. It turned out that thermometers did not return to the proper baseline once they were cooled. The repeated heating and cooling that the thermometers underwent modified the glass so that the bulb, which held the mercury, changed its shape, causing the mercury to creep up. This meant that subsequent temperature readings were not to be trusted. By tailoring the amount of boron, Schott was able to build a glass that did not adjust its shape when heated, allowing thermometers to make proper readings. Schott cranked out different flavors of glasses in collaboration with Abbe. One was the glass for thermometers that did not alter its form with heat. Another was optically superior and perfect for scientific telescopes and microscopes. A final one did not dissolve in water, acid, or other liquids, making it suitable for laboratory experiments. At the heart of his new creations was boron, though boron played different roles in each of Schott’s new glasses. Schott’s glasses had versions with small, medium, and large amounts of boron, the way a chef can make a sauce with different levels of spice—mild, medium, or hot—based on the amount of pepper in it. For glasses with improved optical properties, a small bit of boron was added to windowpane glass, giving it a better ability to bend light. For glasses that did not expand when heated, Schott added lots of boron. Boron tightly grips other atoms with stiff bonds, like a strong spring, causing the resulting glass to resist expanding when it gets hot. Finally, for glasses capable of withstanding dangerous chemicals such as acids, the amount of boron was decreased to a medium level. Boron likes to bond with other atoms, but its bonds are weak in acids. So some of the boron was taken out of harm’s way and substituted with other compounds. Together, all these ingredients stabilized the glass in these harsh environments. Soon, the glasses designed by Schott became the most desired scientific glass on the planet, and Germany became

INTERFOTO/Alamy Stock Photo; World History Archive/Alamy Stock Photo; The Corning Museum of Glass courtesy of John Littleton

Otto Schott (left) came from a family of German glassmakers, but he had dreams of becoming a scientist. In the 1880s, he moved to Jena, Germany, and teamed up with physicist Ernst Abbe (center), who was frustrated by poor-quality glass laboratory equipment, to develop new types of glass that would be better suited to research. Soon, Schott invented

the main source of all glasses for microscopes, telescopes, and laboratory ware (beakers, flasks, and test tubes). Every scientist wanted optical instruments with the name “Jena” inscribed on them. For other glassmakers, penetrating this glass market seemed impossible. Glass Beyond the Laboratory In the early 1900s, American glassmakers wanted to develop an alternative to Germany’s Jena glass. Cracking the code for Jena borosilicate glass wasn’t easy, though. Glassmakers knew that boron was a key ingredient, but the rest of the recipe was a mystery. Schott spelled out in his highly technical papers the factors that allowed glass to withstand high heat and large temperature differences, but few glassworkers could translate the theory into practice on the factory floor. To be successful, one American company, Corning Glass Works of Corning, New York, knew that their workmen were going to need some help from academics. Corning Glass Works was a familyrun company that mostly made decorative glass and tableware, and soon also handblown glass for Thomas Edison’s light bulbs. If they were going to compete with Jena glass, though, they knew they needed better science behind their processes. Corning started to move away from using glass recipes passed down from one generation to www.americanscientist.org

borosilicate glass. Thirty years later in Corning, New York, physicist J. T. Littleton (at left in right image) suspected that borosilicate glass was durable enough to use for cooking. To test his hypothesis, his wife, Bessie (far right), baked a cake in a glass pan, which came out beautifully browned. This experiment led to the development of Pyrex bakeware.

the next and began to apply the scientific method. One of the first things Corning’s management did was tell their workers to write down what they added to a glass melt, so that a batch could be replicated if need be. Starting in 1908, chemists were on Corning’s payroll, and the investment was working out to be a wise one. The scientists knew that boron was a key ingredient in these new glasses, and eventually, by trial and error, they created a version of borosilicate glass called Nonex (short for NON-EXpanding glass). Unfortunately, Corning still could not penetrate the labware market with it. Nonex was no rival to Jena glass, which had a nearly 15-year head start. Additionally, German glass enjoyed low tariffs, since it was an educational product. Customers saw no reason to buy American-made glass when the price of the superior glasses from Germany was not prohibitive. Corning’s management had to find a domestic market for their borosilicate glass and reached out to the most lucrative industry in the nation to help keep the company afloat: the railroad. In the early 1900s, the tentacles of railroads reached some of the farthest corners of the country. The railroad compressed space and time with its speed. That speed came at a cost, however. As trains became faster, many more catastrophic accidents and collisions occurred, and with that came a need for

better signaling to increase safety. Signals on the tracks told trains not to proceed, with warnings from hot arc lights with red glass covers. On rainy or snowy days, however, accidents occurred more frequently. In addition to the inclement weather, another cause for the increase in accidents was the frailty of glass. Glasses on train signals were between a rock and a hard place on days with bad weather. The interior of the glass signal was heated by the hot arc light, causing it to expand; the outside, however, was dramatically cooled by the rain or snow, causing it to shrink. The conflicting messages within the glass gave rise to pent-up stress; when prolonged, this stress resulted in broken glass. A red glass alerted the train to stop, but a broken glass was no longer red, which gave a false message that it was safe to pass, potentially causing a colossal collision. And as if the weather was not enough for the glass to contend with, mischievous boys used train signals for BB gun target practice, smashing the red glass into pieces with a single pellet. The railroads needed better glass to mitigate the weather and the delinquents, and Corning’s strong Nonex glass did the trick. Corning’s glass rarely failed; however, the company soon became a victim of its own success. When the railroad adopted Corning’s glass, there was a boom in sales, but the indestructibility of the glass meant that once the 2022

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railroads purchased their hardy glass, they didn’t need replacements. The meteoric increase in sales was followed by a precipitous drop. This lack of built-in obsolescence, or a limitation that would have required additional sales, caused the company to scramble for new glass markets. Help would come from, of all places, a cake.

had only used one other time, broke. All night, the men talked about the indestructibility of glass, and she insisted that these smart alecks ought to make cookware that did not break. The next day, J.  T. got two cylindrical Nonex battery jars, about as wide as a basketball, cut off the bottom to make round dishes, and brought them home to Bessie. Cooking with Glass Bessie didn’t cook. She had One summer afternoon in 1913, servants to do that. As a child Jesse Talbot Littleton, a physiin the South, her servants were cist and one of Corning Glass freed Black slaves who could Works’s newest scientists, came not escape the grip of the planto work with a sponge cake tation. As an adult in the North, baked by his wife, Bessie. J. T., she hired white immigrant as Jesse preferred to be called, girls whose families had come and Bessie were southerners; to New York State for work. he was from Alabama and she While Bessie was no master was from Mississippi. They had chef, she dominated with her moved a year prior to Cornbaking. As soon as J.  T. gave ing from Ann Arbor, Michigan, her an indestructible glass dish, where J.  T. had been a physics she got to her favorite kitchen professor, and, together, they task and turned sugar, eggs, were trying to get accustomed flour, butter, milk, vanilla, and to their new Yankee home. In baking powder into a sponge a spirit of Southern hospitality, cake. After using every bowl Littleton brought in the cake. and utensil in the kitchen, she B Christopher/Alamy Stock Photo The cake was not just a so- After Littleton demonstrated to his Corning Glass Works col- poured the batter into her newcial offering, though; it was also leagues the power of baking with glass, the company jumped fangled dish and baked. What a science experiment. For the at the chance to break into a new market. This circa 1916 ad- emerged from the oven was an past two weeks, Littleton had vertisement for Pyrex Baking Ware touts the many benefits evenly browned cake with a been trying to convince his col- of their product, including that the glass pans do not absorb color surpassing that provided leagues of the benefits of cook- odors, are easy to clean, and are durable. by her metal dishes. ing with a glass container, but The next day, J. T. brought the they laughed at the notion. For genBessie Littleton liked having com- cake to work, and everyone reported erations, people had been told to keep pany. She was raised on a remote Mis- that it was good. He then told them that glass away from heat, so baking with sissippi plantation where visitors were this cake had been baked in glass, causglass seemed ridiculous. Little did they few. At her new home in upstate New ing scientists to scratch their heads, and know that Littleton was not only a York, she asked J.  T. to bring people men in management to rub their chins. Southern boy, but also a glass man. from work over for dinner. At barely Littleton relayed to his colleagues how Littleton was obsessed with glass. 5 feet tall, with her dark hair in a bouf- easy it had been to remove the cake from He talked about glass at the dinner fant style, she was slight, talkative, and the smooth glass pan, unlike metal cake table. When Jell-O came for dessert, dogmatic. With Bessie things had to be pans. His colleagues did not think glass, he’d break it apart slowly and show just so, and she had very strict rules if it survived, could make a cake as dehis children how it broke like glass. He that J. T. had to follow, including, ac- lectable as the one Littleton had brought even had hopes of being buried in a cording to their son, Joseph (and in in, and, in a sense, they ate their words. glass coffin. He did his 1911 dissertation his words): no lying or liquor; no cigaThey asked that Bessie try out other at the University of Wisconsin on the rettes or cigars; no cussin’ or colored foods and report how the glass pan heating properties of glass. The rest of people at her table. The long and lanky worked. So Bessie, as the resident the Corning scientists, who were chem- J.  T., with his tall frame, eyeglasses, domestic scientist, had a few items ists, assumed that the thick walls of the serious eyes, permanent pout, and cooked, from French fries to steak to glass would prevent food from cook- understated grace, complied. cocoa, although she had a penchant for ing evenly and that the heat would not One night J.  T. brought over a fel- Southern dishes of grits, corn bread, spread as well as it would with a thin low scientist, H. Phelps Gage. When and collard greens. The pan performed metal pan. Littleton, a physicist, knew the men talked about glass after din- well, the food didn’t stick, and the otherwise. When his colleagues did not ner, Bessie had a captive audience for glass pan didn’t retain the flavor of the listen to his words, he decided to follow something that had been troubling her. food the way a metal skillet did. them up with action. And he got some A few days earlier, Bessie’s new On hearing about the success of this help from Bessie. Guernsey casserole dish, which she glass for cooking food, the Corning 182

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management saw promise. But they had to make a few changes and learn a few more things. First, the formulation of Nonex had to be altered, since it contained lead. So the scientists made a borosilicate glass without lead for this bakeware. Next, they had to test the strength of the glass, dropping a weight as heavy as a can of soup onto different types of dishes to see how they survived the rigors of a kitchen. Earthenware cracked with a weight dropped at 15 centimeters, and crockery broke at 25 centimeters, but borosilicate glass laughed off the impact, untouched, even when the weight was dropped from waist high. After these impact tests, the team had to figure out how the glass cooked food. Bessie reported that food cooked quicker than in a metal pan, which was the opposite of what they had believed would happen. They got to the bottom of this mystery with an experiment. A scientist dipped a Nonex pan into a liquid chemical bath full of microscopic bits of silver. The silver settled on the surface, coating the outside with a thin layer, giving it a mirror finish. Then, they baked two cakes: one in a simple Nonex pan and one in the mirrored one. The cake with the silver coating did not cook well. What they learned is that the heat from the oven walls, like the rays of the Sun, transmitted through the clear glass, cooking the cake, whereas the mirrored surface reflected that heat back. A cake in a metal pan gets heated from the hot air in the oven and the heat from the oven rack. The glass, meanwhile, was letting heat into the cake a third way, via invisible rays of heat, the kind of heat that the Sun uses to brown our skin and that helps create the crust of a loaf of bread. To commercialize this glass with a new purpose, it needed a name that informed the consumers, mostly women, what this new glass did. The first commercial piece on the market was a pie tin, which was initially called “Py-right.” It was renamed Pyrex in 1915, to relate to the earlier product, Nonex, and to sound more futuristic and medical, like latex or Cutex. Sales of Pyrex were initially flat, but after the company responded to customers’ needs—by reducing the weight of the ovenware, for example—it became a standard item in households. By 1919, over 4.5 million pieces of Pyrex ovenware were sold. To encourage more sales, Corning created many shapes, sizes, and colors so that new pieces were www.americanscientist.org

always desirable (learning their lesson from the railroad glass episode), which made Pyrex a standard Christmas gift. Corning still had its eye on glass for labware, however. An opportunity to enter that market would be a gift of war. Secret Weapons and Enemy Patents In 1915, with United States’ potential entry into World War I, it became clear that the government needed the ability to make glass for military applications. Jena glass was regarded as the best in the world, but imports from Germany were dwindling. American companies, such as Corning Glass Works, had been

for the shrinking supplies from Germany. In laboratories, there were Pyrex petri dishes, test tubes, and flasks. In homes, there were Pyrex cooking dishes, oven door windows, and percolator tops. In automobiles, there were Pyrex headlights, battery jars, and pressure gauge covers. The United States had unknowingly entered the Glass Age, whereby Corning created a new U.S. industry of scientific and specialty glass. To keep this comfy cushion without competition for their consumer commodities, Corning pushed for legislation to prevent the influx of German glass into U.S. markets after the war. Huge tariffs were placed

At the precipice of America’s entry into the First World War, Corning had developed a borosilicate glass, although the ideal Jena formulas were still locked up in German patents. encouraged years before to create a substitute. These glasses would be used by U.S. soldiers in gun sights and binoculars, by sailors in sextants and periscopes, by airmen in aerial cameras and range finders, by army doctors in thermometers and vials of medicines, and in the laboratory by chemists for the synthesis of explosives. At the precipice of the U.S. entry into the war, Corning had developed a borosilicate glass, although the ideal Jena formulas were still locked up in German patents. What the U.S. companies may not have known is that laws of peacetime do not hold during war. When the United States entered the war, it confiscated nearly 20,000 German patents as part of its war booty. Impenetrable German monopolies protected by patents, for dyes such as mauve and drugs such as aspirin, were blasted open with one of the United States’ secret weapons: the Trading with the Enemy Act. With it, German science—the science of the enemy—became fair game to Americans and American companies. Buried within those patents were those recipes for specialty glasses. After the war, Corning introduced a range of new Pyrex products, filling in

on German glass, preventing Germany from monopolizing these markets as they had done in the past. These actions were out of view for most Americans, including scientists, who used Pyrex glasses to find the causes for diseases in glass petri dishes, and developed drugs to fight them in glass test tubes. What citizens and scientists did not know was that glass also provided containers that cooked up a new narrative of innovation and scientific prowess. There was no doubt that the United States was a science superpower, but what was unknown at the time was that the nation now had the upper hand, particularly in glass, made possible by a curious combination of war and cake. Ainissa Ramirez earned her doctorate in materials science and engineering from Stanford University. She started her career as a scientist at Bell Laboratories and later worked as an associate professor of mechanical engineering at Yale University. In 2021, Ramirez was elected as a Fellow of the American Physical Society. This excerpt is adapted from her book The Alchemy of Us: How Humans and Matter Transformed One Another, copyright 2020 Ainissa Ramirez, by permission of MIT Press. Website: www.ainissaramirez.com 2022

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S c i e n t i s t s’

Nightstand

The Scientists’ Nightstand, American Scientist’s books section, offers reviews, review essays, brief excerpts, and more. For additional books coverage, please see our Science Culture blog channel, which explores how science intersects with other areas of knowledge, entertainment, and society. ALSO IN THIS ISSUE THE ANNOTATED HODGKIN AND HUXLEY: A Reader’s Guide. Indira M. Raman and David L. Ferster. page 186

ONLINE On our Science Culture blog: americanscientist.org/blogs /science-culture Bird Powers Digital features editor Katie L. Burke reviews the board game Wingspan, a fun game of strategy that is now available as an app. Participants learn about the natural history of birds in the course of developing strategies for populating various habitats in a bird reserve.

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Vital Signs Michael Bérubé THE SCIENCE OF LIFE AND DEATH IN “FRANKENSTEIN.” Sharon Ruston. 152 pp. Bodleian Library Publishing, 2021. $40.

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ary Shelley’s Frankenstein, first published in 1818, is literally about the meaning of life: not a meditation on the nature of life in general, but a specific meditation on a debate unfolding as Shelley was writing. The book is most commonly read as a warning about scientific hubris, or more broadly as a warning about the uncontrollable consequences of dangerous endeavors in any realm of human activity—say, the “Frankenstein’s monster” one might unleash by fanning the flames of white nationalism or antivaccination paranoia or some hideous combination thereof. The novel openly invites those readings; it is also a powerful meditation on loneliness and friendship, freedom and slavery, generosity and injustice, and the promises and dangers of polar exploration. But as Sharon Ruston’s brief and lively new book, The Science of Life and Death in “Frankenstein,” makes vividly clear, the novel is thoroughly informed by, and a serious contribution to, early 19thcentury debates about what it means for a clump of matter to be “alive.” It is stunning that this aspect of the novel was overlooked and underread for almost 200 years. It was not until the 1990s that British scholar Marilyn Butler situated the novel in the context of the explosive debate that began in 1815 between John Abernethy and William Lawrence, who were both professors at the Royal College of Surgeons. Over the next five years, the two men alternated in giving an annual series of introductory lectures to medical students about

the nature of life, lectures in which they argued about vitalism (Abernethy’s belief that there is some ineffable essence that distinguishes organic from inorganic matter and human life from all other forms of life) and materialism (Lawrence’s belief that life is just matter that somehow managed to replicate itself and eventually become sentient). Each year’s lecture series was promptly published, and Mary and Percy Shelley were acutely aware of this debate, as were most European intellectuals of their day, even the ones who called themselves poets. Lawrence was personal physician to the Shelleys, who were quite familiar with various radical ideas in the air—the idea that maybe God didn’t exist, for instance, or that all humans were truly equal and therefore it was immoral to use sugar because it was produced by slave labor. (They refused to do so.) Ruston demonstrates that Mary Shelley was an incredibly intellectually voracious teenager, well informed about recent scientific developments in chemistry and experiments with electricity. (Many people assume that Victor Frankenstein shocks his creation into life— this is a staple of the films—but Victor himself is very careful not to disclose his method lest others try to replicate his awful results.) The novel notes that when Victor arrives at the University of Ingolstadt, he is enthralled by one Professor Waldman, who tells his students that science has discovered wonders such as “the nature of the air we breathe.” That would of course be oxygen, isolated and identified less than a half-century earlier in one of the more tangled episodes in the history of science (tangled enough to serve as material for Thomas Kuhn’s The Structure of Scientific Revolutions). The science Mary Shelley focused on was chemistry, but as Ruston points out, Percy Shelley’s editing of the manuscript changed “chemistry” to “natural philosophy,” a more general term for the natural sciences

at the time. But in Mary’s mind, Victor was a chemist—not a medical doctor, or indeed a doctor of any kind, but a precocious student of chemistry who is for some reason allowed to work alone on a secret project for two full years. Ruston’s narrative is full of fascinating details. Although I knew that the era was one of extraordinary developments in the resuscitation of victims of drowning, leading many people to question the permeability of the boundary between death and life, I did not know that a critical ingredient in many such resuscitations was the insufflation of tobacco smoke into the rectum. Nor did I know that the 1752 Murder Act stipulated that the bodies of hanged murderers could be dissected by surgeons, which made it imperative to determine that the hanged murderers were actually dead and would not spring back into consciousness on the surgeon’s table (as some did, to everyone’s horror). Victor famously says, “Life and death appeared to me ideal bounds, which I should first break through, and pour a torrent of light into our dark world.” By www.americanscientist.org

This 1867 engraving by Louis Figuier from Les merveilles de la science, ou Description populaire des inventions modernes depicts Dr. Andrew Ure attempting to resuscitate the hanged murderer Matthew Clydesdale using a galvanic battery. That attempt took place in Glasgow in 1818, several months after the publication of Frankenstein, but similar experiments were conducted in public by Giovanni Aldini more than a decade earlier. Image reproduced courtesy of Houghton Library, Harvard University. From The Science of Life and Death in “Frankenstein.”

“ideal bounds” he means boundaries that are not rigid, that are permeable; the sudden revival of apparently dead bodies, be they the bodies of hanged murderers or drowned innocents, led many people to wonder just how porous those boundaries are. Ruston is especially good at explaining the high stakes (and high drama) of the Abernethy–Lawrence debate. It was framed in explicitly moral terms: Ruston explains that for Abernethy, a belief in “the vital principle .  .  . had moral, religious, and personal implications. Those who see life as the same in all living creatures, from humans to animalcules, would not be able to claim that there is anything especially moral or divine about humans, and this idea is sacrilegious.” Lawrence’s responses involved a surprising degree of snark and

shade. In the second lecture that he delivered to the Royal College of Surgeons in 1816, on “Life,” he mocked vitalism by directly attacking one of Abernethy’s 1815 lectures to the same body: This vital principle is compared to magnetism, to electricity, and to galvanism; or it is roundly stated to be oxygen. ’Tis like a camel, or like a whale, or like what you please. . . . It seems to me that this hypothesis or fiction of a subtle invisible matter . . . is only an example of that propensity in the human mind, which has led men at all times to account for those phenomena, of which the causes are not obvious, by the mysterious aid of higher and imaginary beings. 2022

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Ruston’s paraphrase is brutal: “Believing in Abernethy’s idea of life was tantamount, Lawrence argued, to believing that supernatural beings control our fate. He flew dangerously close to saying that believing in God is for idiots.” Lawrence paid dearly for his audacity. He was stripped of his position in the Royal College of Surgeons (and thereby barred from practicing medicine) and forced to recant his 1819 book, Lectures on Physiology, Zoology, and the Natural History of Man. The materialist theory of life went into hiding until it was resuscitated, decades later, by debates over the origin of species. Ruston argues that Victor bases his experiment on Abernethy’s premises: “Having worked out what the vital principle is and how to infuse it into a body, [Victor] then has to create a body to receive it. The practice set out here fits Abernethy’s theory entirely.” I’m not convinced. There is no indication that the Creature (as he is generally known these days) is animated by anything but sublunary forces; his life seems to be purely a matter of matter. For that matter, there is no hint in the novel of any God at all. In her introduction for the 1831 version of the novel (about which more in a moment), Mary Shelley described her initial vision of Frankenstein’s experiment as “frightful .  .  . for supremely frightful would be the effect of any human endeavor to mock the stupendous mechanism of the Creator of the world.” This is a familiar refrain, surely, to biologists and geneticists who are routinely accused of playing God. But no such phrase occurs in the novel: No one ever refers to “the Creator of the world,” and Victor never thinks in these terms. Ruston notes that “whether the Creature has a soul is a vital unanswered question in Frankenstein,” and that the question “has been asked many times” since the novel’s publication. The pun on vital is clever, but the crucial point obscured here is this: Whether the Creature has a soul is a vital unasked question in Frankenstein. When the Creature tells Victor, “My soul glowed with love and humanity,” and when Victor says, “His soul is as hellish as his form,” no one is invoking the word in its religious sense. Frankenstein seems to me a thoroughly “materialist” book, even if Shelley herself changed her mind about that at some point between 1818 and 1831, as the 186

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political backlash against materialism intensified in the United Kingdom. As for that 1831 revision: Ruston explains that she has chosen to work with the 1818 text “because this version contains more science. By 1831 the novel had become more overtly Gothic.” That’s a good call, but I would make it for a different reason: namely, Shelley’s decision to rewrite her novel so that it explicitly equates Frankenstein’s experiment with Robert Walton’s quest to reach the North Pole. “You are pursuing the same course,” Victor says to Walton in the later edition, “exposing yourself to the same dangers which have rendered me what I am.” This comparison is just plumb foolishness, since polar exploration isn’t anything like the creation of sentient life from dead matter; worse still, it has given rise to the popular misconception that the function of literature is to chastise scientists for pushing the edge of the envelope. In 1831, the novel goes from saying, in effect, “Victor should not have abandoned his creature,” to “People should just stay home and not inquire too much into stuff.” It’s not just that the 1818 version has more science; it’s that the 1831 version is actively anti-science. Ruston notes that even though spectacular resuscitations were much in the news, “Mary’s decision not to use a corpse for the Creature [is] a particularly interesting one.” That it is: Victor cobbles together his creature from assorted human and animal bodies. I wish Ruston had said more about that decision—and more about Victor’s indefensible decision to experiment with the creation of life by starting at the top of the food chain. Surely an enterprising young chemist at the end of the 18th century could have become renowned and celebrated simply for giving life to a lab rat. It is odd that critics of Victor’s hubris don’t make this rather obvious objection to his work, and Ruston is especially well positioned to do so. But then, the story tells better the way Mary Shelley wrote it. Michael Bérubé is Edwin Erle Sparks Professor of Literature at Pennsylvania State University. He is the editor of the Norton Library Edition of the 1818 text of Frankenstein, or the Modern Prometheus, by Mary Shelley (W. W. Norton, 2021). His most recent book, coauthored with Jennifer Ruth, is It’s Not Free Speech: Race, Democracy, and the Future of Academic Freedom (Johns Hopkins University Press, 2022).

Exemplary Science Brian Hayes THE ANNOTATED HODGKIN AND HUXLEY: A Reader’s Guide. Indira M. Raman and David L. Ferster. xiii + 311 pp. Princeton University Press, 2021. Cloth, $110; paper, $39.95.

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he idea that nerves carry electrical signals between the brain and the body goes back to the 18th century, when Italian physician and physicist Luigi Galvani noticed that a small jolt of electricity would cause a dissected frog’s leg to twitch. But nerve fibers are not simple conductors like the copper wires of a telegraph network. Although electrical activity is key to nerve action, the process that moves a pulse of information along the fiber is a good deal more complicated than the flow of electrons through a wire. The search for the true mechanism of nerve transmission culminated in a series of ingenious and painstaking experiments done by a pair of British physiologists: Alan Lloyd Hodgkin (1914–1998) and Andrew Fielding Huxley (1917–2012). They reported their results in five papers, which all appeared in the Journal of Physiology in 1952. Hodgkin and Huxley received a Nobel Prize for this work in 1963 (shared with John Eccles). The five papers are printed in facsimile in The Annotated Hodgkin and Huxley, along with extensive commentary and background material supplied by the editors, Indira M. Raman and David L. Ferster, who are neurobiology professors at Northwestern University. The original papers are freely available on the Journal of Physiology website, but the Raman–Ferster annotations are a valuable resource. Hodgkin and Huxley—or H&H, as they are called in the annotations— began their collaboration in the late 1930s. By then it was already apparent that nerves are not wires. The electric currents that constitute a nerve impulse do not flow along the length of a nerve; instead they are radial migrations of charged particles across the cell membrane, from inside to outside or vice versa. H&H set out to learn what sets these currents in motion, why they are extinguished after a few milliseconds, and

how a localized electrical disturbance can propagate along the fiber as a wave of excitation, known as an action potential. Their experiments required technical artistry. The first step was to extract from the body of a squid a few centimeters of a nerve fiber called the giant axon, the portion of the neuron that carries nerve impulses away from the cell body. (Actually, the very first step was to get a live squid, and the difficulty of doing so was a serious impediment at times.) Although the squid axon is “giant” compared with other nerve fibers, it’s typically only half a millimeter in diameter. So the next challenge was to insert into the interior of the axon a fine glass capillary tube with two even finer wire electrodes wrapped around it. The two electrodes were used in a technique called a voltage clamp. One electrode served as a voltage sensor, measuring the electrical potential of the fluids inside the axon with respect to those outside. The signal from this sensor was delivered to the input of a feedback amplifier (an item of apparatus that H&H had to build for themselves). The output of the amplifier went to the second electrode, injecting current that opposed any change in the measured voltage. The aim of this arrangement was to hold the internal voltage constant—to “clamp” it—allowing changes in the behavior of the cell membrane to be measured with great precision. The first four H&H papers describe several variations on this experiment, including a number of wrong turns, false leads, and dead ends, as well as ultimate success. The final paper presents the authors’ synthesis and interpretation of the results. Carefully marshaling evidence in support of their claims, they argue that an action potential begins with a rapid influx of sodium ions crossing the cell membrane from outside to inside. A counterflow of potassium ions leaving the cell has a slower onset but eventually becomes dominant. When equilibrium is restored, both flows stop. The delay between the sodium and potassium peaks creates a brief electrical imbalance, a voltage spike that we observe as an action potential. What stands out on first acquaintance with this body of work is that H&H are explaining biological phenomena in terms of ideas that would be more familiar to an electrical engineer. The foundation of their whole analysis is Ohm’s law: Current is equal to voltage www.americanscientist.org

The membrane of a nerve cell is a delicate assembly of lipid and protein molecules, not a gadget made of resistors, capacitors, and other electronic components. Nevertheless, a wiring diagram captures important aspects of the membrane’s role in transmitting nerve impulses. The circuit elements shown are resistors (sawtooth lines), voltage sources (just below the resistors), and a capacitor (far left branch). The flow of ions across the membrane is regulated by these devices, shaping the signals called action potentials that propagate along a nerve fiber. This diagram appeared in the last of five papers by Alan Hodgkin and Andrew Huxley published in 1952, titled “A Quantitative Description of Membrane Current and Its Application to Conduction and Excitation in Nerve.” Journal of Physiology 117:500–504. Reprinted by permission of the Physiological Society.

divided by resistance. The first figure in the fifth paper (shown above) depicts the nerve-cell membrane as an assembly of resistors, capacitors, and such—parts one might solder onto a circuit board. Raman and Ferster comment: “The circuit diagram in Figure 1 is a landmark in the history of biophysics, illustrating how physical laws that govern nonliving material are also manifested in, and indeed give rise to, life processes.” H&H go on from circuit diagrams to an even more abstract formalism: a set of equations that describe how the ionic currents rise and fall as a function of time and how they vary with distance along the length of the axon (see page 188). They inferred the equations from their experimental data, without the benefit of knowing anything about the underlying molecular structures responsible for the currents in the nerve cell. However, the formulation of the equations was not a matter of blind curve-fitting, where an equation is simply adjusted to minimize some measure of error. H&H were guided by their ideas about plausible biomolecu-

lar mechanisms, some of which turned out to be prescient. In particular, their model of the potassium current has a factor of n4, where n can vary from 0 to 1. The exponent 4 in this expression was selected because the potassium current’s slow onset suggested that four independent events are needed to initiate the flow. Two decades later it was discovered that the membrane protein serving as a potassium gate has four subunits, each of which must be activated to open the channel. The full set of Hodgkin–Huxley equations has no exact solution. H&H had to work toward a solution using “numerical methods”; essentially, they made a guess and improved it by successive approximation. They had hoped to do this work on an electronic computer at the University of Cambridge (presumably the EDSAC, the Electronic Delay Storage Automatic Calculator, commissioned in 1949), but the machine was down for repairs when they needed it. Huxley did all the calculations with a hand-cranked mechanical calculator. 2022

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One of the most impressive predictions of the Hodgkin–Huxley model of nerve transmission came from close examination of the time course of the potassium current flowing through the cell membrane. In this graph, reproduced from the last of the 1952 papers, the open circles represent experimental observations, and the solid lines are model predictions. The potassium current reaches a plateau in a few milliseconds, and then falls off even more rapidly. Hodgkin and Huxley drew attention to the slow initial rise in the current. Their analysis suggested that four independent events are needed to make the membrane permeable to potassium ions. Two decades later, it emerged that the transmembrane potassium channel is a protein with four subunits, each of which must be separately activated to open the gate. From Hodgkin, A. L., and A. F. Huxley. 1952. A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal of Physiology 117:500–504. Reprinted by permission of the Physiological Society.

The work of Hodgkin and Huxley is described in countless textbooks, including some intended for introductory biology courses. Anyone with a serious interest in the neurosciences is sure to encounter these ideas at some point in their education. But I have the impression that few take the trouble to read the original sources. And why should they? Those papers from 1952 are badly out of date! Raman and Ferster enumerate no fewer than seven reasons for revisiting these 70-year-old publications, but I think this one is sufficient: “The series of papers provide an exemplary (and arguably unparalleled) illustration of the scientific method at its best, with repeated sequences of observations, hypotheses, predictions, experimental tests, interpretations, evaluation of error, and consideration of plausible alternatives.” I would add that H&H also uphold a high standard of civility, viewing rivals and critics not as enemies to be vanquished but as colleagues in pursuit of a shared goal. This is happy science! The Hodgkin–Huxley model of nerve transmission is a major landmark in the neurosciences, but it also has broader significance for biology as a whole. It is an important (and perhaps underappreciated) piece of the 20thcentury movement that brought quantitative and analytical methods into a field that had been largely descriptive and observational. 188

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Although Hodgkin and Huxley did many of their experiments at marine biology laboratories—that’s where the squid are—their home base was Trinity College, Cambridge. They were in good company there in the early 1950s. Just upriver from Trinity, at King’s College, James Watson and Francis Crick were puzzling over the structure of DNA. Across town at the Cavendish Laboratory, Max Perutz and John Kendrew were making progress on making sense of other macromolecules, such as hemoglobin. Most of these people were members of an informal Cambridge group called the Hardy Club, which had the explicit aim of bringing ideas from physics and mathematics into the life sciences. The chance to catch a whiff of the excitement of this extraordinary time and place is another reason to read the original papers rather than retrospective summaries. The Raman–Ferster annotated edition makes an inviting package. At the front of the book the editors provide a historical introduction, beginning with Galvani and including some biographical notes on the principal figures in the story. Hodgkin, whose father had also been a student of natural sciences at Trinity, began with a naturalist’s interest in birds and botany, but he turned to research in physiology at age 20, while still an undergraduate. Huxley, who was a grandson of

Thomas H. Huxley, the champion of Darwinian theory, arrived at Trinity planning to become an engineer, but in his third year he took a physiology course taught by Hodgkin and was soon engaged in the research program, also at age 20. In the main part of the book, the text of the five H&H papers appears on lefthand pages, and the notes by Raman and Ferster appear on the facing righthand pages. Many of the notes fill in background facts and assumptions that were better known in 1952 than they are now. Others bring the reader up to date on how ideas about nerve physiology have developed and changed in the decades since the papers were published. Still other notes point out elements of the work or the exposition that Raman and Ferster particularly admire. Most of the comments seem to be addressed to biologists who might be flummoxed to encounter ideas from mathematics, physics, and electronic technology. I suppose those are the likeliest readers of the book. But I do wish the annotators had also pointed their spotlight into some of biology’s dark and dusty corners. I, for one, would have liked to learn how one goes about dissecting a squid and recovering, intact, that giant axon. I would also have welcomed a fuller discussion of all that has changed in neurophysiology since 1952. Mathematical models of nerve transmission are now supplemented by computational models, some of which are much more detailed; Raman and Ferster do mention one of these models, but only briefly. Similarly, the five appendices that follow the book’s main text cover technical and mathematical aspects of the work that some biology students might find challenging. I would have liked to see an appendix on what’s known about the various ion channel proteins in neural membranes, and how they account for features of the Hodgkin–Huxley equations. I must conclude with a confession. Although I have a long-standing interest in the neurosciences, and I’m a firm believer in seeking out primary sources, I had never read the Hodgkin–Huxley papers until this book came my way. I am grateful that it did. Brian Hayes is a former editor and columnist for American Scientist. His most recent book is Foolproof, and Other Mathematical Meditations (MIT Press, 2017).

Volume 31 Number 03

May–June 2022

Sigma Xi Today A NEWSLETTER OF SIGMA XI, THE SCIENTIFIC RESEARCH HONOR SOCIETY

Call for Leadership Nominations Sigma Xi is seeking nominations for qualified candidates to fill positions for the Board of Directors, Associate Directors, and Committee on Nominations for representation of regions and constituencies. The following positions carry three-year terms: Board Of Directors: • Membership-at-Large Constituency Group • Mid-Atlantic Region • Northeast Region • Research & Doctoral Universities Constituency Group Associate Directors: • Area Groups, Industries, State and Federal Labs Constituency Group • Comprehensive Colleges & Universities Constituency Group • Northwest Region • Southeast Region Committee On Nominations:: • Baccalaureate Colleges Constituency Group • Canadian/International Group Constituency Group • North Central Region • Southwest Region Nominations should be submitted to [email protected] by June 30, 2022. Active full members of Sigma Xi are eligible to run for office. An inactive member may become active at any time through payment of current dues. Sigma Xi seeks diverse and inclusive slates for all its elected positions. Selfnominations are welcomed. Visit sigmaxi. org/2022-elections to view a list of duties, responsibilities, and full qualification criteria for each position. Sigma Xi Today is managed by Jason Papagan and designed by Chao Hui Tu.

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From the President Of Honor and Honoring It has been an honor to serve as president of Sigma Xi for fiscal year 2022 and to carry its banner. During my term, I have often had occasion to explain what our Society is and what it does. I usually begin by mentioning its network of chapters and its tens of thousands of members . . . its Companions in Zealous Research. I speak of the Society’s deep historical roots and its unique mission of recognizing and advancing scientific excellence and integrity. I describe its 100 years of providing Grants in Aid of Research to science students; its mentoring, education, and ethics activities; and its Distinguished Lectureships, Science Cafés, and other public outreach programs. And I always mention American Scientist, which continues to set the standard for science magazines. What I mostly do, however, is try to emphasize what stands behind all these and many other programs— the scientific values that the Society was founded to encourage. The virtues of the scientific mindset are what animate us. These ideals and the many individuals who strive to embody them are what we seek to honor and to advance. It is in these terms that we can best express what is best in science and what we stand for. That is the message of our Society.

The spirit of curiosity The spirit of innovation Those who wonder why Those who wonder why not The discoverers of what is The makers of what may yet be Noticing what others overlooked, They seek a truer picture of the world Rejecting pronouncements of authority, They follow the evidence wherever it leads Seeing failure as informative, They test and troubleshoot They investigate tirelessly, With care and precision To discover To build To better understand our world And make our lives the better for it What does Sigma Xi do? We honor their spirit . . . the spirit of research.

Robert T. Pennock

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MEETINGS AND EVENTS

International Forum on Research Excellence Set for November Sigma Xi has announced plans to hold its inaugural International Forum on Research Excellence (IFoRE) November 3–6, 2022. The four-day conference will welcome scientists, engineers, students, artists, and supporters of science worldwide to participate in discussions and demonstrations of excellence in the research enterprise. Attendees will be invited to present, connect, and collaborate on diverse ideas through professional, student, and public symposia, panels, workshops, and networking sessions. The hybrid event will be held in-person in Alexandria, Virginia, as well as online. The theme for IFoRE ’22 is “Science Convergence in an Inclusive and Diverse World.” Attendees will take part in a variety of multi-track sessions that explore the strength of scientific research when diverse minds converge, as well as ideas that conquer the challenges of increasing equity and inclusion in the research community. “This forum comes at a time when research excellence has proven to be critical to our lives,” said Dr. Jamie Vernon, Sigma Xi’s executive director and CEO. “We’re excited to create an environment where scientists and the public can come together to celebrate great science and work together to maximize the value of scientific research for future generations.” Developed as a successor to Sigma Xi’s Annual Meeting and Student Research Conference, IFoRE will feature reimagined components of past conferences, including in-person and live-streamed plenary sessions; deep dive conversations with keynote speakers; topical sessions on research impact and STEM education; research excellence awards; professional and student oral and poster presentations; workshops, professional development, and networking opportunities; a college, graduate school, and jobs fair; a STEM Art and Film Festival; and Sigma Xi’s annual business meeting and assembly of delegates. Plans are for the conference to be held annually in different national and international locations. Interested attendees, sponsors, and exhibitors can direct questions to [email protected] and visit sigmaxi.org/IFoRE for more information.

World Class Keynotes on Tap for IFoRE ‘22 Sigma Xi has a long history of holding annual meetings and conferences that feature lectures and presentations from some of the most accomplished and innovative minds in science. That tradition will continue this fall with a blockbuster lineup of keynote speakers slated for the new International Forum on Research Excellence (IFoRE) in Alexandria, Virginia. Along with specialized breakout sessions, panels, workshops, and award presentations, the Society is thrilled to welcome the following six distinguished keynote speakers: Gilda Barabino, PhD President, Olin College of Engineering

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Kelly Stevens, PhD Assistant Professor of Bioengineering, University of Washington

Lola Eniola-Adefeso, PhD Associate Dean for Graduate & Professional Education in Engineering, University of Michigan– Ann Arbor

Cato Laurencin, MD, PhD University Professor, University of Connecticut

James Collins, PhD Termeer Professor of Medical Engineering & Science, Massachusetts Institute of Technology

Patrick Couvreur, PhD Emeritus Professor of Pharmacy, Paris-Saclay University

Sigma Xi Today

IFoRE ’22 Tracks Track 1: Excellence in Research • Diversity • Ethics • Open Science Sessions • Interdisciplinary Sessions Track 2: Research Impacts • Science Communication • Policy • Civic Science • Entrepreneurship Track 3: Excellence in STEM Education • K–12 Education • Undergraduate Research • Virtual Teaching • Curriculum Development

GRANTS IN AID OF RESEARCH

of GIAR Deborah Neher Grant: $500 in Spring 1986; $1,200 in Spring 1988 Education level at time of the grant: Graduate student

Project Description: I used my first GIAR grant to purchase supplies for my MS thesis research on the topic of “Epidemic development of pre- and post-emergence damping-off caused by Pythium aphanidermatum on Glycine max and G. soja” at the University of Illinois at Urbana-Champaign. We tested the hypothesis that synchronous germination causes increased seed and seedling mortality from damping-off in two legume species attacked by the fungal pathogen Pythium aphanidermatum. However, we learned the relationship between population age structure and damping-off mortality was species-specific. The research resulted in my very first peerreviewed publication. I used my second GIAR grant to purchase supplies for my PhD dissertation research on the topic of “Inoculum density, irrigation, and soil temperature effects on the epidemiology of Phytophthora root rot on tomato” at the

Peteneinuo Rulu Grant: $1,000 in Fall 2020 Education level at time of the grant: PhD student Project Description: The purpose of my study is to understand potential relationships among sociocultural and familial factors, reproductive and other related factors, and symptom experience at midlife. Despite extensive research on menopause in India, little is known about the personal meaning or perception of the menopausal transition as experienced by Naga women. Since menopausal symptoms are subjective and related to factors such as ethnicity and culture, my study examines menopause from a biocultural perspective. The holism of a biocultural perspective allows anthropologists to understand how biology, culture, and the environment shape the outcome of a particular phenomenon. Additionally, menopause-related changes in levels of estrogen often

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result in weight gain, which can be related to symptoms such as aches, pains, and hot flashes. In my study, the occurrence of hot flashes recorded by a Biolog monitor helps to assess whether women in the Naga community, who tend to have lower body mass indices, experience higher or lower frequencies of hot flashes. This is the first study to apply ambulatory Biolog monitors in northeast India. In this regard, the GIAR award from Sigma Xi greatly helped in starting and facilitating the collection of data necessary for my project.

University of California, Davis. My research was one of the first to quantify the effect of initial inoculum density on the epidemiology of this polycyclic disease in field conditions. How did the grant process or the project itself influence you as a scientist/researcher? It provided me both experience and confidence. In 1987, I was elected as an associate member of Sigma Xi. I have been a continuous member ever since. While I was a postdoctoral associate at North Carolina State University in 1995, I was nominated for Sigma Xi’s Young Scientist Award. Where are you now? I am professor of soil ecology in the Department of Plant and Soil Science at the University of Vermont. I was hired as department chair in 2004, and I served in that capacity for 14 years. In 2018, I resigned my chair position so I could focus more on research, my first love. How did the grant process or the project itself influence you as a scientist/researcher? In my interviews with participants, women were keen to learn and hear more about the menopausal transition and the accompanying waves of symptoms that might bother them. As symptoms may vary individually, learning how different Naga women cope with such midlife experiences greatly shaped my own perceptions about menopause. For instance, it was interesting to understand that some women were delighted that their symptom experiences were not unusual but natural. This further reinforced to me the notion of how important biocultural perspectives are to understanding the menopausal phenomenon, which I hope to employ and build upon in my future work. Where are you now? I am currently in the process of writing my dissertation at the University of Massachusetts Amherst.

2022 May–June 191

MEMBER STORIES

Celebrating Generations of Women in STEM In March, Sigma Xi continued its annual celebration of Women’s History Month by showcasing both aspiring and accomplished women in STEM at various points in their careers. Krishna, Luisa, and Roha share snippets about the beginnings of their STEM journeys, along with advice they would pass on to other women starting out or considering a future career in STEM.

Krishna Foster, PhD

Luisa M. Rebull, PhD

Roha Kaipa, PhD

What is your current role? I am a professor of chemistry and special assistant to the vice president of diversity, equity, and inclusion at California State University, Los Angeles. Who or what inspired you to pursue a career in STEM? It’s difficult to select one person or event that inspired me to pursue STEM. My third grade teacher, Ms. Jenkins, nurtured my creativity by allowing us to make picture books on anything we wanted, including my purple elephant without a trunk. My high school chemistry teacher, Ms. Larivee, showed me how exciting and fun chemistry can be. The Elementary Institute of Science introduced me to scientific research during high school, and none of this would have happened without parents who taught me to work hard and question everything. What is one career accomplishment you are most proud of? I am proud of the research I did in the High Arctic showing how sea salt generates free radicals that change the chemistry of air in coastal regions. Here, I pushed my boundaries as a scientist, worked closely with others from around the world, and gained a new respect for the power of nature. This is also when I decided I wanted to work at Cal State LA, preparing diverse students to make future contributions to science. What advice do you have for other women starting careers in STEM? Use your mind and your heart as you build your brilliant career. Don’t shy away from challenges, and always remember that your voice matters. Address science questions that are important to you and your communities, and you’ll never regret it!

What is your current role? I am an associate research scientist at Caltech-IPAC/IRSA, which is a science and data center for astrophysics and planetary sciences at the California Institute of Technology in Pasadena, California. Who or what inspired you to pursue a career in STEM? I have always wanted to be an astronomer. I grew up in Washington, D. C., and my favorite museum was the National Air and Space Museum. I was a “NASA Junkie” and collected NASA lithographs as a kid. I was born after Apollo 11, but the images from the Voyager mission hit me at just the right time to really entrance me. What is one career accomplishment you are most proud of? Unfortunately, there are very few high school science teachers in this country who work with real scientific data. I run a program called NITARP, the NASA-IPAC Teacher Archive Research Program which partners small groups of mostly high school educators with a research astronomer for a yearlong authentic astronomy research project. Almost 20 years running, we have changed the lives of so many teachers by changing the way they think about science, about scientists, about using data in the classroom, and about teaching science. And, by extension, we continue to impact the lives of hundreds of students every year. What advice do you have for other women starting careers in STEM? Don’t take criticism personally. This is good advice for everyone but especially for women entering the STEM workforce or other fields that have historically been male-dominant. Let it roll off your back, pick off the legitimate criticisms from trusted mentors, and move forward.

What is your current role? I am an assistant professor in the Department of Communication Sciences and Disorders at Oklahoma State University (OSU). I also direct the language learning lab at OSU. My research focuses on how individuals (adults and children) learn novel words and the factors that influence vocabulary learning. Who or what inspired you to pursue a career in STEM? My mom was always passionate about learning. However, she did not have the opportunity to pursue higher education because of her early marriage and family responsibilities. My dad supported her while pursuing her dream to complete a master’s degree when I was in ninth grade. She always told me not to wait for opportunities, but to create them. She inspired me to pursue a career in science and complete my PhD. What is one career accomplishment you would love to achieve? I would love to work with infants and toddlers who have difficulty acquiring language and provide them and their families with tools and resources to communicate efficiently. What advice do you have for other women starting careers in STEM? Embrace the challenges you face in your life, both personally and professionally. If you settle for an easy goal within your comfort zone, you may lose an opportunity to learn and grow in life. Be true to yourself, your principles, and to others.

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