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Features ON THE COVER: © GUNNAR PIPPEL/SHUTTERSTOCK

© AL GRANBERG; PIETRO CECCATO; 28 37 44 Driven to Extinction Outbreak Observatory The Sum of Our Parts The eradication of smallpox set Increasingly precise remote-sensing Putting the microbiome front and the standard for the global elimination data are helping researchers monitor center in health care, in preventive of a devastating infectious disease. and predict cases of infectious disease. strategies, and in health-risk Will the ongoing polio and guinea BY JYOTI MADHUSOODANAN assessments could stem the epidemic worm campaigns be as successful? of noncommunicable diseases. BY JEF AKST BY RODNEY DIETERT AND JANICE DIETERT BY CENTER/GRAPHIC THE CARTER

07.2015 | THE SCIENTIST 3 BioResearch

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Department Contents

11 FROM THE EDITOR 60 LAB TOOLS Intelligence Gathering Breaking Down Barriers Disease eradication in the 21st century Finding and recruiting diverse BY MARY BETH ABERLIN populations for clinical studies BY CARINA STORRS 14 NOTEBOOK The Lies That Scars Tell; Brrrr-ying 63 CAREERS the Results; Hunting Off the Hook?; Staying Active in the Lab High-Flying Ducks Retiring as a professor, and even shutting down your own lab, doesn’t 25 CRITIC AT LARGE necessarily mean quitting research. When Does a Smart Mouse BY JENNY ROOD Become Human? Ethical issues attend the creation 66 READING FRAMES 14 of animal-human chimeras. The War Rages On BY JOHN D. LOIKE The conflict between science and religion continues, with effects on 55 27 MODUS OPERANDI health, politics, and the environment. How to Make a New Species BY JERRY A. COYNE Scientists mutate a yeast mating pheromone and its receptor to 67 CAPSULE REVIEWS promote speciation. BY BOB GRANT BY RUTH WILLIAMS 72 FOUNDATIONS 50 THE LITERATURE Half Mile Down, 1934 Nutrient turnover in complex BY JENNY ROOD ecosystems; DNA interference in metazoans; microbial symbionts IN EVERY ISSUE and phosphorus sequestration in marine sponges 9 CONTRIBUTORS

52 PROFILE 12 SPEAKING OF SCIENCE Sold on Symbiosis THE GUIDE DORLING KINDERSLEY/GETTY IMAGES DORLING KINDERSLEY/GETTY Gutless sea worms and their 68 nurturing bacterial symbionts keep Nicole Dubilier at the leading edge 71 RECRUITMENT of marine microbiology. © SIMCOCK; BY ANNA AZVOLINSKY PAUL

55 SCIENTIST TO WATCH Shawn Douglas: DNA Programmer BY ANDY EXTANCE CORRECTION: Update: Re: “A Plague on Pachyderms” (June 2015). After the issue went 57 LAB TOOLS to press, the announced death of a five-year-old Asian elephant at the Albuquerque BioPark raised the number of elephants killed by EEHV since Tools for Drools 2008 to two. A general guide to collecting and In “Memorial Research” (June 2015), the fieldwork conducted by processing saliva Christopher Rodriguez took place in the Davis Mountains near Fort Davis, 57 not the Franklin Mountains near El Paso.

07.2015 | THE SCIENTIST 5 JULY 2015

Online Contents

THIS MONTH AT THE-SCIENTIST.COM:

VIDEO VIDEO SLIDE SHOW Orb-iters You Gutless Worm Monkey Business See how William Beebe and Otis Barton Meet the digestive tract–lacking Travel to Bangladesh to meet the Bedey, descended to the ocean’s depths in oligochaete that has fueled Max Planck a band of river nomads, and their trained an early submersible designed to allow researcher Nicole Dubilier’s interest macaques, which perform shows observation of the mysterious life-forms in symbiosis and marine science. and seldom transmit a monkey virus inhabiting the deep sea. to their handlers.

AS ALWAYS, FIND BREAKING NEWS EVERY DAY, AND LEAVE YOUR COMMENTS ON INDIVIDUAL STORIES ON OUR WEBSITE.

Coming in August ERIC ISSELEE/SHUTTERSTOCK HERE’S WHAT YOU’LL FIND IN NEXT MONTH’S ISSUE:

• Bio-inspired medical innovations

• The placenta: a vital conduit between mother and fetus

• Deleterious effects of pharmaceuticals in the environment

• Lymphatic system development

• Humanized mouse models

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6 THE SCIENTIST | the-scientist.com CALL FOR ENTRIES!

Send Us Your Top Innovation! Announcing The Scientist’s annual Top 10 Innovations Competition

Submit your cutting-edge, life-sciences technology innovation for consideration by a panel of expert judges. The winners will be the subject of a feature article in the December 2015 issue of The Scientist.

• A n “innovation” is defined as any product that researchers use in a lab: machines, instruments, tools, cell lines, custom-made molecular probes and labels, software, apps, etc.

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Contributors

When Rodney Dietert began his scientific career studying the immune system in animal models as an immunogenetics PhD student at the University of Texas at Austin, he had no idea his path would lead him so deep into public health and human microbiome research. Now a professor at Cornell University, Dietert credits his wife, Janice Dietert, a science editor and novelist, for spurring his venture into public-health research. As a former learning-disabilities specialist at the State University of New York at Binghamton, Janice Dietert noted connections between her husband’s immunology, toxicology, and microbiome research, and the chronic health and neurological issues plaguing many of the disabled adults she had worked with. When he was invited to write a journal paper describing what he thought was the key biological sign of a healthy life, Rodney Dietert says the concept of the “completed self” came to him in the middle of the night, ousting his previous immune system–centric focus for the article. To him, the microbiome a baby acquires during a natural birth and early life is vital to the development of an adequately functioning immune system. “We are intended in our healthiest state to be majority microbial,” he says. The Dieterts, who live in Lansing, New York, with their two dogs, discuss this concept of the completed self in “The Sum of Our Parts,” page 44.

As long as geneticist Jerry Coyne has been in science, he’s enjoyed writing for nonscientists. He has written more than a hundred book reviews and articles for publications like The Times Literary Supplement and The New Republic, beginning during his days as a graduate student at Harvard University, then as a postdoc at the University of California, Davis, and finally as a faculty member, first at the University of Maryland and later at the University of Chicago, where he has studied speciation since 1996. Throughout his career, Coyne has remained active in the lab, mentoring just one student at a time. “My philosophy’s always been that if you replace yourself with one good student, you will be a success.” He’s now replaced himself five times over. “I come from a lineage of scientists

PHIL STRAUS who not only worked in the lab with their own hands, but refused to take credit for their students’ work,” says Coyne. “I’m proud of that lineage.” Now, as Coyne starts winding down his research, he looks forward to focusing on writing. He says that while “science long ago became less challenging, in terms of what skills one must acquire,” he is still mastering the craft of writing. Coyne opines on the perpetual conflict between science and religion in “The War Rages On” (page 66), based on his new book, Faith vs. Fact: Why Science and Religion Are Incompatible.

Although copy editor Annie Gottlieb enjoyed science as a college student, she didn’t have the stomach to decapitate mice and was not interested in spending all her time with lab equipment. For more than 35 years, she worked as a freelance critic and writer, contributing reviews to publications such as The New York Times Book Review and The Village Voice, and authoring several books. But in 2006, the opportunity to edit and blog for Natural History rekindled her scientific curiosity. “Here was my love of science flooding back,” she says. The job fit well with her other occupation at the time, which was caring for her ill husband, an author, actor, and Gulag escapee who died in 2010. Gottlieb says that copyediting for The Scientist has allowed her to experience the challenge of working with technical material while remaining “on the sidelines” of science. When she’s not copyediting, writing, or reviewing books, Gottlieb studies karate—a practice that has taken her to Japan several times over the last 40 years. She also maintains a blog called A Cold Eye, where she explores how science influences culture. As a science communicator, Gottlieb sees herself at the intersection of science and culture, and she wouldn’t have it any other way. “It’s

07.2015 | THE SCIENTIST 9 THE CLOSEST THING TO REPLACING FILM

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Intelligence Gathering

Disease eradication in the 21st century

BY MARY BETH ABERLIN

o get an idea of the terrible dread that polio intervene and how to used to evoke in your parents or grandpar- ration resources, while Tents, read the opening chapter of Nemesis, helping farmers decide Philip Roth’s aptly named 2010 novel set in 1944 in where to pasture their a steamy Newark, New Jersey, neighborhood. Roth’s animals to avoid outbreak is fictional, but ever since the first US disease-carrying pests. polio epidemic in June 1916, summer’s arrival came Researchers around the world with the fear of infection, and parents often limited are using the techniques to monitor a whom their children could play with and where they number of diseases, including sleeping sickness, were allowed to go. cholera, West Nile virus, Lyme disease, and malaria. And that dread was not an overreaction. This month’s third feature, “The Sum of Our Although sporadic polio outbreaks occurred every Parts” (page 44), by Rodney Dietert and Janice Diet- summer, 1952 saw the worst epidemic in the United ert, switches gears from epidemics caused by infec- States, with almost 58,000 reported cases. Of those, tious disease to those of the noncommunicable sort, 3,145 people died and 21,269 suffered paralysis examining the intimate relationship between the ranging from mild to disabling. The development human microbiome and our environment—from the of the Salk vaccine three years later, followed by the food we eat to the way we give birth—and the health problems that can result from its disruption and Polio and guinea worm disease imbalance. Unless an infant “completes” its microbiome in the most efficacious manner, ailments are on the brink of total eradication. such as allergies, obesity, and inadequate immune responses can result, they argue. introduction of an oral vaccine, turned polio from a If microorganisms are, after all, not only ene- frightening nemesis to a disease virtually eradicated mies but allies of our health, they are also proving in industrialized countries. crucial to the health and species richness of that But worldwide, the picture was vastly different. warm-weather mecca, the ocean. To celebrate sum- In 1988, when an initiative was launched to stamp mer we have a couple of nods to marine biology: a out polio worldwide, 1,000 children around the profile of Max Planck microbiologist Nicole Dubil- globe were crippled by the infection every day. Epi- ier, which details her lifelong fascination with the demiologists and public-health workers set out with symbiosis between marine worms without a mouth the firm belief that they could reduce that number or a gut and the filamentous bacteria that serve as to zero. In “Driven to Extinction” (page 28), Senior their digestive system (page 52); and a short litera- Editor Jef Akst examines the obstacles, both politi- ture summary of the bacterial symbionts that part- cal and scientific, to the permanent eradication of ner with sponges to cycle phosphorus through coral any infectious disease, using polio and guinea worm reef ecosystems (page 51). disease as examples of two human afflictions that If The Scientist is your vacation companion this are on the brink of total eradication. summer, remember that our freedom from the fear In a companion article (“Outbreak Observatory,” of polio—as we enjoy beaches, swimming pools, and page 37), science writer Jyoti Madhusoodanan family cookouts—is a gift of the ongoing march of describes a new kind of epidemiology, one that translational research. g employs satellites and cell phones to acquire the data necessary to draw increasingly sophisticated disease risk maps. Ecological monitoring of land- cover changes from the air and direct reports phoned in from the field allow public-health Editor-in-Chief

ANDRZEJ KRAUZE officials to fine-tune assessments of where to [email protected]

07.2015 | THE SCIENTIST 11 QUOTES

Speaking of Science

Cooking reshaped our anatomy, physiology, ecology, life history, psychology, and society. Signals in our bodies indicate that this dependence arose not just some tens of thousands of years ago, or even a few hundred thousand, but right back at the beginning of our time on Earth. —Harvard anthropologist Richard Wrangham, in Catching Fire, his 2009 book about how the control of fire and the cooking of food shaped hominin evolution

Our results indicate that several of the fundamental psychological abilities necessary to engage in cooking may have been shared with the last common ancestor of apes and humans, predating the control of fire. —Harvard psychologist Felix Warneken and Yale postdoc Alexandra G. Rosati, in a recent research article showing that chimpanzees understand the process of cooking As long as your adviser and prefer the cooked version of certain foods (Proc R Soc B, June 3) does not move on to other advances, I suggest Although the routine use of misnomers is more often an annoyance than you put up with it, with a critical threat to medical research, this phenomenon can stunt progress good humor if you can. and further demonstrates a certain lack of rigor in the scientific process. —Vincent Giguère, associate editor of Molecular Endocrinology, in an editorial warning of the dangers Just make sure that he is of giving misleading names to genes and gene products (June 1) listening to you and your ideas, taking in the results The Ask Alice article, “Help! My adviser won’t stop looking down you are presenting, and my shirt,” on this website has been removed by Science because it taking your science did not meet our editorial standards, was inconsistent with our seriously. His attention extensive institutional efforts to promote the role of women in on your chest may be science, and had not been reviewed by experts knowledgeable about unwelcome, but you laws regarding sexual harassment in the workplace. We regret need his attention that the article had not undergone proper editorial review prior on your science and to posting. Women in science, or any other field, should never be his best advice. —Caltech virologist Alice Huang, in a swiftly expected to tolerate unwanted sexual attention in the workplace. retracted Science Careers column responding —A notice posted by Science Careers staff about the retraction of a controversial advice column post to a female postdoc who sought advice about advising a female postdoc who was uncomfortable with her advisor’s inappropriate how to handle her advisor’s inappropriate USA GAROFEANU/BARCROFT LAURENTIU

sexual behavior to “put up with it” (June 1) sexual behavior (June 1) ©

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Notebook JULY 2015

of Dhamrai, they drove past a man walking TIGER STYLE: Melia, a trained macaque adorned The Lies That a monkey painted with tiger stripes. with stripes of dyed fur, grooms her Bedey owner. “I thought, ‘What the hell was that?’” Scars Tell Jones-Engel, an anthropologist and pri- for the monkey, she says, and on this par- bout a decade ago, Lisa Jones- matologist at the University of Wash- ticular day, her chance encounter launched Engel was traveling through rural ington, recalls. The caravan stopped and her on an entirely new research project. ABangladesh in a caravan of col- Jones-Engel approached the monkey. The man was a member of the Bedey, leagues she calls “Team Monkey,” a band of She does this a lot in her work on nonhu- a group of nomadic people, some of whom international researchers comprising a vet- man primate–human interactions, often stage informal shows featuring their erinarian, her husband (a physician/epide- approaching the monkey first before pay- macaques. The monkeys are completely miologist), zoologists from Jahangirnagar ing any attention to its human companion. integrated into Bedey life—not only do University, her daughters/field assistants, It’s her way of forging relationships with they provide every bit of income the fam- and others. The group had been collecting strangers. Jones-Engel says the reaction ilies survive on, they also physically inter- macaque feces as part of a project with the is usually, “What is this crazy white blonde act with humans all the time. As a result, Centers for Disease Control and Prevention woman doing next to this monkey? She’s bites are a frequent occurrence among the (CDC) to understand how picornaviruses going to get bitten.” (She never has been.) monkey trainers, and Jones-Engel recog- may be moving between humans and mon- “And the next thing you know, I’m groom- nized that this community could provide keys in the region. As the travelers turned ing their monkey, it’s climbing all over me.” an excellent opportunity to study the trans-

off a paved road to head toward the village The handlers recognize her appreciation mission of simian foamy virus, a common JOHNSON LYNN

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retrovirus among nonhuman primates that cies to take a closer look at simian foamy all—that perhaps they develop neutraliz- is transmitted through contact with saliva. virus. Beginning in the 1990s, Bill Switzer, ing antibodies to the virus. This renders Jones-Engel teamed up with Maxine the non-HIV retrovirus surveillance activ- them unable to be infected.” Another pos- Linial, a virologist at the Fred Hutchinson ity lead in the laboratory branch of the sibility is that the Bedey have different Cancer Research Center, and colleagues to Division of HIV/AIDS Prevention at the alleles at innate immune genes, such as quantify the prevalence of the retrovirus CDC, and his colleagues sampled zookeep- APOBEC3G, which encodes an enzyme among 38 performing monkeys and doz- ers and researchers who work with non- that suppresses retrovirus replication. ens of free-ranging macaques in Bangla- human primates in the lab. “The rates [of “This can be possible,” says Gessain, add- desh. Thirty of the performing primates simian foamy virus infection in humans] ing that it will be important to expand the and 119 of the 126 wild macaques tested varied depending on the types of exposure. study to larger numbers of Bedey to con- positive (Emerging Microbes & Infections, In research workers it was 1 to 3 percent. firm the differences between the groups. doi:10.1038/emi.2013.23, 2013). In some zoo workers we saw it as high as “It’s quite interesting, but this is speculation.” It stood to reason, then, that Bedey were 11 percent,” says Switzer. In Cameroon, a Jones-Engel adds another possible being exposed to the virus, especially given study led by Antoine Gessain of the Insti- explanation for their results—a long shot, how often they were bitten. Jones-Engel tut Pasteur in Paris found that 18 percent but one to be explored: medicines. The remembers that when she first started ask- of people who reported being bitten or Bedey have a long history as healers and use ing Bedey monkey trainers if they could scratched by a nonhuman primate tested herbal medicines on themselves and on their recall specific experiences being bitten, they positive for simian foamy virus, while only monkeys. Perhaps that could account for the just showed her their scar-covered arms. The 0.2 percent of the general population was low prevalence of the virus, but the group blood work, however, told a different story. positive (PLOS Pathog, 7:e1002306, 2011). will need to collect more data to say for sure. Only 1 of 45 Bedey sampled was sero- The Bedey, it seemed, should also have Linial is applying for grants to fund fur- positive for antibodies against simian a high infection rate. “We were very sur- ther research on the Bedey performers and foamy virus, while 17 of 269 villagers who prised to find out that the evidence of their monkeys, but she says it can be a hard don’t work with monkeys were positive. At infection in [the Bedey] is much less than sell when funders want to focus on diseases first, Jones-Engel didn’t believe the results. [in] the ordinary village residents,” says with public-health impacts. Although there “I remember saying to Maxine, ‘Is every- Linial. Her team has not yet figured out is no evidence that simian foamy virus is thing OK with the assay?’ These folks were why, but Linial has hunches. She does not pathogenic to humans, it’s clear from the never, ever positive, and it’s just astonishing think it has to do with the virus or the mon- AIDS pandemic that benign retroviruses given their exposures.” keys (the Bedey capture them from the are capable of evolving into pathogens. Simian foamy virus is known to infect wild instead of breeding them), but per- “My idea is, we should understand viruses humans. Interest in the virus picked up haps with the people—specifically, their before they become pathogenic,” Linial steam in the 1980s, when scientists pin- innate or adaptive immune systems. “The says. “If we had known more about lenti- pointed apes as the reservoirs of HIV. Con- Bedey, even when they’re little children, viruses before HIV emerged, maybe things cern over zoonotic transmission of other are around monkeys all the time. So it is would have happened differently.” retroviruses led the CDC and other agen- possible—[though] there’s no evidence at —Kerry Grens

Brrrr-ying the Results A few years ago, tumor immunologist Elizabeth Repasky realized that she had heard from too many oncologists, colleagues, and friends that cancer patients regularly reported feeling cold and unable to regulate their internal ther- PUT HER THERE: A young male rhesus mometers. At her lab at the Roswell Park macaque stretches out his hand at a Bangla- deshi Bedey encampment, where 20 macaques Cancer Institute in Buffalo, New York, and nearly 100 people live together. she decided to build on her experience studying thermal physiology and immunology to see exactly what might be going

on with regard to temperature and can- JOHNSON LYNN

16 THE SCIENTIST | the-scientist.com cer. “I’ve always gone around telling peo- rate. “Across biomedical ple it’s really important to be warm,” she research, we need to pay says. “Being warm is a really important attention to the model part of dealing with diseases like cancer.” we’re increasingly using,” Laboratory mice are routinely held at Repasky says. “Our con- temperatures well below what’s called their trol groups are too cold. “thermoneutral zone,” or the temperature We’re not even modeling range in which their metabolism func- the healthy mouse with tions most efficiently, without the need to our current conditions.” expend excess energy to heat their bodies. And this means that The murine thermoneutral zone (TNZ) cold-stressed mice could is variously defined as from about 26–34 be skewing countless °C or, more narrowly, 30–32 °C. But the experimental results, Guide for the Care and Use of Laboratory past, present, and future. Animals, a near universally accepted set “A lot of these animals of recommendations for the housing and may have been more use of model organisms, mandates that stressed than we could mice should be held at just 20–26 °C—well know, and that could below their natural TNZ. This led Repasky have affected the interpretation of what- at the colder temperatures comfortable for and her team to wonder: Are the count- ever effect [the researchers] were looking their human caretakers. Such measures less mice used in cancer research too cold? at,” says Chris Gordon, a physiologist at allow mice to “create a microclimate within Is there a fundamental physiological shift the Environmental Protection Agency who the cage,” Gaskill says. And she has quan- that occurs in these chilly mice that may be has studied the effects of cold stress in mice tified some of the physiological benefits of skewing research results? and who participated in Repasky’s study. environmental enhancements that enable So Repasky and her Roswell Park col- John Norton, a Duke University patholo- this thermal microenvironment change. leagues held mice modeling tumor growth gist, agrees. “Any stressors could affect the In a study that Gaskill and colleagues con- at two different temperatures—either at immune system and other physiological ducted on several strains of mouse models, the standard temperature of about 22 °C processes to give you different data out- they found that including 8 grams of nest- or at 30 °C, a temperature in the mid- comes,” he says. ing materials raised temperatures in the dle of their TNZ. What Repasky and her But solving the problem isn’t as simple cages to about 32 °C, compared with the colleagues found was nothing less than as cranking up the thermostat in mouse 20 °C temperature of the room. This local astonishing. Tumors in colder mice grew facilities at research institutions. For one temperature change reduced circulating faster and more aggressively than those in thing, keeping mouse rooms at around thyroid hormones in male mice that had mice housed at the warmer temperature. 30 °C would make the environment nigh access to nesting material. And in at least And this trend held true across a variety on intolerable for the researchers and lab one of the strains provided nesting materi- of cancer types—breast, skin, colon, and techs who care for the animals. Typically, als, the activation of UCP1—a protein that pancreatic. Looking deeper, the research- they wear layers of protective garb, includ- is pivotal to thermogenesis in brown fat— ers found a systemic suppression of the ing full body suits, masks, and goggles to decreased (Phys & Behav, doi: 10.1016/j. antitumor immune response in the colder prevent contaminating cages or becoming physbeh.2012.12.018, 2013). mice. Mice held at warmer temperatures contaminated themselves. Also, the ther- As the evidence has mounted that tem- had increased numbers of tumor-attack- mal preferences of mice change through- perature affects mouse physiology, the ing T cells and reduced numbers of immu- out the day, throughout their life spans, authors of animal care guidelines and the nosuppressive cells and regulatory T lym- and with changes in behavior. agencies that use those guidelines to accredit phocytes (PNAS, 110:20176–81, 2013). There may be more subtle ways to pro- facilities for the use of laboratory animals Repasky’s results add to the grow- vide mice with temperatures that approach have paid attention. In 2011, the National ing body of research that illustrates dra- their preferred climate, according to Bri- Research Council committee charged with matic physiological differences in mice anna Gaskill, an animal welfare specialist updating the Guide for the Care and Use of housed at temperatures below their TNZ: at Purdue University’s veterinary college. Laboratory Animals changed the recom- they have twice the heart rate of animals Increasing the numbers of mice allowed mended housing temperatures for mice used housed in warmer conditions; gain weight to inhabit a single cage and providing ade- in research from 18–26 °C to 20–26 °C. And faster and become more obese at earlier quate nesting material furnish the animals Chris Newcomer, executive director of the ages; have higher levels of lipids in their with ways to increase their ambient tem- Association for Assessment and Accredita-

ANDRZEJ KRAUZE blood; and exhibit a higher respiration perature, even in a room that is maintained tion of Laboratory Animal Care (AAALAC)

07.2015 | THE SCIENTIST 17 NOTEBOOK

International, says that though his organiza- rooms with different temperatures with thus could not explain the later drop.) Now, tion is concerned primarily with animal wel- approval of [Duke’s Institutional Animal a more recent study by another team of sci- fare rather than research outcomes, it does Care and Use Committee] and our clini- entists suggests that hunting may not have strongly recommend that the research insti- cal veterinary staff,” he says. “You’ve got to been solely responsible for the decline. tutions it works with be aware of the grow- have the proper controls in any experiment Alastair Baylis of Deakin University in ing body of literature that indicates physi- to properly test your hypotheses.” Australia and the South Atlantic Environ- ological perturbation in cold-stressed mice. —Bob Grant mental Research Institute of the Falkland “We tell the institutions and the [Institu- Islands and colleagues followed up with tional Animal Care and Use Committees] another population survey last year. Baylis that in the course of reviewing protocols you arrived in the Falklands in 2008 as a fisher- should be conscious of emerging science and Hunting Off ies observer, fresh from a PhD spent study- best practices,” he says. “We like to convey ing New Zealand fur seals in South Australia. that to organizations, but we don’t use it as the Hook? “The Falklands is not only a stunning place the linchpin to whether or not an organiza- “There is good reason to suppose that the in terms of scenery and just the abundance tion is accredited.” sea lions of the Falklands can be exploited of species here,” Baylis says, “but because profitably, and that if due precautions are there’s so little research that’s been done on Our control groups are too taken a sealing industry can be established things like sea lions, it’s an opportunity to cold. We’re not even modeling on a permanent basis,” scientist James live out my childhood dreams” of being both Hamilton wrote in 1934. He had traveled a scientist and an explorer. He soon became the healthy mouse with our to the remote South Atlantic archipelago interested in the sea lions and spent three current conditions. with a British scientific team in 1929 and weeks surveying roughly 800 kilometers of — Elizabeth Repasky, spent three years observing the southern sea the Falkland Islands’ corrugated coastline to Roswell Park Cancer Institute lion, Otaria flavescens, estimating popula- visit 70 scattered colonies. Baylis and his col- tion size. From 1933 to 1937, Hamilton and leagues counted about 4,500 pups. AAALAC and other accrediting and a small team of assistants recorded sea lion Next, Baylis’s team combed through regulatory bodies, including the National populations at 56 rocky, exposed rookeries hunting tallies from 1928 to 1966, which Institutes of Health’s Office of Laboratory by rushing at colonies from the water, caus- recorded a cull of 60,723 southern sea Animal Welfare, may consider expand- ing frightened adults to stampede off while lions—93 percent of which were killed in ing on the recommendations they make leaving the slower-moving pups behind to the decade when Hamilton conducted his regarding the provision of nesting mate- be counted. “The bite of the pup, although research. A mathematical model based on rials, shelter, and other means of regulat- annoying, is not serious,” he noted. The final the new and historical population data ing the thermal environment. “I do think count of 80,555 pups, which included esti- suggests that even these staggering num- there’s a breaking point,” Newcomer says. mates of sea lion numbers at eight other bers could not account for the steep sea “This has been discussed already in the cir- rookeries in the Falklands, allowed Hamil- lion drop in the middle of the 20th century. cles of laboratory animal science. There is ton to estimate that there were more than The new research also suggests hunt- a breaking point, but I just don’t think that 380,000 animals in the full population. ing on the Argentine mainland is likely not that breaking point is here yet.” The sea lions were not surveyed again to blame. Significant numbers of sea lions In the meantime, the people at research until 1965, when researchers counted only would have had to migrate to the mainland institutions who are tasked with maintain- 5,506 pups, revealing a shocking decline. over the winter, but it was unknown if this ing colonies of experimental animals are Yet no one sought to explain the drop for actually occurred. In 2011, the scientists fit- ready to assist scientists who want to test another 30 years, until Dave Thompson of ted 10 juveniles with GPS tracking devices to the effects of housing temperatures on their the University of St. Andrews in the U.K. map their winter movements and found that mice. Sandra Sexton, the facility director and colleagues decided to survey the sea lion the sea lions did not stray as far as Argentina, and attending veterinarian for Roswell populations of the Falklands again in 1995. about 483 kilometers away. Given the new Park’s Laboratory Animal Resources, At that point, the team found only about data, “the case for a hunt-related decline is says she’s prepared to replicate Repasky’s 2,000 pups. “[The results were] terrifying,” less compelling,” Thompson says. experiments in other model organisms Thompson recalls. A second survey in 2002– Instead, Baylis and his colleagues sug- under her care. “I will be the first one to ’03 found a slightly higher number. gest that environmental changes could be assist any of our researchers to explore that Thompson and his colleagues posited the cause. The researchers found histor- and do something similar to what we did that hunting had caused the sharp decline ical records indicating that sea-surface for [Repasky],” she says. Norton, direc- between Hamilton’s initial surveys and 1965, temperatures rose between the 1930s and tor of Duke’s Division of Laboratory Ani- both in the Falklands and off the Argentine the 1950s and between 1965 and 1980. mal Resources, agrees. “We could provide mainland. (Legal hunting ended in 1966 and Warmer waters could have disrupted food

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in ocean climate, then that really funda- population hasdeclined[dueto]changes prove thehypothesis, Baylis says. “Ifthe drop, althoughtherearen’tenoughdata to viding important tosealions,possiblypro- webs important andvulnerabilityiency ofspecies,” headds. theresil- mentally altershowweinterpret make spent a didn’tfindstudy a the the decline,butAtkinsonalsobelieves likely ofanimalsmost didn’tcause vest says that Baylis’s researchshowsthehar- the University ofAlaska,Fairbanks. She by warmerseas,says ShannonAtkinsonof caused ofnutritionalstress mental evidence jubatus) species like theStellersealion( ent because,bychance, therewasa . . wholestory . “The entists. population declineisserendipitousforsci- don’t declineduetoa gun,” shesays. “In hunting as the primary cause of exonerate huntingastheprimary data historical that couldpotentially collect being ableto decline,buteven mid-century marine the mammal’sexplain precipitous constrain howdefinitively researchers can the Falklands populations ofsealionsmay forwhichsuchdata exist. the planet” tunately, “there’s nospeciesanywhere on says.prior tothe1930s,Thompson Unfor- ature requires lion sea census numbers tal change.” To tion change totherecordedenvironmen- todomoretiethepopula- need totry availableThe data onsouthernsealions Thompson 30-yeargapsininformation about The thema“fabulousmodel” forother an explanation for lot oftime looking for a forwhichthereisscantenviron- blame sea-surface temper- blamesea-surface agrees that “you would reality, populations most definitive cause.“We’ve singlecause.” thepopulation isonlyappar- Eumetopias smoking commer-

ing,” says. Thompson one hastaken onthepopulation monitor- It’s does tothepast. research as looks much tofuture the as it sity a is,” big question cies. “The says Bill Milsom, the effects that altitudeimposes onotherspe- at are are onlyabout65percentofwhat they oxygen levels plano. Atnearly4,000meters, son adds.Most hadaccessto,Atkin- researchers wishthey and hiscolleaguesis available detail says. historical toBaylis The inhuntingsealions,”cial interest Thompson With speciesinhabitingtheAndeanalti- waterfowl Punashore. The tealisoneofmany resident six duckstotheresearcherswaitingbackon deliver into theboat, andby3:00a.m.they Puna tealwhilehissonreadiesa blue-billed boat towardsanunsuspecting ber oftheUro with a surface son crouchesonthebow, scanningthewater’s hiswoodenboatsteer throughthereeds.His islands on Lake A Ducks High-Flying away: “How doit?” dothey teal reeds, paddle then among fly the tortora effort toovercomethe effects ofhypoxia, encouraged togulpdown coca teainan comparative physiologist fromtheUniver- Peruvian manfromthefloating man-made sea level, butthebirdseemsobliviousto sealevel, just 30,000 in1965 from 370,000+ Islands, where thepopulationdeclined (Otaria flavescens) breeding attheFalkland SEEING SEALIONS: of British Columbia, as he watches Human visitorstoLake a quick swipe, the boyhauls the duck people,silentlymaneuversthe flashlight. The father, flashlight. The a Titicaca uses a importantly, though,the animalsinthe1930s to “reallynice[that] some- that something Southernsealions —Jenny Rood Titicacaare long pole to handnet. a mem- many

Puna

COURTESY OF ALASTAIR BAYLIS or low oxygen levels. A short flight of stairs than more-recent arrivals that may still fuel their cells with oxygen at extreme alti- leaves you breathless, and your body com- mix with lower-altitude populations. tudes, sometimes upwards of 7,000 meters. pensates by increasing heart rate and Air pressure drives oxygen down its But they only fly at such altitudes transiently. breathing faster and deeper. But these cascade: from the atmosphere to the In contrast, the ducks in Peru all live at alti- changes are energetically costly to main- lungs, from the lungs to the blood, and tude permanently, and each species colo- tain. To thrive at altitude, populations from the blood to the body’s cells, where nized the region independently. “We get to adapt and evolve. And that takes time— mitochondria use oxygen to make energy look at replicate evolutionary experiments,” tens of thousands to millions of years to and heat. Lower air pressure at high alti- says Graham Scott of McMaster University in acquire increasingly efficient adaptations. tude decreases that physical force. Ontario, Canada, “where animals have come But rising global temperatures will “Strong environmental changes, like alti- up to high altitude and evolved these unique test species’ adaptability much sooner. For tude, act like an evolutionary bottleneck,” traits many times.” example, researchers predict that climate says Lucy Hawkes, a physiological ecolo- In a makeshift lab, the team preps gas change will force species to seek cooler envi- gist at the University of Exeter who was not analyzers and tanks, instruments to mea- ronments at higher altitudes. Yet an aver- involved in the study, “and failing to sur- sure lung volume, and a spectrophotometer age low-altitude bird brought to Lake Titi- vive them would mean failing to migrate or designed by team member Peter Frappell of caca wouldn’t fare well. “You’ll see about 90 breed.” She says that insights from studying the University of Tasmania that analyzes the percent hatching mortality in the eggs. The high-altitude physiology can inform conser- oxygen-binding properties of hemoglobin. pores in the eggs aren’t big enough; they vation biology by helping scientists under- Each experiment examines a different seg- don’t have the right hemoglobin gene vari- stand “how animals can really push the pos- ment of the oxygen cascade. The researchers ants; there’s just not enough oxygen,” says sibilities of their biology to survive in the compare lung volume and measure the birds’ Kevin McCracken, an evolutionary geneti- ever-changing world around us.” As climate cardiorespiratory responses to experimen- cist from the University of Miami. The 10 change forces species to move to higher ele- tally altered oxygen levels; they take heart, percent that survive, he adds, carry traits vations, understanding the variety of adap- lung, and muscle samples from each species that make them more robust in the face of tations available can help scientists predict to study metabolic enzymes, muscle fibers, hypoxia. Over time, beneficial mutations how far animals can stretch their existing and the degree of tissue vascularization. accumulate along the oxygen cascade, a physiology to cope in a low-oxygen environ- The team has found that the Puna teal, series of events that moves oxygen from the ment. Milsom says that these predictions which colonized the region several million atmosphere into the mitochondria of cells. depend on our knowing how much plastic- years ago and has speciated from its low- Milsom, McCracken, and colleagues ity there is within a species and how much land ancestors, readily copes with extreme are in Peru to compare how five differ- time the species has to adapt. hypoxia. Even when the researchers dial ent duck species cope with reduced oxy- Members of Milsom’s Peru team also down oxygen levels to mimic conditions gen levels. The ducks are all year-round study creatures in Mongolia that have adapted at the peak of Mount Everest, almost residents, but each species colonized the to extreme hypoxia. They recently published 9,000 meters up, the Puna teal deepens region at different points in their evolu- a study on the flight dynamics of bar-headed its breathing, but otherwise remains unaf- tionary past, and each one independently geese, which migrate from their breeding fected. In contrast, the yellow-billed pin- evolved a set of unique adaptations to deal grounds in Mongolia across the Himala- tail colonized Lake Titicaca only a few tens with hypoxia. Species that colonized the yas to their winter refuge in India (Science, of thousands of years ago and has more area first, and are isolated from lowland 347:250-54, 2015). These geese have a host contact, and therefore gene flow, with its

PHOTOGRAPHY MOFFAT populations, have different adaptations of adaptations that maximize their ability to lowland counterparts. Less time at altitude means less-efficient adaptations: the pintails are far more sensitive to hypoxia and breathe much deeper and faster. Even the teal’s hemoglobin has adapted to bind oxygen with greater affinity than that of other species. Individuals can acclimatize to altitude in the short-term, but long- term adaptations spread throughout populations are a function of natural selection. Over time, teals have acquired a variety of adaptations and lost their ancestral accli- SITTING DUCKS: A pair of Puna teals rest on matization response. “They are making the totora reeds surrounding Lake Titicaca. the best use of every bit of air they bring in,” says Scott. —Sarah Hewitt

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When Does a Smart Mouse Become Human?

Ethical issues attend the creation of animal-human chimeras.

BY JOHN D. LOIKE

ate last year, Steve Goldman of the University of Rochester and his col- Lleagues reported that they had trans- planted immature glial cells from donated human fetuses into the brains of immuno- deficient mouse pups. These human glial cells matured into astrocytes and developed as the primary astrocyte population in the newborn mouse brain. One unexpected outcome of the team’s research, published in the Journal of Neuroscience (34:16153- 61), was that these human-mouse chimeras outperformed normal mice almost fourfold in a variety of cognition tests, underscoring the importance of astrocytes in regulating as opposed to monkeys? The scientists scientists and policymakers to resolve the synaptic plasticity and neural connectivity have not addressed this question, perhaps question of how to define humanlike intel- to enhance learning and memory. But the because it is a difficult one to answer. ligence regarding the genetic or chime- study also raised important ethical consid- Human intelligence, as difficult as it is ric alteration of animals. While there is no erations—namely, what biological proper- to define, is often thought to be one of the clear answer to these questions, I advocate ties differentiate Homo sapiens from other most important characteristics that differ- that intelligence is a valid criterion when organisms, and when should such “human- entiate Homo sapiens from all other organ- considering what is humanlike or animal- ized” animals be afforded the rights that isms. However, the capacity to humanize like, and that scientists must develop both people currently enjoy. animals has the potential to complicate this psychometric and neurophysiologic cri- Goldman is quick to state that the assessment of being human. For example, teria in the definition of humanlike intel- enhanced memory and learning perfor- should the definition of human or human- ligence. Most importantly, we should not mance of these human-mouse chimeras like intelligence be psychometric, based move forward on creating any human- did not make the mice more human. “It’s on a constellation of cognitive processes, animal brain chimeras before fully explor- still a mouse brain, not a human brain, or should it be neurophysiologic or neuro- ing the social and ethical implications but all the non-neuronal cells are human,” genetic because it is inextricably linked to of endowing nonhuman animals with Goldman told New Scientist at the time the brain? The question of distinguishing humanlike personality characteristics. of the publication. “This does not pro- human and nonhuman characteristics has While scientists and the public value vide the animals with additional capabili- arisen regarding our close primate relatives. technological development and discov- ties that could in any way be ascribed or Last October, a New York Appeals Court ery, such experiments should only be done perceived as specifically human. Rather, announced that it will consider the issue under conditions where there are clear and the human cells are simply improving the of whether chimpanzees are entitled to important scientific benefits to be gleaned. efficiency of the mouse’s own neural net- “legal personhood.” Similarly, in December, Indeed, the scientific community must works. It’s still a mouse.” an appeals court in Argentina recognized always consider the bioethical ramifications At the same time, the team had ethical orangutans as having basic legal rights, of emerging biotechnologies and remember reservations about repeating these types of stating that these primates deserve living that research investments in new discover- experiments on monkeys, presumably fol- quarters in a sanctuary and not in a zoo. ies should be assessed not by what we can lowing the National Academies’ guidelines Reconstituting human glial cells or do, but by what we should do. g ´ that no human embryonic stem cells should neurons in animal brains could eventu- be introduced into nonhuman primates ally impart complex cognitive behaviors, John D. Loike is the director of special at any stage of fetal or postnatal develop- self-awareness, and/or other humanlike programs at the Center for Bioethics, ment. Is there really an ethical difference personality characteristics to these chime- Columbia University College of DUŠAN PETRIČIC DUŠAN

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How to Make a New Species

Scientists mutate a mating pheromone and its corresponding receptor in yeast to promote speciation.

BY RUTH WILLIAMS

he emergence of one species from another occurs when the two ously made mutants of the M-factor gene, mfm1, which prevented M groups can no longer interbreed. Such reproductive isolation is cells from mating with wild-type P cells. Now, the team has randomly Tconsidered a key evolutionary process, and yet our knowledge mutated the gene for the M-factor receptor, map3, in P cells to pro- of the mechanisms and mutations by which it actually occurs has been duce individuals with which the mfm1 mutants can once again repro- confined to conjecture. “We can speculate on the history of evolution duce. In total, they’ve created four mfm1/map3 mutant pairs that can from various observations,” says Masayuki Yamamoto, director general reproduce with each other but not with their wild-type forebears. of the National Institute for Basic Biology in Okazaki, Japan. “However, “Although their observation may not reflect the real natural his- it is virtually impossible to reproduce it experimentally.” tory, it supports the concept that changes in the mechanism to select Virtually, but not entirely, impossible, it seems. Chikashi Shi- mating partners can be an initial step for speciation,” says Yama- moda’s team at Osaka City University in Japan has achieved experi- moto, who did not participate in the research. mental speciation in the yeast Schizosaccharomyces pombe. Pheromone-receptor interactions that drive reproduction have The two sexes of S. pombe—M and P, for “minus” and “plus”— been studied in a variety of life-forms, particularly amphibians and each secrete a pheromone (M factor and P factor), which binds to insects, says Shimoda. He therefore suggests pheromone mutagen- a corresponding receptor on cells of the opposite sex. This interac- esis might allow researchers to “extend our achievement to other tion is essential for successful mating. Shimoda’s team had previ- organisms.” (PNAS, 112:4405-10, 2015)

Pheromone Receptor

Wild type Wild type Mutant Wild type Mutant Mutant M-cell P-cell M-cell P-cell M-cell P-cell

The yeast S. pombe has Mutating M’s A mutated receptor two sexes, M and P, pheromone gene gene in P yields a protein whose complementary disables the that accepts the altered pheromone-receptor pheromone’s ability to M pheromone, and the pairing is essential for bind P’s receptor, and the mutant couple sexually mating. mutant–wild-type pair reproduces. These cells produces no progeny. cannot mate with wild- type cells, distinguishing them as a new species. 112:4405-10, 2015 112:4405-10, AT A GLANCE , PNAS SPECIATION EXPERIMENTAL APPEARANCE METHOD POTENTIAL OTHER ORGANISMS? TECHNIQUE ORGANISM CHANGES Transgenic synthetic Drosophila Smaller eyes; Mutate five genetic sites to produce flies Yes, any organism amenable to speciation (PLOS ONE, melanogaster different wing that can successfully reproduce with each transgenesis doi:10.1371/journal. veination pattern other, but produce nonviable offspring pone.0039054, 2012) when mated with wild-type flies. Pheromone/receptor Schizosaccharomyces No obvious Mutate mating pheromone and receptor Possibly others that use ligand-

GEORGE RETSECK; SCANS: GEORGE RETSECK; mutations pombe differences genes to cause reproductive isolation. receptor interactions for reproduction ©

07.2015 | THE SCIENTIST 27 EXTENDING THE REACH: A health worker administers polio vaccine to a child while her sisters watch, during a Polio National Immunization Day in Karachi, Pakistan.

28 THE SCIENTIST | the-scientist.com Driven to Extinction The eradication of smallpox set the standard for the global elimination of a devastating infectious disease. Will the ongoing polio and guinea worm campaigns be as successful?

BY JEF AKST

n the spring of 2000, Stephen Cochi, that had once killed tens of thousands of then-director of the Global Immuni- people each year and paralyzed hundreds zation Division at the US Centers of thousands more. But the scene was also for Disease Control and Prevention a stark reminder of how far those fight- I ing for polio eradication had to go, he says. (CDC), stood in the town of Torkham on the border of Pakistan and Afghanistan, “[I could] see how the eradication of polio watching thousands of Afghans exit their in Afghanistan is completely linked to the country through the storied Khyber Pass. eradication of polio in Pakistan. This was They were fleeing for their lives from the a living, breathing, visible representation violence that had become a regular occur- of that. We’re still dealing with that today.” rence as Afghanistan entered its fifth year Indeed, while researchers and public- of civil war against the then-ruling Tali- health officials have made great strides in ban. But Cochi and his colleagues from ridding the world of the virus—the num- the World Health Organization (WHO) and Pakistan’s Federal Ministry of Health saw another opportunity to save lives. As Epidemiologists, public- the families crossed into Pakistan on their health workers, and way to the city of Peshawar, public-health researchers involved in workers escorted any groups that included eradication campaigns are children who looked to be less than five confident that polio and years old to a tent set up to the side of the guinea worm can meet crowd and delivered two drops of an oral polio vaccine into the children’s mouths. the same fate as smallpox. “There were people streaming across the border,” Cochi recalls. “I would guess ber of polio cases has dropped to just a that, over the course of a full day, they few hundred from more than 350,000 in probably vaccinated in the thousands of 1988, when the eradication campaign was children.” Cochi found it gratifying to see launched—the final steps in extinguish- END POLIO PAKISTAN/ASAD ZAIDI. WWW.ENDPOLIO.COM.PK END POLIO PAKISTAN/ASAD

07.2015 | THE SCIENTIST 29 migration of people into and out of polio- “It starts with knowledge and then it mann, a medical epidemiologist at the affected countries. “I think Afghanistan carries on to medical practice and then London School of Hygiene and Tropical would be a polio-free country were there it extends into medical research to get Medicine who worked for two years on the not so much back-and-forth movement to insights into what is going on,” says the smallpox-eradication program in India. Pakistan,” Cochi says. University of Florida’s Grant McFadden. But smallpox eradication held some Even more threatening to the eradica- “If everything works right, all those things other advantages over the polio campaign. tion campaign’s success, perhaps, are the flow into new ideas for therapies, contain- For example, “every infection was clinically challenges in immunizing all vulnerable ment, and, ultimately, eradication.” expressed in the same way,” Heymann says. children, many of whom reside in regions “There weren’t, as is the case with polio, occupied by antigovernment forces such as Putting polio in its place people without symptoms.” Indeed, fewer the Taliban. And beyond the logistical hur- Not every infectious disease is eradicable. than 1 in 200 cases of polio results in paral- dles, eradication efforts must overcome In fact, even with all the resources in the ysis, making most infections invisible to scientific challenges—such as the potential world, most of the pathogens that cur- public-health workers. For this reason, a for the attenuated, noninfectious versions rently plague humans would be extremely search-and-containment strategy wouldn’t of the poliovirus used in the oral vaccine to difficult, if not impossible, to banish from work, as it would often miss infected but mutate into an infectious agent. the planet. “When you look at the huge asymptomatic individuals who could con- A better understanding of pathogen array of microorganisms out there, there tinue to spread the virus. Instead, the polio transmission may be even more critical in really is a relatively small number of campaign must continue to vaccinate every supporting the world’s only other ongo- microbiological agents that would be con- child, and therein lies the principal chal- ing eradication campaign: the abolish- sidered to be good candidates for disease lenge to clinching the virus’s eradication. ment of guinea worm disease. Tradition- eradication,” says Cochi. In Afghanistan and Pakistan, the Taliban

I consider the Holy Grail to give up using all polio vaccines altogether. We’d like to take those dollars and apply them to other public-health priorities. —John Modlin, Bill & Melinda Gates Foundation

ally, humans have contracted the disease by One criterion that makes a pathogen has repeatedly interfered with the eradi- ingesting water contaminated by parasite- a good target for eradication is the lack cation campaign, prohibiting vaccination infected copepods, and simply ensuring of an animal reservoir. Even though out- and even killing health workers deliver- that affected regions have access to clean breaks of SARS and Ebola have been con- ing immunizations. “I think there’s gen- CENTER/E. STAUB CENTER/L. GUBB; THE CARTER THE CARTER drinking water has succeeded in reduc- trolled a number of times, for example, the eral agreement that the biggest obstacle is ing cases of the disease from more than causative pathogens can continue to jump access to children in Pakistan,” says John 3.5 million in 1986 to just 126 last year. from their animal hosts to kindle new epi- Modlin, deputy director of the polio arm But recent cases of guinea worm disease demics. Another important feature of an of the Bill & Melinda Gates Foundation. in dogs, which likely contract the parasite eradicable disease is, typically, that there But the campaign has faced, and over- by eating the scraps of infected fish butch- be an effective treatment or vaccine. come, such challenges before. In 2009, the ered on the shore by local fishermen, have Smallpox fit the bill on both counts, northern states of Nigeria—the headquar-

researchers rethinking the final stages of and in 1966, the World Health Assembly, ters of the violent extremist group Boko ZAIDI. WWW.ENDPOLIO.COM.PK END POLIO PAKISTAN/2012/ASAD eradication. “That’s a new wrinkle in what WHO’s highest governing body, voted to Haram, which, like the Taliban in Paki- Mother Nature has to offer us,” says Ernesto initiate a worldwide smallpox-eradication stan, has prohibited vaccinations and even Ruiz-Tiben, director of the Carter Center’s campaign. It started out as a mass vaccina- killed to enforce this ban—was the scene of Guinea Worm Eradication Program. tion program, then converted to a search- a polio outbreak that resulted in more than Despite these setbacks, epidemiolo- and-containment strategy, in which all 350 cases over a period that had seen fewer gists, public-health workers, and research- contacts of smallpox patients and nearby than 65 infections the year before. Then, in ers involved in the two eradication cam- households—depending on the country, 2013, polio jumped from Nigeria to Soma- paigns are steadfast. They’ve done it once sometimes entire apartment buildings— lia, causing an outbreak of 194 infections in before—declaring the world free of small- were vaccinated to prevent further trans- a country that had not recorded a case of pox in 1980—and experts are confident that mission of the pathogen. In less than 15 nonvaccine-related poliovirus since 2007. ROW: BOTTOM BEAUBIEN/NPR. JASON ORGANIZATION; HEALTH WORLD

polio and guinea worm can meet the same years, case numbers dropped from more In response to the spike in cases, the ZAIDI; © END POLIO PAKISTAN/2013/ASAD © fate. And the lessons learned from these than 15 million to zero. “The strategy for Nigerian government and partners set

campaigns could set the stage for other eradication was very straightforward and up an emergency operations center and ROW: MIDDLE ROW: infectious diseases on the chopping block. successful in the end,” says David Hey- enacted a national emergency-action plan, TOP

30 THE SCIENTIST | the-scientist.com A LOOK AT ERADICATION: (Top row, left) A health worker vaccinates a child against polio during an immunization campaign in Quetta, Pakistan; (right) a polio vaccination team wades through flood water in the Sindh province in Pakistan. (Middle row, left) Cheshire Home for Handicapped Children in Freetown, Sierra Leone; (right) a polio vaccination booth in Rawalpindi. (Bottom row, left) An emerging guinea worm is wound around a moist bandage to prevent it from breaking; (right) a Nigerian woman uses a simple cloth filter to remove the tiny copeopods that harbor the guinea worm parasite.

07.2015 | THE SCIENTIST 31 POLIO INFECTION STATS

AFGHANISTAN IRAQ SYRIA

PAKISTAN

SOMALIA NIGERIA

CAMEROON ETHIOPIA SOUTH EQUATORIAL SUDAN GUINEA

MADAGASCAR

POLIO: g Still endemic g Countries with cases in 2014 g Countries with cases in 1988 350,000350,000

300,000300,000 1988 250,000250,000 The World Health Assembly passes a resolution to 200,000200,000 eradicate polio by the year 2000; the Global Polio 150,000150,000 Eradication Initiative is launched. 100,000100,000

50,00050,000 2003 0 In northern Nigeria, polio 1990 1995 2000 2005 2010 2015 immunization campaigns are suspended following unfounded rumors regarding the safety of the polio vaccine. Subsequently, NUMBER OF POLIO CASES a new outbreak occurs. 1988–2015

2,0002,000

1,500 1,500 2008 A new outbreak of polio spreads from Nigeria to 1,000 1,000 West Africa.

NUMBER OF 500500 POLIO CASES 2000–2015

0 2000 2005 2010 2015 Sources: World Health Organization, US Centers for Disease Control and Prevention © ISTOCK.COM/VECTORIKART; REDRAWN FROM WORLD HEALTH ORGANIZATION; © ISTOCK.COM/MSTAY Polio Eradication Initiative. a of politicalwill,” agreesOliverRosenbauer, because only get Pakistan. andfinance “Biotechnology will for Polio Eradication and inAfghanistan ber ofWHO’s Technical Groups Advisory Anglia’sof East Taylor, Sebastian amem- type 2 attempts asa disease viously unvaccinated, Cochinotes. some halfa giving public-healthworkers accessto in Taliban-occupied summer, regions last the production of the most anti- ofthemost spurring theproduction viruses—targets polio vaccine—made fromlive,attenuated One reasonforthisisthat theoriginaloral poliovirus. against protection complete toensure tiple vaccinations arenecessary polio. Anothermainchallenge isthat mul- role toplay infinalizing theeradication of That’s Improved targeting In being replicated inPakistan,” says Modlin. wellinNigeria andnowis that worked very isa ters inhigh-riskareas.“This operation emergency cen- new ing several being put into place in Pakistan, includ- free Africa,” says Cochi. that“we arehopeful wenowhave apolio- be declared eradicated the continent,from poliocan another coupleofyearsbefore than a caseinSomaliawasrecordedless last The inNigeria inlatepolio reported July 2014. the efforts paidoff, hours.In afew as possibleinjust tovaccinate asmany children the country regionsof rush intothewar-tornnorthern units ofhealth-careworkers whowould mobile forcesprotected in whichsecurity including “hit-and-run” immunizations with thereplication of types interfering actually tract, in theintestinal virus, andtype 2 spokesperson fortheWHO’s Global addition, the Pakistan Army intervened “If polio[eradication] failsitwon’tbe “To emergency actions arenow actions Similar emergency virus is immunogenic,thus the most nottosay monthlater. Althoughitwillbe me, that’s of infectious- the story of technical yousofar.” elimination millionchildrenwhowerepre- whole,” says theUniversity all three serotypes of that science doesn’thave a replicates robustly most reasons, with the last caseof withthelast and 1 it will be lack eradication and3.The strategy theend, polio-

the thefirstas wellinthebloodafter doseof siteforpoliovirusreplication— the primary bodies byimmunecellsinthegutlining— “As from a 2 typeof poliocausedbynaturally occurring today’s childrenmuchgood, case asthelast has beentheexclusive vaccine usedinthe which the inactivated polio vaccine (IPV), type 2.Byeliminating type 2 onlyoneofwhichwasnot for example, of suchvaccine-derived polioinfections, yearsaw outbreaks. Last the vast this way, While allthreevirustypes canmutate in again. can mutate to become infectious nated individualsand,onrare occasion, vaccine ofvacci- canbeshedinthestool live virusesusedtomake thetrivalent oral it intoroutinecarebytheendofyear. lent oral vaccine, with thegoal ofadopting licensingforthebiva- process ofsecuring inthe programs. Countriesarecurrently bivalent formforroutineimmunization up to transition trivalentfrom the tothe says. Public-health officials arenowgearing ered at tries andthosecountrieswhichareconsid- coun- cination campaignsinpolio-infected and India. “It campaign acrosstheMiddle Africa, East, been introducedintothepolio-eradication Cochi says.bivalent vaccine The hasalready types 1 completely gone. That’sisn’t completely the turnofcentury, thetype 2 poliovirus hasn’tbeenseensincebefore make theswitchtoabivalent oral vaccine. vaccine-derived these children against continue toprotect form, andhealthofficials needa toaninfectious the virusthat couldrevert harborattenuatedals willstill versionsof Cochi. Butuntilthen,vaccinated individu- forever, includingthevaccine virus,” says all type 2 from theoral vaccine, “theideaistohave virus occurred morethan15yearsago. virusoccurred a vaccine. But such antibodies don’t do solutionistoremovetype 2,goingThe roleofbridgingthat gapfallsto The Although result,theimmuneresponseagainst highriskofreinfection,” Rosenbauer and3 trivalent toa majority of vaccine-derived polio thetype 2 form isresponsiblefor virusesdisappearfromtheworld isthevaccine ofchoiceforvac- [is]enhanced,dosefordose,” naturally type occurring 2 type 2 bivalent oral vaccine. a viruses totalof55cases becausethe poliovirus as they way virus to

provide immunity against thetype 2virus. intramuscular injection,to polio vaccine, whichisadministered via begin to type 2vaccine-derived virus. 3 whilepreventing continued emergence of will boosteffectiveness against types 1and serotypes, to vaccine, whichcontains allthree polio virus  ERADICATION STRATEGIES   virus, allchildren mustbeimmunized. vaccination: to polio eradication campaignismass 2 3 1

At Transitioning from atrivalent oral

The thesametime,healthofficials will numberonegoal ofthe introduce theinactivated trivalent 07.2015 | Trivalent vaccine abivalent form lackingtype 2 stop thespread ofthe THESCIENTIST continue to Bivalent vaccine

33 GUINEA WORM INFECTION STATS

GUINEA WORM: g Countries with cases in 2014 g Endemic countries, 1986

1,000,0001000000 1986

800,000800000 The World Health Assembly passes a resolution to eliminate guinea worm. Estimates indicate there are 600,000600000 3.5 million cases of guinea worm disease annually, with approximately 400,000 400000 120 million people at risk in 21 countries in Africa and Asia.

200,000200000

0 1986 0 1990 1995 2000 2005 2010 2015

NUMBER OF GUINEA WORM CASES 1989–2015 10,00010000

8,0008000

6,0006000

4,0004000

NUMBER OF 2,0002000 GUINEA WORM CASES 2007–2015 0 2007 2010 2015

Source: The Carter Center THE CARTER CENTER/GRAPHIC BY AL GRANBERG we can.” them tootherpublic-health priorities, if “We’d polio vaccines altogether,” says Modlin. sider theHoly Grail togiveupusingall smallpox. “Speakingformyself, [I]con- altogether,be stopped ashappenedwith possibility that polio vaccinations could cation campaignissuccessful,therethe oral forms ofthevaccine. five years,easingthetransition fromthe trials, couldbeavailablet withinthenex rently undergoing inearlyPhase1 testing a require that the microneedlevaccines wouldnot ting ona patche asput- s, assimpletoadminister now exploringtheuseofmicroneedle As remains achallenge. tion mode ofdelivery ButIPV’s derived viral infections. of IPV, to transition use allcountriestoexclusive cine. IPVhas been introduced into world fect supplementastheseregionsofe astheper- types ofthevirus,itcouldserve affagainst allthreesero- ords protection ing high-risk countries. Butbecauseit eradication , thisvaccinealforthe ister isnotpractic requires a trained professional to admin- is more expensive and as thefactthat IPV spreading thevirus.For entering andreplicating inthegut—and naturallyg poliovirusesstop from occurrin where itcancauseparalysis, butitdoesn’ t the virusfromreachingspinalcord provides andpersonal prevents protection thus bytheoralIPV triggered vaccine. The blood, incontrast togut-basedimmunity provokes animmuneresponseonlyinthe and lar injection viaintramuscu istered United isadmi n- States since2000.IPV , August 21,2014.)Scientist, August Two of theswitch,” Modlin says . (See“For Polio, tine immunization programs]bythetime is tohave in[rou- allcountriesusingIPV campaigns inaffected areas,and“thegoal microneedleversionofIPV, a Even longer-term, ifthepolioeradi- Eventually, Vaccines Work One,” Better Than possiblealternative, researchersare like totake thosedollarsandapply transition to the bivalent cold storage. eliminating theriskofvaccine- Band-Aid.Anaddedbonusis ill st fo campaignrts ef health-care officials hope Cochispeculates this reason, as well - whichiscur - vac oral ongo- injec- polio t tha The

drinking water. Riv- and Chari Logone The route thantheclassic path of contaminated possibly includinghumans,via a worm may have inEthiopia. alsobeenreported A the yearbefore. requisite eradicab for ility. While Chad is a animal reservoir Molyneux, especiallygiventhalackofan worm—one that is quite concerning,” says new phenomenonasfarhumanguinea isanentirely guinea wormisendemic.“This remaining countries(allinAfrica)where oneoffour ng dogsinChad, began infecti asite hasthrownofficials a measures.” icate] itbyimplementingpublic-health of Liverpool.“A [erad- youcanstill nd yet c Guinea worm—theonlyotherpathogen Worldwide deworming infected. year, inhumanslast reported 113dogswere had onlycases 13 of guineaworm disease at tropical-disease expert real diagnostic,” says David Molyneux, a year. last 126infections worm, tojust bly passeda in 1986,whentheWorld Health Assem- frommorethan3.5million Africa andAsia ceeded inreducingcasesofguineaworm to affect hassuc- strategy ed villages. This ply beentoprovidecleandrinkingwater oftheeradication campaignhassim- focus to haltguineawormdisease,theprimary overagain.Thus, the cycle starting larvae, water, thefemalewormsdischarge new the waterpain. Upon to relieve sensing the plunge into often which theirhumanhosts or ankle,andescapeviaburningblisters, worms,migratemeter-long tothefoot mature andmate.they Females growinto copepods areingested byhumans, where sis. parasitic nematode of the life cycle predictable the extremely the diseasemay a even that thereisnovaccine. In dramatically fromsmallpox andpolioin targeted foreradication—differsurrently targeted Guinea worm larvae hidingininfected Guineawormlarvae canine cases suggest that guinea caninecasessuggest The st coupleofyears,thepar- But inthepast e’s]“[Ther no no drug, vaccine, and no treatment. Instead, elimination of A be infecting mammalian hosts, be infecting similar pattern resolutiontoeliminate guinea be achievable thanksto beachievable handfulofdoginfections

Dracunculus medinen- c ommonly cited pre- the University fact, thereisn’t fact, wasobserved curveball: it curveball: different

larvae. guinea worm fleas ingest known aswater copepods crustacean   GUINEA WORM LIFECYCLE larvae migrate to person’s stomach. The delivers infected water fleasto   the intestinal wall. where they burrow through blisters. form painful where they extremities, to typically travel long and up to females grow of ayear, the the course ingestion. Over months post- two mate within mature and new the worms to soaking theirlegsincool water, triggering caused blisters seekrelief often by 4 2 3 1 thelower Drinking contaminated water Tiny The People suffering from guinea worm– to larvae. ameter three larvae

07.2015 | release tens ofthousands

thesmallintestine, THESCIENTIST guineaworm a

35 SIMPLE SOLUTION: Pipe drinking straws that filter out tiny parasite-carrying water fleas are an important tool in combatting guinea worm disease. The pipe filters are distributed to nomads and people displaced by war in South Sudan, which has become one of the last frontiers on the path to eradicating this debilitating disease.

ers that feed Lake Chad support a thriving fishing industry, in which fish are caught by hand and with baskets in the dry season, when the water levels drop and the rivers become more like large lagoons of stagnant water. “It’s quite significant and unique to Africa,” Ruiz-Tiben says. “I’ve never seen this intensity and dependency on fish products for food.” While the fish- neux. “But as always, the last few cases are says, with deaths from the disease drop- ing industry supports the local economy, all the most expensive and the most difficult.” ping by 75 percent since 2000. signs seem to point to infected fish, which Despite such progress, measles still prey on copepods, as a new source of guinea Next on the chopping block kills about 140,000 children each year. worm infections. As the fishermen bring in When polio was selected to be the object And that number means that even regions their catch, they clean the fish on the river of a worldwide eradication campaign in of the world that were once measles-free, bank, dropping the guts on the ground. The the late-1980s, it wasn’t the only pathogen such as the United States, are still at risk, local dogs, of course, are all too happy to that officials considered. Another potential a fact highlighted by the recent outbreak clean up the mess. In all likelihood, these candidate that made the shortlist was mea- that originated at a Disney theme park fishy meals are the source of the outbreaks sles, says Cochi. Like polio, it has an effec- in California in late 2014. “This is just a of guinea worm in Chad’s dogs. And if peo- tive vaccine—the combination measles, reminder that there’s still a lot of measles ple do not fully cook the fish themselves, mumps, and rubella (MMR) vaccine— elsewhere in the world,” Cochi says. “These they, too, may become infected. and no animal reservoir. The World Health organisms don’t respect borders.” That only sporadic human cases of Assembly’s decision to target polio may Measles eradication does face a few chal- guinea worm have been seen in Chad sug- simply have been a matter of circumstance. lenges that the polio campaign has largely gests that this is exactly what’s going on. “Beginning around 1980, first Brazil and avoided, however, most notably the fact that Rather than mini-outbreaks, in which one then an increasing number of countries in the MMR vaccine must be administered by or a couple of infected individuals leads Latin America began nationwide polio cam- a trained professional. “Because measles is to bouts of dozens of cases in the follow- paigns,” Cochi says, which “knocked polio an injectable vaccine, we can’t go house-to- ing year after the worm has completed disease burden way down to low levels. . . . house,” Cochi says. “[It requires] more of a its cycle and contaminated the village’s That was one big factor—there was dem- facility-based measles mass campaign.” But, water source, there have been just a hand- onstration of success in a large geographic he added, the MMR vaccine does have one ful of cases in Chad villages, and often no area. The other big factor was [that] Rotary advantage over the polio immunization: it repeat cases the following year. “That was International became interested in polio needs to be given only twice, instead of the one clue that transmission is not occur- eradication in the mid-1980s and signed on four times recommended for the oral polio ring via drinking water,” says Ruiz-Tiben. as the largest private-sector [participant] in vaccine. “The measles campaigns are far less Public-health workers are now striving to the polio eradication effort.” frequent and therefore less disruptive to the educate affected villages about this pre- But as polio eradication approaches health-care system,” he says. sumed new mode of guinea worm trans- what may soon be a realistic near-term For now, however, there is no official talk mission, encouraging people to cook their goal, some epidemiologists are starting to of a worldwide measles-eradication effort. fish thoroughly; dispose of the fish entrails turn their sights back to measles, which, With polio still circulating, most say it’s too in a sanitary way; and keep infected dogs like polio in the 1980s, is now the target soon to think about diverting resources out of the water. of numerous regional campaigns. In fact, away from the ongoing campaign. “Measles “The change in the number of new each of the WHO’s six regions now has an is the next disease that people talk about for [guinea worm] cases in the last 20 years ongoing measles elimination effort. As a eradication,” says Heymann. “[But] no one has been spectacular; it’s a remarkable result, “there’s been a real acceleration in is willing to talk about measles eradication

g public-health achievement,” says Moly- reduction of measles worldwide,” Cochi until polio is finished.” CENTER/L. GUBB THE CARTER

36 THE SCIENTIST | the-scientist.com NASA IMAGE BY JEFF SCHMALTZ, MODIS RAPID RESPONSE TEAM researchers monitor andpredict BY Increasingly precise remote- JYOTI MADHUSOODANAN cases ofinfectious disease. sensing data are DISEASE DETECTOR: phytoplankton blooms North Atlantic.North Similar Vibrio infections along linked to (blue-green) inthe blooms have Satellites capture European coasts. outbreaks of helping been P by a heavy village itself, The with dust. populated and acacia trees; the summer was air dry a bright red andbluerobes,wasnomore than sha traversed a problems andfatigue, cancauseneurological fever ing sickness. Infection, whichbegins with the parasitic protozoansthat causesleep- asa for theflies, whichserve the land, creating ideal breeding grounds the rainy season,grasses and shrubscarpet a threat more insidiousthanlions.During to count tinyflies, which pose black tsetse He itsculture. simply toobserve University inNew cato, anenvironmental at scientist village tokeep track ofhiscattle, recallsCec- touchingbasewithmembersofhis example, wasfrequentlyonhiscellphone,for chief modern lifeinthecommunity. village The and hyenas out.Buttherewerealsohintsof to boththevillagers and theirlivestock. Observatory Outbreak small cluster of huts fenced in to keep lions Ceccato cattle-herding tribalgroupdressedin and death, and is a hadn’t traveled to the village bus hecaughtinthecity ofAru- For zanian Maasai village July. last his triptoa ietro flat more than Ceccato vividly remembers York City. landscapesprinkledwith northeastern Tan- northeastern two

serious threat hours, the vector for vector wasthere Columbia

sleeping sicknessrisk. fly tsetse satellite data asaway mental conditionsusingremote-sensing his collaborators aretracking environ- linked torain andwarmth,Ceccato and in thebud. to are If you cess blue He els was a flies there was were when less there tsetse etation,” years when says Ceccato. “The andspacesintheveg- butnottoodry; wet, nice warmweather, butnottoohot; the ground. based modelscompareto conditions on fly nail polish, the researchers obtain atsetse censustoimprovehowtheseclimate- we are able to forecast[such] events.” occur, you andhiscolleagues arenowinthepro- Because the fly’s fly tsetse “The of making their models, or risk maps, mesh traps baitedwith the scent of favorable for drought,andusingourclimate mod- —Rita Colwell, University ofMaryland know theconditions numbers and, therefore, spikes numbersand,therefore, in is very particular—it likes particular—it isvery cannipit life cycle is lifeclosely cycle 1 to predict spikes in topredict Then, usingbright- Then, anepidemic

22 Mar2015-6Apr 2015 via cell phones are being used to lected ical diseases. Lyme trop- neglected disease,andseveral including cholera, malaria,West tion to modeloutbreaks globe, researchersareusingthisinforma- other environmental variables acrossthe monitor climate conditionsandnumerous providingthecapacity to (GIS) technology modern geographic information system Tanzania. in eastern asitic infections With ing cattle tograze. fly-dense patches of whentak- vegetation high,allowinghimtoavoid be particularly bitemight insect the riskofaninfectious him ofspecific days when,orareaswhere, clickscouldinform A quickswipeorfew suchastheMaasainection, village chief. available toanyone withacell-phonecon- Latitude Disease riskmapsaren’tuniquetopar-

0W1˚ 0W5˚W 10˚W 15˚W 20˚W 0˚ 5˚N 10˚N 15˚N 20˚N 25˚N 30˚N 35˚N 40˚N Low vegetation 2 Meanwhile, localdata col- of diversediseases, ESTIMATE OFHEALTHY VEGETATION Nilevirus,

Longitude zones. risk ers estimate andprepareforshifting both human and animal—to help research- track thepresenceofdiseasecarriers— helped andAfrica,diseasemapshaveAsia already well oftheUniversity ofMaryland.Across casualties, says RitaCol- microbiologist iskey breaks arelikely tooccur vice inGainesville,Florida. Agriculture’s ResearchSer- Agricultural oftheUS director thicum, Lin- says Kenneth public-healthbiologist inthenearfuture,” tosomeextent dictable bemonitoredandpre- logical factors—will thoselinked toeco- diseases—particularly the weather.demic asprecise as predicting ulations could make an epi- forecasting 0˚ And knowingwhenandwhereout- commonplacethat many bevery “It’ll 3 In reduce the a few years, few ˚ 0E1˚ 20˚E 15˚E 10˚E 5˚E impact of impact these improved sim- High vegetation growth, Department of Department several dis- toreducing such asforest

taminated water. Disabling the pump’s break’s sourcetoapumpdispensingcon- the summerof1853.Snowtraced theout- in as thediseasesweptthroughLondon John Snowmappedthespreadofcholera physician satellites before existed, century A action. preventive resources ortarget to identify at-risk regionsandallocate cases ofreported based ontheoccurrence Historically, researchersmappeddiseases Bird’s-eye view can nipitinthebud,” says Colwell. are favorable foranepidemicto occur, you accordingly. “If you know the conditions sanitation andtherapyand direct efforts helping authoritiesidentify at-risk regions miasis, dengue,andmalaria—primarilyby riverblindness,trypanoso- thic infections, eases, includingsoil-transmitted helmin-

COLUMBIA IRI MAP ROOM PIETRO CECCATO that was very controversial.”that wasvery ronmentally led tomy tion of cus wasthere,” shesays. “Butthedistribu- plankton. “Iknew zoo- themselves totheshellsofcrustacean gen species—including discovered that an abundance of of theChesapeakeBay ing longhoursspentsamplingthewaters rather In thancity streets. and hastrained hersightsontheoceans, uses muchmoresophisticated methods dition ofmappingcholera, thoughshe 1855,” 2010.) TheScientist,August (See “John Snow’s ‘Grand Experiment,’ handle contributedtotheepidemic’s end. Today, ColwellcontinuesSnow’s tra- that causescholera—readily attached cholerae wasa understanding that understanding itisanenvi- native At the time bacterium. Vibrio parahaemolyti- V. cholerae, thepatho- surprise,andthat inMaryland,she the1960s,dur- Vibrio

from space. and fallofplanktonicpopulations visible rial abundancecorrelated withtherise found that peaksandtroughsinbacte- algal blooms.Colwellandhercolleagues that after theirnumbersspiked shortly in theimages, andresearcherscouldsee zooplankton tintedthecolorofocean Populations of including anic bacteria, couldalsotrace oce- across theplanet, images ofmassive algal blooms inseas satellites, whichhadbeguntocapture predicting theweather. an epidemicasprecise as soon make forecasting Improved simulations could Colwell began towonder whether

V. cholerae–harboring Vibrio species.

Similarly, seasonalpatches ofgreen inTarangire National are MODIS sensor(mapatleft)

to of weather-related vegetation changes, whichcanhelp predict changes inpopulations ofmosquitoes, tsetse Park, Tanzania, (above) canbemonitored by

WATCHING THEGRASS GROW: forecast malariaoutbreaks ofAfrica. insomeparts

along populations of seasons in2003and2006,forexample, in humans.Following unusuallywarm anddeaths troenteritis, wound infections, sporadic outbreaksof planktonic bloomshave beenlinked to present inoceansaroundtheworld,and firmed that pathogenic Baltic Germany orSweden. Germany waded orswaminwaters off (from advanced sepsis)amongpeoplewho andonedeath infections reported studies ing pathogens inthe rightclimatic condi- forlurk- of whichcanturnintoreservoirs swaths any land, ofirrigated agricultural bodies ofwater: dams,rivers,ponds,and then, several studies have studies Since then,several con- Satellites canalsomonitorsmaller European surrounding coasts Sea. During these several periods, flies, andotherdisease vectors. 07.2015 | usedto V. vulnificusincreased 4 Data from NASA’s Vibrio-caused gas- create estimates Vibrio speciesare THESCIENTIST the coasts of thecoasts satellite the

39 tions. In parts of India, Bangladesh, and other developing countries, such water bodies host Vibrio species year-round, TSETSE TRACKERS: Entomologist John Hargrove of the causing low levels of endemic infection University of Stellenbosch in South Africa shows locals common in people who live in the area. how to set up traps to measure tsetse fly populations But seasonal changes that grow pathogen (top). Locals clean up after a traditional meal in the populations can trigger outbreaks. Maasai village where Hargrove and other researchers Increasingly detailed maps from space are tracking disease-carrying tsetse flies (bottom). can also yield insights about conditions of terrestrial habitats. (See “Casting a Wide Eye,” The Scientist, February 2012.) Cec- cato and his collaborators use satellite data to map dense, humid patches of vegetation in Tanzania where tsetse flies might breed. And in the northeastern U.S. and Canada, similar imagery of forested patches, heavy with plants and moisture, helps researchers predict the risk of tick-borne Lyme disease. Watching the edges of fragmented forests on satellite images also tells researchers where people are most likely to encounter ticks or other forest-dwelling vectors of human disease.5 But probably the most commonly used type of satellite data incor- porated into disease risk maps is weather. “Particularly when working in the developing world, it’s often very challenging to get meteorological data from local weather stations,” says ecologist Michael Wimberly of South Dakota State Univer- sity. “Satellite remote-sensing is a really rich source of information on the environment—everything from climate change to land cover change.” As the Earth’s climate continues to change, incorporating weather patterns into disease risk maps will become even more important. Research has suggested, for example, that when temperatures climb, ticks, mosquitoes, and other disease vectors invade new territories, bringing their pathogens along for the ride. In central Ethiopia and northwest Colom- bia, malaria was thought to be restricted to low-lying regions; cooler temperatures at high altitudes have been known to deter mosquito breeding. But last year, researchers reported temporary shifts in the spatial distribution of malaria cases: in El Niño years—such as 1997 and 2005—when the world experienced globally higher temperatures, the disease occurred at higher ele- 6 vations than in cooler years. PIETRO CECCATO

40 THE SCIENTIST | the-scientist.com In 2009, climate data suggested the No model is perfect, however, Ceccato records for the Punjab region in north- possibility of an El Niño–like event simi- notes; even the best simulations struggle ern India from annual reports made to lar to that seen in 1997, leading the direc- to cope with the complexity of outbreak the Indian government between 1875 tor of the malaria control program in prediction. In addition to environmen- and 1900. The researchers also gathered Eritrea, Ethiopia’s northern neighbor, to tal conditions, the accuracy of a model records of cholera fatalities during the ask the researchers if a large outbreak of depends on how and when the disease same time frame from annual reports of malaria was likely. “We checked on it, and vector breeds, what controls have been the Sanitary Commissioner to the Gov- it seemed a little different, so the risk of put in place, and whether the disease can ernment of Punjab. They investigated a malaria was not as high,” says Ceccato. be transmitted by people traveling to and period during which few disease inter- “But now [the program director] is moni- from endemic regions. “To model every ventions were available to better deduce toring the rainfall and vegetation, because behavior in every region is almost impos- the link between climate and disease. that still gives him a heads up two months sible,” he says. The data revealed that abnormally high in advance where there might be a risk.” temperatures followed by unusually high rainfall usually preceded an epidemic of cholera. Refining environmental models As temperatures climb, ticks, mosquitoes, and other disease based on these records, Colwell and her vectors are invading new territories, bringing their pathogens colleagues can now predict potential out- along for the ride. breaks of cholera two to four months in advance, based on average temperatures and rainfall in a region.7 Climate data are proving particu- Adding local color “When we have an abnormal increase larly useful for tracking areas where To build optimally accurate and predic- in air temperatures, we start to monitor diseases persist at low frequencies but tive disease risk maps, researchers must the region more closely. If there’s rainfall are at risk of spreading to new locales. supplement satellite data with infor- shortly after, we’re sure there is a chance For example, in some tropical regions mation from old-fashioned surveys and of cholera outbreaks,” says West Virginia that harbor malaria-carrying Anophe- case reports gathered on the ground. University hydrologist Antar Jutla, who les mosquitoes year round, such as the This local surveillance helps research- collaborates with Colwell. “Then, we Ethiopian lowlands, the mosquitoes ers nail down correlations between dis- use finer-scale data to see which areas breed more quickly—and spread more ease risk and specific environmental cir- may or may not be at risk.” The team is infections—at the beginning or end of cumstances that are critical to accurately now adapting its methods to model the the monsoon season. People who live in predicting an epidemic. “One of the most spread of West Nile virus, which last year such endemic areas may grow immune difficult things is to get good disease caused more than 2,000 infections in and suffer less-severe infections, but data,” says Linthicum of the Agricultural the U.S. alone. when the rate of infections rises, patho- Research Service. Yet another source of data for improv- gens can spill over into new areas, which One common proxy for disease risk is ing disease-risk models is the global cel- may trigger an epidemic. vector abundance. The bright-blue traps lular-communication network, through In the past, epidemiologists identified that Ceccato’s collaborators set around which local residents can inform such endemic zones based on the occur- the Maasai village in Tanzania, for exam- researchers of disease cases in real time. rence of actual disease cases; mapping ple, allow the team to assess how tsetse Rebecca Flueckiger, an environmen- these cases to specific regions helped to fly numbers shift with the changing sea- tal scientist at the Task Force for Global focus preventive efforts as well as to allo- sons. To track ticks that carry Lyme dis- Health in Atlanta uses cell-phone data to cate medicine and other resources. Now, ease in the northeastern U.S. and Can- build maps of diverse endemic diseases in newer technologies enable researchers to ada, many researchers trail a large white severely affected regions. Field data gath- proactively use climate and geographic sheet through the forest and see what ered by trained local residents or volun- data in these endemic areas to foresee sticks. Other groups walk miles along teers help Flueckiger and her colleagues potential outbreaks. irrigation canals in Kenya to pinpoint pinpoint each occurrence of a disease to “When there’s an outbreak [in an how snails that spread disease-caus- a specific locality. Other groups in sev- endemic region], it has the potential to ing parasites are distributed near water eral parts of Africa rely on residents to move elsewhere,” says Uriel Kitron, an sources in local villages. monitor malaria cases in their neighbor- environmental scientist at Emory Uni- Historical data can also help bolster hoods. Mobile-phone networks also clue versity. “We see that with the Chikun- disease-risk models. To link weather pat- researchers into the movements of bigger gunya virus, which is moving essentially terns to potential cholera epidemics, Col- disease carriers: people who travel to or throughout the world.” well and her colleagues gleaned climate from areas where infections are rampant.

07.2015 | THE SCIENTIST 41 Putting maps into action In addition to sending data to the researchers building epidemiological MALARIA IN MOTION: models, mobile phones enable regional With human travel public-health agencies to access the risk tracked via cell phones maps to monitor for impending outbreaks and estimates of disease in their districts or villages. “People who risk, researchers can predict how malaria is don’t have a background in remote sens- likely to be transmitted ing or climate data are now able to access between different the information and use it,” says Ceccato. regions in northern “This is really the big change there. This Source Namibia. Areas in red information that was just in the hands of are likely to be sources of infection; blue areas specialists is now available to everybody Sink are those vulnerable to for their decision-making processes.” receiving infections from Last year, Andrew Tatem of the U.K.’s red zones. University of Southampton and his colleagues at the Sweden-based nonprofit Flowminder Foundation integrated satellite imagery of rainfall, temperature, eleva- tion, and other environmental factors with case reports of disease and data on human movement monitored through mobile- phone networks to create high-resolution maps of malaria risk levels in northern Namibia. (See maps on this page.) Putting HITTING HOTSPOTS: these diverse data sets together, the group The patch outlined in identified specific regions where a high risk aqua (arrow) is a region at high risk of exporting of infection converged with increases in malaria to the rest of human travel. Although current guidelines Namibia. Targeting in Namibia categorize the entire northern <1% interventions to this part of the country as a high-risk region, 1–5% tiny region can reduce this new map highlighted a few areas cru- disease risk nationwide. 5–10% Percentages and colors cial to transmitting infections (below). The 10–15% show how much the risk refined estimates reduced the population >15% could decrease across that required interventions from 1.3 mil- the country. lion in the entire northern zone to fewer than 200,000 who live in the predicted areas with higher risk.8 “We went through the whole chain from case reports from the government, combined that with remote-sensing data to create high-resolution risk maps, and then added the mobile-phone data to see what areas are exporting and import- ing infectious persons,” says Flowminder

THEN AND NOW: In the past, preventive actions were targeted to the entire northern region of Namibia, covering a population of 1.29 million in 2011 (top). Risk forecast maps suggest 2014 MALARIA JOURNAL, DOI:10.1186/1475-2875-13-52, similar protection could be achieved by focusing

on a much smaller region, with a 2011 population ET AL., of just 190,000 (bottom). TATEM

42 THE SCIENTIST | the-scientist.com

cofounder and executive director Linus but to wipe out disease altogether. In References Bengtsson. “In the end what we get is a Namibia, for example, officials aim to use 1. P. Ceccato et al., “Climate and environmental map that tells us where it’s most efficient the improved risk models offered by Flow- monitoring for decision making,” Earth to put in resources. That’s what the gov- minder to eradicate malaria in that coun- Perspectives, 1:16, 2014. ernment of Namibia is now using to steer try. Similar efforts to extinguish malaria 2. S.Y. Liang et al., “Climate change and the their allocation of preventive resources.” using predictive risk maps are underway monitoring of vector-borne disease,” JAMA, 287:2286, 2002. The group is also working on a similar in other African countries as well as in 3. C.W. Schmidt, “Trending now: Using social media project directed at an ongoing cholera epi- parts of Asia. In the end, such maps may to predict and track disease outbreaks,” Environ demic in Haiti. be key to staying one step ahead of the Health Persp, 120:a30-33, 2012. As disease risk maps continue to prove world’s worst pathogens. 4. C. Baker-Austin et al., “Emerging Vibrio risk at high latitudes in response to ocean warming,” their worth in pinpointing potential epi- “Just because the conditions are Nature Climate Change, 3:73-77, 2013. demics, the field is attracting funding to optimal doesn’t mean there has to be an 5. S. Li et al., “Consequences of landscape build even better models. Just last year, for outbreak,” says Colwell. “You can take fragmentation on Lyme disease risk: A cellular example, DARPA announced a challenge, precautions, and when cases appear, automata approach,” PLOS ONE, doi:10.1371/ with total awards of more than $150,000, you can react much more effectively journal.pone.0039612, 2012. 6. A.S. Siraj et al., “Altitudinal changes in malaria for maps that could help forecast the instead of waiting to see if there might incidence in highlands of Ethiopia and spread of Chikungunya in the Americas be an epidemic.” g Colombia,” Science, 343:1154-58, 2014. and the Caribbean. Researchers in some 7. A. Jutla et al., “Environmental factors influencing parts of the world are now implement- Jyoti Madhusoodanan is a freelance sci- epidemic cholera,” Am J Trop Med Hyg, 89:597- ing the data not just to predict outbreaks, ence writer living in San Jose, California. 607, 2013. 8. A.J. Tatem et al., “Integrating rapid risk mapping and mobile phone call record data for strategic malaria elimination planning,” Malaria Journal, 13:52, 2014.

VECTOR OBSERVERS: From acacias to zebras, using modern technology to track organisms can help predict and prevent outbreaks of infectious disease. PIETRO CECCATO

07.2015 | THE SCIENTIST 43 CREDIT LINE The Sum of Our Parts

Putting the microbiome front and center in health care, in preventive strategies, and in health-risk assessments could stem the epidemic of noncommunicable diseases.

BY RODNEY DIETERT AND JANICE DIETERT

ooking across generations at how ruptors, or particular drugs, increase one’s ing surrounded by sanitizers, and a general health concerns have changed over risk of developing an NCD. Psychosocial tendency to limit contact with the environ- L the past century is an enlightening stressors also play a role. But any assump- ment have changed our relationship with exercise. For your ancestors living in the tion that the ongoing NCD epidemic is due the microbes that are an integral part of our roaring ’20s, fear of infectious diseases— solely to external factors would be missing biology. In today’s world, our best chance of including typhoid fever, cholera, and influ- a key part of the story: the human micro- acquiring microbes might be from touching enza—far outweighed concerns about heart biome. In reality, the NCD epidemic is our computer keyboards and cellphones or disease or cancer. Autism, Alzheimer’s, as much about the ways we have altered frequenting shopping malls, hotel rooms, attention deficit disorder, and Parkinson’s our microbiomes in recent decades as it is or doctors’ offices—and many are not bugs disease were virtually unheard of. Aller- about our changing external environment. you want in and on your body. gies, then called hay fever, were around, but not common. Ratchet ahead through Our microbial gatekeeper the rock-and-roll and disco generations In less than 100 years, leading The human microbiome plays a critical and on to the ’80s and ’90s, and the fear of diseases and causes of death role as a filter between us and the world. In cancer grew enormously, while a number of have shifted dramatically fact, it is the microbiome that determines new diseases began to appear on the radar away from infectious our actual exposure to the environment. screen. Asthma, autism, lupus, arthritis, diseases and heavily toward Substances such as foods, drugs, and envi- inflammatory bowel disease, attention def- ronmental chemicals—collectively termed icit disorder, celiac disease, multiple scle- noncommunicable diseases. xenobiotics—must first pass through the rosis, obesity, and diabetes, among others, layers of microbiota on the skin, in the became common concerns. Fast-forward Commensal microbes that live on and gut, and in the airways where, depending another two decades to present day, and it in us are critical for our health. By cell upon the microbes present, the chemicals is not a matter of whether you, your friends, numbers, we are approximately 90 per- will be sequestered, excluded, or metabo- or family members have one of these ail- cent microbial, and the vast majority of lized before they ever enter our cells. The ments, but which ones and how many. the genes expressed in our superorganism common gut actinobacterium Eggerthella In less than 100 years, leading diseases are not on our mammalian chromosomes lenta, for example, can significantly change and causes of death have shifted dramat- but in the bacteria, archaea, and single- the potency of the cardiac drug digoxin.2 ically away from infectious diseases and celled eukaryotes that call the human body Likewise, microbiome composition affects heavily toward noncommunicable diseases home. Normally, a robust microbiome the toxicity of certain environmental (NCDs), not just in developed countries, would be part of our inheritance, a legacy chemicals such as arsenic, with some sul- but around the globe. NCDs are now the passed, largely maternally, from generation fur-reducing gut bacteria able to generate number one killer worldwide, accounting to generation. But recently that chain has highly toxic, thiolated species of arsenic, for 63 percent of all mortalities.1 There is been broken, usually more than once. The thereby increasing health risks follow- no question that environmental variables, increase in cesarean deliveries, the reduced ing exposure.3 And, of course, diverse gut including exposure to cigarette smoke, cer- prevalence and duration of breastfeeding, microbes are critical components of our tain dietary factors, and chemicals such as overuse of antibiotics both as prescription gastrointestinal system, helping us process DUNG HOANG

07.2015 | THE SCIENTIST 45 There is also a flip side to the xenobi- appears to influence the composition of between the human immune system and otic-microbiome relationship: the external the microbiome and the body’s susceptibil- the microbiome, it is once again not sur- environment affects the composition of our ity to some xenobiotics. In recent studies, prising that alterations in our microbial microbial populations. Even some xenobi- Yale toxicologist Gary Ginsberg, also of the makeup can greatly affect health. otics that were previously thought to be Connecticut Department of Public Health, Microbiome-based immune program- safe may need to be reexamined in light of and others demonstrated that NCDs, ming largely takes place during a critical effects on the microbiome. For example, such as cardiovascular disease, obesity, or window early in postnatal development commonly used food emulsifiers such as chronic kidney disease, affect one’s vulner- and extends well beyond the gastrointes- polysorbate 80 and carboxymethylcellulose ability to certain heavy metals.7 tinal tract, affecting immune-cell reser- have been reported to adversely affect the The current gold-standard model for voirs in the bone marrow and spleen as microbiome of rodents, predisposing them assessing environmental health risks was well as the functional capacities of resident to chronic inflammation and elevated risk developed in 1987 by the US National immune-cell populations in distant organs of metabolic syndrome. In one study, mice Research Council during a time when and tissues. Microbiome-driven immuno- that drank the emulsifiers in water showed the role of the microbiome was largely modulation occurs via cell surface receptor reduced overall diversity of the gut micro- unknown. In effect, toxicologists and risk signaling—involving Toll-like and NOD- biota, decreased representation of gener- assessors have been missing the impact like (nucleotide-binding oligomerization ally beneficial Bacteroidales species, and of the microbiome for decades. This year, domain) receptors, among others—and higher numbers of some potentially pathogenic bacteria, such as Ruminococcus gnavus.4 In some rodent strains, exposure to Given the intimate relationship between the human immune the emulsifiers also thinned the mucus bar- system and the microbiome, it is not surprising that alterations rier, reducing the physical distance between in our microbial makeup can greatly affect health. bacteria residing on the surface of the barrier and gut epithelial cells by more than 50 percent. Such alterations can affect the one of us (R.D.) and Ellen Silbergeld of also through epigenetic regulation, driven interactions between bacteria and cells the Johns Hopkins Bloomberg School of by microbe-produced short-chain fatty of the innate immune system, increas- Public Health proposed a new health-risk acids, that can affect the expression of hun- ing the risk of inflammation-driven dis- assessment model that places the micro- dreds of genes related to immune function. ease. Not coincidentally, microbiomes that biome as the filter between the external Germ-free (gnotobiotic) mice provide have been impoverished or unbalanced by environment and the human body’s own a sobering model for what happens to a environmental factors often have a skewed cells.8 The new model relies on biomarkers developing human immune system in the bacterial metabolism, affecting their host’s that correlate with microbiome composi- absence of microbiome-based training.9 energy utilization, hormone status, and tion—such as volatile organic compounds When microbiota are absent, normal post- control of inflammation. (VOCs) and short-chain fatty acids—to natal immune maturation is blocked, and Thus, it should be no surprise that help to connect environmental exposures, tissue homeostasis is never fully estab- altered microbiomes and elevated risk of microbiome status, and risk of NCDs. lished. Lymphoid deficiencies occur in both NCDs go hand in hand. Myriad studies have the body’s mucous membranes and its sys- linked specific NCDs to an altered diversity Microbial role in immunity temic tissues, such as the lymph nodes and of gut microbiota in early life, with possible In addition to playing gatekeeper between spleen. Germ-free mice also develop imbal- risk factors including maternal and infant our mammalian cells and the external ances among specialized immune cell pop- diet, birth delivery mode, perinatal envi- environment, the human microbiome is ulations that result in improper immune ronmental toxicant exposures, and psycho- critical to the maturation and function of responses when challenged with injury social stressors.5,6 Many disease-associated our immune system, affecting the entire or a pathogen. Depending on the nature microbiomes can serve as a type of finger- spectrum of immune processes. Com- of the challenge, defective host immune print, reflecting the underlying disease con- mensal microbes have been shown to responses may include increased suscepti- dition. In some cases, these skewed, lim- influence, for example, the body’s overall bility to certain infections, reduced vaccine ited-diversity microbial communities may cytokine milieu; the balance among T reg- responses, and/or inflammation-induced help cause or promote the disease; in oth- ulatory cells and inflammation-promoting tissue pathologies, such as asthma or colitis. ers, they may be a consequence. Th17 cells; T cell–driven adaptive immune Not surprisingly, perinatal treatment And if the status of the microbiome responses; macrophage and dendritic cell with antibiotics can compromise the micro- appears to affect the outcome of xenobiotic function; and natural killer T-cell activity, biome, depleting or eliminating the micro- exposures and risk of NCDs, the reverse among other immunomodulatory prop- bial signals needed for a newborn’s postna- appears also to be true. Having an NCD erties. Given this intimate relationship tal immune development. The result can

46 THE SCIENTIST | the-scientist.com THE MICROBIOME CONNECTOME The human microbiome plays an integral role in our relationship with the external world, and both the composition of our microbial communities and our environmental exposures influence our risk of contracting certain noncommunicable diseases (NCDs). Conversely, some NCDs can impact our microbiome status and our reactions to certain xenobiotics. The microbiome is also intimately involved in the function of the human immune system, further affecting health and disease. The interplay between our internal and external environments must be considered when evaluating health risk factors.

• Mice exposed to commonly used food emulsifiers such as polysorbate 80 and carboxymethylcellulose have reduced overall diversity of the gut microbiota, Staphylococcus with decreasing numbers of beneficial Bacteroidales species and increasing numbers of potentially pathogenic bacteria, such as Ruminococcus gnavus. XENOBIOTICS The foreign substances we are exposed to can affect our microbiome composition and our risk of disease.

Streptococcus MICROBIOME The microbial inhabitants of the gut, skin, and airways serve as a first line of defense Eggerthella lenta against the environment. These microbes can sequester, exclude, or metabolize foreign substances before they ever enter the cells of the body. The microbiome also plays a critical role in the development of human immunity, learning what external factors warrant inflammatory reactions and learning to recognize and NONCOMMUNICABLE DISEASES ignore internal targets. Our risk of developing noncommunicable diseases (NCDs), such as asthma, allergies, inflammatory bowel disease, and diabetes, is influenced by both our microbiome composition The common gut Actinobacterium and our exposure to xenobiotics. • Eggerthella lenta can significantly change • Many people with NCDs have an altered microbial the potency of the cardiac drug digoxin. fingerprint, which may be a cause or a consequence of the disease. • Some sulfur-reducing gut bacteria are able to generate highly toxic, thiolated species • In addition to altering one’s microbial communities, NCDs of arsenic, thereby increasing health risks following arsenic exposure.

CATHERINE DELPHIA CATHERINE can influence susceptibility to some xenobiotics, such as © certain heavy metals. be an immune profile that bears worrying obesity,12 and some investigations have “the completed self hypothesis.”13 Single- similarities to those of germ-free mice. For reported an association between antibiotic celled organisms from all three domains example, antibiotic-induced disruption use and an elevated risk of celiac disease. It of life—eukaryotes, archaea, and bacte- of the neonatal microbiota can result in is likely only a matter of time before more ria—join our mammalian cells to create a aberrant immune maturation with altered links between disease and an infant’s com- superorganism. Inadequate or inappropri- cytokine production, the creation of a pro- promised microbiome are revealed. ate seeding of the microbiome is in many inflammatory state, shifts in both host and ways the equivalent of being born with microbial metabolism, and altered epigen- Self-completion a serious birth defect, resulting in inap- etic programming.10 And the results can Given the undeniable importance of com- propriately matured physiological sys- be long-lasting. Antibiotic administration mensal microbes in both training our tems.14 In the absence of effective micro- in infants is associated with higher risk of immune systems and serving as a barrier biome-based training, the immune system asthma later in childhood, a risk that scales between ourselves and the outside world, does not learn what is safe outside of the with the number of rounds administered.11 one of us (R.D.) has posited that a complete body, resulting in haphazard, inappropri- Increased use of antibiotics in infants is also microbiome, seeded at birth, is absolutely ate reactions to innocuous environmental associated with a higher risk of childhood critical for a healthful life, an idea called factors—allergens such as pollen, mold, cat dander, and peanuts. It also fails to properly recognize and ignore internal targets, resulting in autoimmune and inflamma- MANIPULATING THE MICROBIOME tory responses that are misdirected, inef- In contrast to our human genome, our microbial genome is more amenable to fective, and sometimes never-ending. Such adjustment by altering the composition of the microbial communities inhabiting reactions can eventually compromise the our bodies. Some researchers and doctors have already recognized the power of function of our own tissues and organs. microbiome manipulation—think probiotics and fecal transplants (Microb Ecol A newborn’s microbiome is largely Health Dis, 26:25877, 2015). Probiotic mixtures can be ingested to shift microbial inherited from the mother, with birth being balance and metabolism in the gut, translating to potentially useful physiological the most pivotal step in seeding. During alterations. Recent reports suggest that probiotics can prevent diarrhea in children vaginal delivery, the passage of the baby taking antibiotics, for example, as well as increase the efficacy and reduce the side down the birth canal allows exposure not effects of anti–Helicobacter pylori therapies and aid peanut oral immunotherapy for only to the vaginal microbiota but also to a the treatment of peanut allergy. The more radical approach of fecal transplantation, film of maternal intestinal flora. This pro- in which microbiota are installed in the gut via a gastric or nasoduodenal tube, an cess is thought to provide direct seeding of enema, or colonoscope, or orally administered frozen capsules, has proven successful the newborn’s gut with maternal microbes. for the treatment of Clostridium difficile infection (Infect Dis Clin North Am, 29:109-22, Skin-to-skin seeding is also important at 2015), and other potential uses are currently under investigation. Fecal transplants birth. When natural childbirth is inter- have also been used subsequent to antibiotic administration to reinstate a healthy rupted—for example, by cesarean deliv- microbiome. Identification and selection of donor microbes is likely to be an important ery—the baby is seeded by default with future consideration for these therapies. microbes from the local environment, typ- While microbiome manipulation may have benefits at any age, once certain ically from the largely sterile hospital staff developmental programming of our physiological systems has occurred, it is likely to and equipment. Invariably, this results in be much more difficult to correct underlying dysfunctions. Intervention early in life is incomplete and/or inappropriate infant the most comprehensive technique, as it allows for self-completion in the newborn microbial seeding. Indeed, numerous stud- prior to most postnatal developmental programming. We believe that no baby should ies have suggested that cesarean-delivered go unseeded or be left to haphazardly acquire the daily menu of microbes from a babies typically have altered immune pro- given hospital environment. If elective cesarean delivery is planned, deliberate seeding files and are at an elevated risk for NCDs of the baby should be considered. Maria Gloria Dominguez-Bello of the New York such as asthma, type 1 diabetes, and obe- University Langone Medical Center, for example, has promoted the use of vaginal sity. A recent study of 98 Swedish infants swabs immediately after cesarean birth to simulate the baby’s exposure to maternal and their mothers, for example, found that microbes in the birth canal, and preliminary results are encouraging (Trends Mol cesarean delivery significantly blocked ver- Med, 21:109-17, 2015). Potential medical complications should be considered in any tical transmission of the maternal microbi- 15 decision regarding microbial manipulation therapies. These must be balanced against ome to the infant. Additionally, the micro- the immune and other long-term health risks that are created if the baby cannot self- biome transition toward an adult-type complete as a superorganism. profile was shaped by the infant’s feeding pattern after birth, including both breastfeeding and the transition to solid foods.

48 THE SCIENTIST | the-scientist.com Disruptions to complete microbiome potential risks, and the ethical implica- New York. His wife Janice Dietert is a sci- transfer can also occur before birth, as the tions of microbiome manipulation, as ence editor and writer with Performance mother’s microbial makeup is influenced our microbial partners are really a part of Plus Consulting. by her diet, environmental exposures, our biological identity. (See “Who Are We and health. Microbiota originating from a Really?” The Scientist, March 2012.) References mother afflicted with one or more NCDs or For now, we need to rethink the way 1. D.E. Bloom et al., “The global economic burden from a mother who was treated with anti- antibiotic treatments are handled. There has of noncommunicable diseases,” Geneva, World biotics during pregnancy are likely to dif- already been a widespread call for priority Economic Forum, 2011. fer from the microbiota transferred from shifts in the use of antibiotics, designed to 2. H.J. Haiser et al., “Mechanistic insight a mother who is NCD- and antibiotic-free. slow down the selection of multidrug-resis- into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics,” Gut Microbes, 5:233-38, 2014. 3. S.S.C. Rubin et al., “Arsenic thiolation and A better understanding of normal microbiome maturation the role of sulfate-reducing bacteria from the may inform potential microbial-manipulation therapies, human intestinal tract,” Environ Health Perspect, in which life stage–specific adjustments to the microbiome 122:817-22, 2014. 4. B. Chassaing et al., “Dietary emulsifiers impact can improve health outcomes. the mouse gut microbiota promoting colitis and metabolic syndrome,” Nature, 519:92-96, 2015. 5. S. Carding et al., “Dysbiosis of the gut microbiota in To understand which microbes are crit- tant bacteria and preserve effective antibiot- disease,” Microb Ecol Health Dis, 26:26191, 2015. ical for the proper development of a baby’s ics for the most serious conditions. But there 6. C.E. West et al., “The gut microbiota and inflammatory noncommunicable diseases: immune system, it is first important to is another consequence of antibiotic use Associations and potentials for gut microbiota know what a healthy microbiome looks that has been largely overlooked: a severely therapies,” J Allergy Clin Immunol, 135:3-13, 2015. like and what happens to it during normal altered and/or largely destroyed microbi- 7. G.L. Ginsberg et al., “Susceptibility based upon childhood maturation. Merete Eggesbø of ome. Evidence continues to mount regard- chemical interaction with disease processes: the Norwegian Institute of Public Health ing the potential disease outcomes thought potential implications for risk assessment,” Curr Environ Health Rpt, 1:314-24, 2014. and his colleagues have provided a useful to be related to the destruction of the infant 8. R.R. Dietert, E.F. Silbergeld, “Biomarkers for picture of normal development of a prop- microbiome. It’s becoming clear that we the 21st century: Listening to the microbiome,” erly seeded microbiome across infancy in should not be leaving children deficient Toxicol Sci, 144:208-16, 2015. the absence of antibiotic administration in most of their microbiome just to wipe 9. M. Yamamoto et al., “A microarray analysis and overt disease. They reported that the out one pathogenic bacterium. The short- of gnotobiotic mice indicating that microbial exposure during the neonatal period plays an term gain comes at the cost of an increased gut microbes present in four-day-old Nor- essential role in immune system development,” wegian newborns were useful in predicting chance of developing NCDs later in life. BMC Genomics, 13:335, 2012. the composition seen at three months of age That is not to say that antibiotics should 10. C.T. Peterson et al., “Immune homeostasis, (in the absence of medical interventions).16 not be used, but that antibiotic administra- dysbiosis and therapeutic modulation of the gut The recent study of 98 Swedish mother- tion as recently practiced is an incomplete microbiota,” Clin Exp Immunol, 179:363-77, 2015. 11. L. Hoskin-Parr et al., “Antibiotic exposure in therapy with unacceptable long-term risks. child pairs provides further documentation the first two years of life and development of of infant microbiota composition during the Future treatments with antibiotics should asthma and other allergic diseases by 7.5 yr: A first year of life.14 Going forward, it will be be accompanied by complementary thera- dose-dependent relationship,” Pediatr Allergy important to collect similar data on normal pies to restore the commensal microbes that Immunol, 24:762-71, 2013. microbiome development across different were never intended to be killed. 12. L.C. Bailey et al., “Association of antibiotics in infancy with early childhood obesity,” JAMA Indeed, the goal of any medical proce- regions of the world, as geographic differ- Pediatr, 14:2036-65, 2014. ences do exist among microbiomes. This dure should be to leave patients with the 13. R. Dietert, J. Dietert, “The completed self: An information can help researchers evaluate best possible microbiome. The importance immunological view of the human-microbiome the risks and benefits of various birthing, of our microbial partners has for too long superorganism and risk of chronic diseases,” infant-feeding, and treatment practices. been overlooked by the medical establish- Entropy, 14:2036-65, 2012. 14. R.R. Dietert, “The microbiome in early life: ment. A new treatment standard that takes A better understanding of normal Self-completion and microbiota protection as microbiome maturation may also inform a complete microbiome into consideration health priorities,” Birth Defects Res B: Dev Reprod potential microbial-manipulation thera- could result in sweeping changes in health Toxicol, 101:333-40, 2014. pies, in which life stage–specific adjust- care, such that more integration and better 15. F. Bäckhed et al., “Dynamics and stabilization of the human gut microbiome during the first year ments to the microbiome can improve personalization are likely outcomes. g of life,” Cell Host Microbe, 17:690-703, 2015. health outcomes. (See “Manipulating the 16. M. Eggesbø et al., “Development of gut Microbiome” on opposite page.) Of course, Rodney Dietert is a professor of immuno- microbiota in infants not exposed to medical such therapies should always consider any toxicology at Cornell University in Ithaca, interventions,” APMIS, 119:17-35, 2011.

07.2015 | THE SCIENTIST 49 EDITOR’S CHOICE PAPERS The Literature

ECOLOGY 1 + 1 = 1

Grasshopper Spider eating Spider eating eating leaves woodlouse grasshopper

Feces

HERBIVORE DETRITIVORE HERBIVORE + DETRITIVORE FOOD CHAIN FOOD CHAIN FOOD CHAINS

THE PAPER NOT ADDING UP: Three experimental ecosystems demonstrate the R.W. Buchkowski, O.J. Schmitz, “Detritivores ameliorate the effects of herbivore (left), detritivore (middle), and combination (right) enhancing effect of plant-based trophic cascades on N cycling in an food chains on soil nitrogen levels (N). In the herbivore food chain, grasshoppers’ feces elevate nitrogen levels over those in a plant-only old-field system,” Biology Letters, doi:10.1098/rsbl.2014.1048, 2015. control ecosystem (not shown). In the detritivore and combination food chains, nitrogen levels are the same as the control, suggesting the food Life on Earth may be carbon-based, but it wouldn’t exist with- chains interact to dampen the nitrogen-elevating effects of the herbivores. out nitrogen. Soil microbes transform nitrogen from the air and from decaying organic matter into forms of the element available this could have been due to the experimental conditions). But what to plants and, in turn, the animals that eat them. was striking was that the combinations of detritus and plant food Within their respective food chains, detritivores—dirt-dwelling chains also yielded no increases in soil nitrogen. The researchers con- invertebrates that feed on decaying matter—and herbivores have been cluded that the presence of the detritus-based food chain must have shown to raise soil nitrogen levels. And although it stands to reason erased the nitrogen-adding impact of the plant-based food chain. that interactions between these food webs might act synergistically on Buchkowski speculates that the ground-dwelling woodlice might nitrogen levels, it was unknown what their combined impact might be. be aggressively competing with the grasshoppers for space, forcing To examine this question, graduate student Robert Buch- the grasshoppers to spend more time above the ground level and kowski and his advisor Oswald Schmitz at Yale University set up are thus more vulnerable to being eaten by spiders. The increased 45 mesocosms: cage-covered pots one foot wide by three and a predation would therefore cut into the grasshoppers’ impact on soil half feet tall that hold self-contained ecosystems. Each mesocosm nitrogen through their herbivory. In the future, Buchkowski hopes contained soil and one of nine different permutations of herbivore to test whether this is the case. “We need to consider the interaction and detritivore food chains: a plant-only control; two herbivore- between species that are in these two different food chains,” he says. based food chains including plants, plant-eating grasshoppers, The real questions, says Richard Bardgett of the University and grasshopper-eating spiders; two detritus-based food chains of Manchester in the U.K., are whether these effects on nutrient of plants, detritus-eating woodlice, and woodlice-eating spiders; cycling happen in different and more-complicated ecosystems in and four combinations of herbivore and detritivore food chains. the wild and how the interactions among food chains alter nitro- The researchers left their simplified ecosystems untouched for 46 gen content on the ecosystem level. summer days, then measured the soil’s nitrogen content. “People very rarely look at these two food webs in unison,” says THE SCIENTIST

At the end of the experiment, the herbivore food chain of spider, Bardgett, who studies interactions between aboveground and below- grasshopper, and plants increased the nitrogen content of the soil. ground organisms. “Nutrient turnover in ecosystems is a very com- The detritus-based food chains alone, on the other hand, did not plex issue that’s driven by not just decomposer organisms but also

appear to impact nitrogen levels (although the researchers suspect their interactions with the food webs aboveground.” —Jenny Rood PHEBE LI FOR

50 THE SCIENTIST | the-scientist.com DNA INTERFERER: Just a few millimeters long, this marine tunicate, Oikopleura SUCK UP: Bacterial symbionts living in tropical sponges, like this giant dioica, has provided the first glimpse into DNA interference by an animal. barrel sponge, produce polyphosphate granules.

GENETICS & GENOMICS MARINE BIOLOGY Metazoans in the DNAi Club Sponging Up Phosphorus THE PAPER THE PAPER T. Omotezako et al., “DNA interference: DNA-induced gene F. Zhang et al., “Phosphorus sequestration in the form of silencing in the appendicularian Oikopleura dioica,” Proc R Soc B, polyphosphate by microbial symbionts in marine sponges,” PNAS, 282:20150435, 2015. 112:4381-86, 2015.

ACCIDENTAL DISCOVERY DYED SURPRISE Scientists often exploit the natural phenomenon of RNA interference Fan Zhang, a graduate student in Russell Hill’s lab at the University of (RNAi) to knock down specific genes in model organisms. Although Maryland Center for Environmental Science, was using microscopy much less common than RNAi, DNAi has been described in plants, to study how Caribbean coral reef sponges process nitrogen. But the ciliates, bacteria, and archaea. And now, thanks to an accidental finding sponges autofluoresced so brightly that their nitrogen-fixing bacterial by Tatsuya Omotezako of Osaka University, it appears that DNAi can symbionts were difficult to see. To detect the bacteria, Zhang applied also silence genes in a metazoan, specifically, the tiny tunicate Oikopleura a blue fluorescent stain called DAPI, but to his surprise, he saw dioica. “I introduced DNA fragments for another purpose,” Omotezako something else: bright yellow dots. explained in an e-mail, but instead he found a surprising phenotype— one he would have expected from RNAi. BACTERIAL ORIGINS An Internet search suggested that polyphosphate—chains of phosphate AS GOOD AS RNAI molecules—could be the cause, and indeed, with specific extraction To validate the hunch that DNAi was responsible for the effect, methods and scanning electron microscopy, Zhang’s team observed Omotezako and his colleagues microinjected fragments of the widely polyphosphate granules that accounted for up to 40 percent of the conserved developmental gene brachyury into O. dioica oocytes. They phosphorus in three sponge species. To find the source, the researchers found tail defects in developing larvae that were indistinguishable from cultured the symbiotic cyanobacteria, finding that they contained not those induced by RNAi. Injected double-stranded DNA also reduced only polyphosphate granules but the genes necessary to make them. levels of targeted mRNA transcripts and proteins, indicating that DNAi was operating in the animal. NUTRIENT NETWORK Sponges were already known to provide carbon and nitrogen to the FINDING THE MECHANISM reef community. The symbiont-synthesized polyphosphate granules The chordate has nine homologs of the protein Argonaute, which sequestered in the sponges now made it clear “that sponges are right at mediates RNAi in multiple plant and animal species and DNAi in a the center of cycling of phosphorus in coral reef ecosystems,” Hill says. bacterium. Edze Westra, who studies Argonaute proteins at the University of Exeter, says the next clear step is to knock down those homologs, if SPONGE SINKS? possible, to validate the biological relevance of DNAi in O. dioica. Sponges may serve as sinks that remove phosphorus from the ecosystem, says Fleur van Duyl of the Royal Netherlands Institute for Sea A HANDY TOOL Research. This could explain why phosphorus is considered the limiting “Preparing DNA fragments is much easier, faster, and less expensive than nutrient on some reefs, she adds. Filling in the remaining details of the preparing [double-stranded] RNA for RNAi,” says Omotezako. His lab is sponge phosphorus cycle could help researchers predict what might already taking advantage of DNAi to study O. dioica development while happen to the nutrient balance on reefs as the climate changes and

NISHIDA; IMAGE COURTESY OF ANDIA CHAVES-FONNEGRA COURTESY IMAGE HIROKI NISHIDA; working to figure out the mechanism behind it. —Amanda Keener sponges become more prevalent there, Hill says. —Jenny Rood

07.2015 | THE SCIENTIST 51 PROFILE

Sold on Symbiosis

A love of the ocean lured Nicole Dubilier into science; gutless sea worms and their nurturing bacterial symbionts keep her at the leading edge of marine microbiology.

BY ANNA AZVOLINSKY

icole Dubilier doesn’t have fond memories of her high DUBILIER DISCOVERS school science classes. “Unlike many scientists who say Romantic notions. Growing up, ballet and the ocean were Nthey loved to dissect frogs and insects, I was not inter- Dubilier’s two loves. At age 14, she chose not to continue with ballet ested in science when I was young,” says Dubilier, director of the because it would have meant quitting formal schooling. But the sea Symbiosis Department at the Max Planck Institute for Marine continued to draw her. “I had this unrealistic concept that I would Microbiology in Bremen, Germany. spend half of my day diving, one-third doing research, and then Dubilier grew up in Manhattan, where her exposure to nature the rest with the beautiful men I imagined on Jacques Cousteau’s was limited to Central Park. But, vacationing on Fire Island in the ships! That was the concept of marine biology I had in my head.” summer, she fell in love with the ocean and decided to become a marine biologist. “It wasn’t so much the biology,” she says. “There Back and forth. After her parents divorced when she was 13, was absolutely nothing I found inspiring or interesting about biol- Dubilier and her siblings were moved by her mother, a native of ogy class. It was my worst subject in school; it was about learning Berlin, to Wiesbaden, Germany. Every summer, she came back to without understanding.” New York to visit her father and developed what she calls “trans- Atlantic schizophrenia.” “A more positive way to put it is we had the best of both sides of the Atlantic,” she says. “I am just really interested in how two species come together: Why are they associated? Starting from the bottom. After graduating high school, Dubil- What is the benefit?” ier worked at a marine station on Helgoland, Germany’s only deep-sea island. “This was pivotal in my decision to pursue marine biology. Even though I had a menial job of cleaning fish tanks, there was something Dubilier is unapologetic about her early science experience about the physical closeness of the ocean around me and working with and emphasizes that an early and vivid interest in chemistry, marine organisms that inspired me. I got a basic, emotional satisfac- physics, or biology is not a necessary prelude to a successful sci- tion from it,” she says, and she immersed herself in learning the Latin ence career. “I actually don’t think it’s that important,” she says. names of marine species and understanding their taxonomy. Her love of the ocean and its marine inhabitants led Dubil- ier to pursue a PhD in marine biology at the University of Ham- Butt bacteria. Dubilier received a bachelor’s degree in zoology burg. After completing her doctoral studies, she was still not sure from the University of Hamburg and then—always seeking travel she had the passion and stamina required to be an independent opportunities—took a summer course in tropical marine ecology at researcher. Dubilier says she was jealous of colleagues who said a biological station in Bermuda. She went on to pursue a master’s they thought of project ideas in the shower. “I thought of every- degree in the University of Hamburg laboratory of Olav Giere, who thing else but my research!” But a postdoc year spent in the lab studied the biology and ecology of marine oligochaete worms. Giere of Harvard professor Colleen Cavanaugh studying symbiosis in suggested that Dubilier study how a marine oligochaete from mud gutless marine oligochaetes—a type of worm—cemented her love flats off the coast of Germany lives at low oxygen and high sulfide for research. “It was the first time I started to work in depth on concentrations. Then Dubilier discovered that long, filamentous marine symbiosis, and this topic evoked a deep, deep interest that bacteria grew on the tail end of these worms, and became really is emotionally right next to marine biology for me. I am just really excited. “For no reason, really,” she says, laughing. The observation interested in how two species come together: Why are they asso- turned into her first (single-author) publication. “Twenty years later ciated? What is the benefit? And why these two species and not I went back and looked at these funny bacteria [the worms] had on another two? Simple questions, really.” their tail ends, and we made fun of this and called it their butt bac- Here, Dubilier talks about the research cruises that add teria.” Those bacteria are similar to the ones she studies now, found elements of beauty and adventure to her work, how diving in on and in invertebrates living in hydrothermal vents. Bermuda beats wading in freezing German waters, and how Researchers discovered deep-sea hydrothermal vents in 1977 in sheer persistence first landed her a coveted position at the Max the Pacific Ocean off the coast of the Galapagos Islands, just a few

Planck Institute. years before Dubilier became interested in chemosynthetic sym- DUBILIER OF NICOLE COURTESY

52 THE SCIENTIST | the-scientist.com biosis. “Suddenly there was a lot of interest in bacteria associated with invertebrates, and particularly those bacteria that use reduced sulfur compounds as an energy source, because the hydrothermal vent worms didn’t have a mouth or a gut and were being fed by their symbiotic bacteria that use hydrogen sulfide as a source of energy.”

Mucking around. For her graduate work at Hamburg, Dubilier spent a lot of time on the German coast, “freezing to death” she says. The silt and sand sediments off the coast exuded a rotten-egg smell from hydrogen sulfide, used by the bacteria living on the tail end of Tubificoides benedii, the inch-long marine oligochaete she studied for her PhD. Wading into the muddy water, Dubilier used a sieve to collect worms to bring back to the lab for analysis. “This was not the glorious image of diving I had envisioned. The sediments were so muddy that you could lose your rubber boots if you were not careful. The mud would end up in almost every opening in your body. That was where I swore that, after finishing my PhD, the next NICOLE DUBILIER group of animals I would work on would live in warmer climates!” Professor, Marine Biology, University of Bremen Director, Symbiosis Department DUBILIER DIVES IN Max Planck Institute for Marine Microbiology Molecular biology for dummies. After completing her PhD in Bremen, Germany 1992, Dubilier was still not convinced research was for her. “It was clear to me that if you are not absolutely dedicated to your research, Greatest Hits you are going to be very miserable. I had realized that I could not con- • Identified the first sulfate-reducing bacterial species as an tinue in this profession without being dedicated and excited about obligate animal endosymbiont, as well as the first example it.” To help her decide, Dubilier took a molecular biology course for of a symbiotic, syntrophic relationship that includes multiple marine biologists offered by the University of Southern California on symbionts within a marine host—two species, both living in Catalina Island. “It could have been molecular biology for dummies O. algarvensis for all I knew about molecular biology! But it was taught by some • Conducted the first detailed metagenomic analysis of an endo- of the best marine microbiologists who were just starting to use the symbiotic microbial community in a eukaryotic marine host—a newly developed molecular biology methods, including PCR.” gutless worm (O. algarvensis) associated with four bacterial species that provide the animal with energy and waste clearance Warmer climes. When Dubilier was still a grad student, she met • Identified hydrogen as a third, previously unknown energy source Colleen Cavanaugh at a Woods Hole course, and the Harvard pro- for bacterium–animal symbioses, providing energy for mussels fessor, who had been among the first to characterize hydrother- within deep-sea hydrothermal vents—the first new symbiotic mal vent symbioses, suggested postdoctoral work in her lab. There chemical energy source discovered in 25 years Dubilier sequenced the 16S RNA genes—used as phylogenetic • Provided the first combined metaproteomic and metabolomic markers—of bacteria found on gutless marine worms, concluding analysis examining a host with multiple symbionts—the gut- that the worms harbored two symbionts. The two-to-three-centi- less marine worm O. algarvensis and four of its bacterial symbi- meter-long worms Dubilier characterized are found in coral reef onts. The study also identified carbon monoxide as a previously sediments in tropical environments such as Belize, Bermuda, and unknown energy source for marine invertebrate symbiosis. Australia. “The fieldwork was much better than during my PhD. • Organized the first Gordon conference on animal-microbe These trips alone were magnificent.” With better tools, Dubilier’s

CREDIT LINE symbioses, which took place last month lab later identified an additional three symbionts in these worms.

07.2015 | THE SCIENTIST 53 PROFILE

Back to Germany. After her postdoc, Dubilier returned to Ger- An unexpected finding. On a 2005 research cruise to the Mid- many along with her husband, an orthopedic surgeon. In 1995, Atlantic Ridge to study hydrothermal vents that emitted high con- she had funding from both Harvard and the University of Ham- centrations of hydrogen, Dubilier thought that the bacteria living on burg and began to knock on the door of the Max Planck Institute. mussels in these vents might be using hydrogen as an energy source. In 1996, the Molecular Ecology Group welcomed Dubilier as a Up until that point, there were only two known energy sources for postdoctoral fellow. “They finally broke down and gave me a con- chemosynthetic symbioses in hydrothermal vents: hydrogen sulfide tract,” she says. “I was persistent to the point that they later told and methane. Both gases, as well as hydrogen, are produced by geo- me they were worried I was going to be this super-annoying per- chemical processes in the hot hydrothermal vents. “Naively, I was son once I arrived.” Dubilier decided to continue to work on the not aware of the negative results on this. Thomas Pape from the gutless oligochaetes because no one else in the world of marine MARUM in Bremen, also on the cruise, conducted a 24-hour exper- symbiosis was working on their molecular biology and ecology. iment to measure hydrogen concentrations of the symbiosis com- “They were small and difficult to work with because everything munity that suggested that hydrogen indeed was being consumed was complicated, including that they had more than one symbi- by these symbiotic bacteria. It took another five years to really piece ont. So it was great not to have any competition, although for the the data together,” says Dubilier. The study, published in 2011, made first 5 to 10 years, almost no one cited my papers.” the cover of Nature, and showed that hydrogen provides energy for symbioses in mussels and other hydrothermal vent animals. “Our Her own cheerleader. By 2001, Dubilier transitioned to a work is at the crossroads of environmental microbiology and molec- research associate position at the institute. That year, her labora- ular microbiology. We use omics methods to form hypotheses but tory published a paper describing the first example of two symbi- then validate them using physiology and imaging methods.” Using otic bacteria that, rather than competing, provide each other with metaproteomics, the lab has also found evidence that carbon mon- a growth advantage. In the gutless oligochaete Olavius algarven- oxide is used as an energy molecule in marine invertebrate symbi- sis, the primary bacterial symbiont is a sulfur oxidizer that uses oses. The lab has since uncovered physiological evidence that this hydrogen sulfide as an energy source to fix carbon dioxide and pro- is the case, and this study has just been accepted for publication. vide organic carbon compounds to its host. Surprisingly, Dubilier could never measure hydrogen sulfide in the worm’s environment. DUBILIER DIVULGES This puzzle was solved when she discovered a second symbiont Career-life balance. Dubilier says that she rarely mixes her work in the worms, a sulfate reducer. The sulfate reducer produces the with her family. Her son and husband have come with her on several hydrogen sulfide used by the primary symbiont, which in turn pro- research expeditions to collect gutless worms in the Bahamas, Belize, duces oxidized sulfur compounds for the sulfate reducer. and Australia, but research cruises—typically six weeks long—are To prove that the second symbiont was producing hydrogen restricted to scientists only. “I am not sure it’s a good thing for meet- sulfide, Dubilier collaborated with Max Planck colleagues Dirk ings or excursions to bring your kids along. If you’re there with a part- de Beer and Tim Ferdelman to design a laboratory experiment ner and kids at a meeting, you’re usually rushing home to take care of in which the bacteria were incubated with radiolabeled sulfate, kids, and you don’t have time for some of the most important parts of which was then converted to radiolabeled sulfide by the bacte- a conference—the socializing. For myself, I question the integration of ria. Because sulfide precipitates on silver, the team stuck silver family with work, and whether it benefits your family or your work.” needles into live worms and then observed if radiolabeled sulfide had precipitated on the needles by exposing the needles to auto- Improv. “I loved and still love fieldwork. It’s completely indepen- radiography film. The New York Times covered the work because dent work where you have to adjust to a situation immediately and Dubilier had written to one of paper’s science writers. “I told him to improvise. You need to be clear about what you want and to be that my dad is a businessman and a golfer and does not under- able to deal with going out three times when things don’t work, and stand my work and how cool would it be for him to read about it then if you’re lucky, on the fourth try, it might work out. I was also in The New York Times? And he said that had to be the best plug on the ocean, which was immensely satisfying. That mix of feel- he had ever read.” ing that with a little forethought, afterthought, and engagement, that I could bring my work to a productive level, I always enjoyed.” Evolution driver. In 2006, Dubilier’s lab produced the first detailed metagenomic analysis of a marine animal–microbe An American at heart. After her postdoc at Harvard, Dubil- symbiotic community. The analysis demonstrated that four bac- ier and her husband, who had completed a research fellowship in terial symbionts of O. algarvensis act as the energy source and orthopedic surgery during their stay in Boston, made a two-body excretory system for the invertebrate—the first example of such decision to return to Germany. “I would like to have stayed, and an adaptation among free-living marine animals. The work pro- that was when I really realized that I am an American at heart. vided evidence of the worm’s evolution to a gutless animal that But my husband is a German at heart, and he made the point, relies solely on its symbiotic relationships for both digestion and which I agreed with, that he would rather live in Europe and vaca- waste functions. tion in the U.S. than the other way around.” g

54 THE SCIENTIST | the-scientist.com SCIENTIST TO WATCH

Shawn Douglas: DNA Programmer

Assistant professor, Cellular and Molecular Pharmacology, University of California, San Francisco. Age: 34

BY ANDY EXTANCE

hawn Douglas traces the origins of caDNAno we could really focus on churning REFERENCES his current work fashioning nanoscale out sequences for all kinds of DNA objects,” 1. S.M. Douglas et al., “Rapid prototyping of SDNA robots to his boyhood backyard Dietz says. 3D DNA-origami shapes with caDNAno,” workshop. From age five on, he spent count- Dietz made a breakthrough of his own Nucleic Acids Research, 37:5001-06, 2009. less hours with his father building model on DNA self-assembly protocols in late (Cited 208 times) cars, planes, and rockets. “My dad is the 2007, fuelling a friendly rivalry with Doug- 2. S.M. Douglas et al., “Self-assembly of DNA most patient and noncritical person I’ve ever las, with each seeking to trump the other’s into nanoscale three-dimensional shapes,” met,” Douglas says. “He never grabbed any- group meeting presentations. That relation- Nature, 459:414-18, 2009. (Cited 761 times) thing and did it for me. Without that I don’t ship helped spawn two 2009 papers push- 3. H. Dietz et al., “Folding DNA into twisted think I would be here.” ing the field from two-dimensional to three- and curved nanoscale shapes,” Science, Despite the ability he cultivated, dimensional assembly2 and enabling twisted 37:725-30, 2009. (Cited 407 times) Douglas’s desire to study at Yale Univer- and curved structures.3 4. S.M. Douglas et al., “A Logic-gated sity surprised his parents, who didn’t think Working with Church as a postdoc, nanorobot for targeted transport of they could afford it until they discovered Douglas used his nascent skills in synthetic molecular payloads,” Science, 335:831-34, need-based financial aid. After study- biology to develop nanoscale DNA robots. 2012. (Cited 400 times) ing literature at Yale, Douglas eventually In a 2012 paper, he described DNA boxes opted for computer science, but then real- loaded with antibody fragments that could ized he didn’t want a tech job. “I don’t like be opened with two different molecular working on things that are going to hap- keys, such as cell surface antigens.4 “This pen anyway without me,” he says. “I had really inspired people to dream about the a gut feeling I could take programming therapeutic potential of information-pro- skills into an area that was not mature and cessing nanorobots made out of DNA,” make more impact.” stresses Shih. This thinking steered Douglas to a bio- In 2011, Douglas established an annual physics PhD at Harvard Medical School, competition called BIOMOD to help stu- working with William Shih and George dents enter the molecular programming Church. In mid-2005, shortly after Douglas community. Every year, undergraduate started working with the synthetic biolo- teams compete to build the cool- gists, Shih heard Caltech’s Paul Rothemund est stuff using biomolecules. talk about creating self-assembling DNA Since Douglas became an shapes and patterns. “I came back to Bos- assistant professor at the ton very excited, and Shawn was the first University of California, one with whom I could share the news,” San Francisco, in 2013, Shih recalls. his lab has worked At first Douglas tried to enhance and towards next-gener- expand software Shih had written to design ation DNA nanoro- DNA sequences that would self-assem- bots. “The Sci- ble. Then he built his own, called caDNAno, ence paper from scratch.1 Douglas worked on caDNAno from 2012 was through early 2008, limiting his work in the a prototype,” wet lab and leaving Shih “frustrated with his he empha- priorities.” But now Douglas considers creat- sizes. “Some- ing the program his most important accom- thing that will be

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A general guide to collecting and processing saliva

KELLY RAE CHI

ealthy adults secrete roughly 1 to 1.5 liters of saliva each day from three major pairs of glands that are in close con- Htact with the bloodstream. Mostly water, spit also contains electrolytes and proteins, including glycoproteins that form mucus, enzymes that break down food and bacteria, and secre- tory antibodies. Besides maintaining our oral health, saliva harbors clues about our ancestry and whether we might be fighting an infection, are overstressed, or have a hormonal imbalance. In the future, the watery fluid may even provide a rapid screen for a recent heart attack or distinguish between bacterial and viral infections. Indeed, characterizing the oral microbiome, the collection of all of the microorganisms in a person’s mouth, and its potential links to health and disease is its own emerging field. (See “The Body’s Ecosystem,” The Scientist, August 2014) “In the past few years, there’s been a lot more optimism about what can be done [using] saliva,” says Paul Slowey, CEO of Oasis Diagnostics in Vancouver, Washington. That’s because technologies are now sensitive enough to detect and quantify DNA, RNA, metab- olites, and proteins generally present in saliva at levels anywhere from 100 to 1,400 times lower than their concentrations in blood. Many tools are on the market, tailored for collecting samples from amud, professor of basic science and of craniofacial biology and people of all ages, and purification techniques are also improving. director of the HIV/AIDS Research Program at the New York Although saliva is easier and cheaper to collect, store, and University College of Dentistry. In addition, the fluids are a good transport than blood, studies of the fluid and the development of source of IgG antibodies, of which there are limited amounts in new saliva- and oral-based diagnostics are not necessarily simple. the mouth. For example, the FDA-approved OraQuick ADVANCE Planning around the analyte of interest should take into consider- Rapid HIV-1/2 Antibody Test collects antibodies in the muco- ation the myriad collection tools now commercially available, as sal transudate—an ultrafiltrate of blood that passes through the well as suitable processing, stabilization, and freezing strategies. mucosal surface of the cheek and palate—by swabbing the upper These factors can affect your results, especially if you’re aiming and lower gums using a flat, absorbent pad. Gingival crevicular for quantification. fluid is contained in the crevice between tooth and gum. “You can The Scientist talked to saliva experts about their cuspidor of collect that fluid on a paper point,” Malamud says. “Although it’s tricks. Here’s what they told us. only a few microliters, people can do biochemistry on that.”

SAMPLE TYPES WHAT CAN YOU ANALYZE? WHOLE-MOUTH SALIVA. This is salivary fluid and all the extras: DNA. Characterization of the DNA found in epithelial and white cells from the mouth, nasal mucus, blood from any tiny mouth or gum blood cells present in spit is one of the most active areas of saliva sores, microbiota, and food debris. It is collected by spitting or drool- research. Investigators are probing saliva for genes associated ing into a tube. To increase yield, you can stimulate saliva production with cystic fibrosis, autism, and other disorders. Oasis Diagnos- mechanically by chewing on something that doesn’t interfere with an tics, for example, has validated the DNA•SAL collection device assay, such as unflavored gum, wax, or silicon tubing. Even more saliva for research on a variety of genetic diseases and predispositions, is produced by adding citric acid to gum, mouth rinses, or candy. such as Gaucher disease, thalassemias, and cardiovascular disease, Slowey says. MUCOSAL TRANSUDATE AND GINGIVAL CREVICULAR FLUID. Many companies that sell collection tools also offer extraction These fluids feed into spit but are generally better reflections of kits that are customized for preserved saliva samples (see below). DAVID TROOD/GETTY IMAGES TROOD/GETTY DAVID

07.2015 | THE SCIENTIST 57 LAB TOOLS OTHER FLUIDS LINING CELLS • bronchial and • epithelial cells nasal secretions

BLOOD AND BLOOD DERIVATIVES • intraoral bleeding • gingival crevicular fluid Parotid gland • electrolytes EXTRINSIC SUBSTANCES • small organic molecules • food debris • toothpaste and mouth- Sublingual rinse components gland

Submandibular gland

SALIVARY GLANDS • water MICROBIOTA • proteins • oral bacteria • electrolytes • viruses • small organic molecules • fungi

THE COMPONENTS OF SALIVA

gen sequencing is available in Journal of Visualized Experiments growth factors, and antibodies. Researchers are evaluating salivary (doi:10.3791/51697, 2014). proteins as potential markers of system inflammation, Alzheimer’s, Although estimates vary, roughly 30 percent of the DNA in and diabetes. Proteins, along with RNA, are especially sensitive to whole saliva comes from bacteria in the mouth. New England Bio- degradation by enzymes and to different collection methods. Labs offers a kit for boosting microbial DNA (NEBNext Microbi- ome DNA Enrichment Kit) in samples collected for oral micro- HOW DO YOU COLLECT IT? biome studies. There’s no universal method for collecting saliva; it depends primarily on the age of the participant and your plans for analysis. But the way RNA. RNA holds promise for probing more than oral disease. that you collect saliva, both the sampling location in the mouth and David Wong and his team at the University of California, Los Ange- the time of day, can matter. “If there’s differences in collection [and les, have recovered extracellular RNA from saliva, linking certain processing] it will make it challenging to compare results across dif- of those RNAs to the presence of oral and other cancers. Wong’s ferent labs,” Wong says. That’s especially important if you are studying method for profiling salivary microRNAs, a type of noncoding RNA biomarkers that you hope will be clinically useful, he adds. in cell-free saliva, is available in Methods Mol Biol, 936:313-24, Passive drool (in which the participant allows saliva to collect 2013. Wong has developed a collection tool (for nucleic acids and on the floor of the mouth, then leans forward and dribbles into a proteins) called RNAPro•SAL, which is sold by Oasis Diagnostics. tube) is considered the gold standard of collection methods across It works by compressing an absorbent pad soaked in a proprietary different analytes. However, it requires compliance from patients medium to remove cells and other debris from the sample. Other and might even be difficult for some adults. researchers have developed methods for isolating RNA from the Researchers whose study subjects are preterm and newborn cells present in saliva (Clin Chem, 59:1118-22, 2013). babies collect saliva via suction, a normal procedure for a neona- Much of the RNA in saliva comes from microbes in the mouth. tologist, but one that is becoming more accessible to other clini- A study by Wong’s group found that an additional low-speed cen- cian researchers with the development of Pedia•SAL, a device that trifugation step, and boosting sequencing depth, helps minimize connects with a pacifier but that doesn’t require suction by the interference from microbial RNA (Clin Chem, 58:1314-21, 2012). infant to work, says Jill Maron, associate professor at Tufts Uni- versity School of Medicine. For older babies and toddlers, Sali- PEPTIDES AND PROTEINS. About 30 percent of proteins found in metrics makes tools for collection that work even when partici- DORLING KINDERSLEY/GETTY IMAGES DORLING KINDERSLEY/GETTY

58 THE SCIENTIST | the-scientist.com Many collection tools work by absorbing saliva. It’s crucial to HOW DO YOU PRESERVE IT? find out whether a given tool has been validated for your mol- Saliva contains enzymes that can rapidly degrade your analyte. ecule of interest. “We know that when you absorb a saliva sam- Some analytes, such as cortisol or melatonin, are more stable at ple through any kind of a foam or cotton product, you change room temperature than others. But in general, it’s a good idea to that sample’s integrity in ways that may or may not be known. chill saliva in the fridge immediately after collection, and “clean Depending on what you’re interested in testing, you may or may it up” before you freeze it, Slowey says. not be able to use that sample,” says Douglas Granger, director of The particulars of purification depend in part on whether your the Institute for Interdisciplinary Salivary Bioscience Research at molecule resides inside or outside of the cell, but there are com- Arizona State University and founder of Salimetrics. mercial extraction kits available for either option. For extracellu- In a 2013 study, for example, researchers compared protein pro- lar RNAs, researchers spin cells down and analyze or freeze only files of saliva collected using passive drool, paraffin gum, or a com- the supernatant. Researchers studying human DNA, on the other mercially available cotton swab. The total protein concentrations the hand, use the pellets of cells, lysing them and employing spin researchers obtained across the samples were similar; however, the columns that bind genomic DNA and allow the rest to wash off. protein profiles themselves were somewhat distinct, especially the Stabilizing buffers (sold by Norgen, Qiagen, and others) help profile of saliva collected via the swab (Clin Chim Acta, 419:42-46). neutralize enzymes that can degrade DNA and RNA. If you can’t It’s best to choose the commercial collection device carefully, and get samples to a freezer right away, then these reagents (such as to keep collection methods consistent across multicenter studies. Qiagen’s RNAprotect Saliva Reagent) can help. DNA Genotek’s Oragene family of kits for the collection of human DNA and RNA HOW DO YOU ENHANCE COLLECTION? in saliva contains preservatives that allow researchers to store The passive drool method usually produces enough sample, but if you samples at room temperature. need to stimulate saliva flow, a recent study of meat eaters shows that For those researchers interested in microbial DNA and RNA, the smell of microwaved bacon enhances saliva flow without interfer- DNA Genotek’s OMNIgene Discover kits for microbial DNA and ing with hormone concentrations (Clin Ther, 37:515-22, 2015). Besides a whiff of bacon, there are lozenges, mouth rinses, and Researchers are probing saliva for genes, chewing gums that you can use if you need to stimulate saliva pro- microRNAs, and protein markers associated duction. Make sure you have established that the method you’re interested in using for saliva stimulation doesn’t interfere with with a wide variety of diseases. your ability to detect your analyte of interest. Mouth rinses, for example, will dilute your sample, Malamud says. RNA (OM-505) or DNA only (OM-501) are also ideal for long- Also, be warned: “There’s a difference between nonstimulated term storage, notes David Speicher, a researcher at Griffith Uni- saliva, which is just spitting it in a cup or collecting it with a tool like versity in Queensland, Australia, who has studied extraction and ours, versus stimulated saliva,” Slowey says. Altering your flow rate storage methods. may change the concentration of certain analytes more than others. Proteins are the most labile of all the analytes, and DNA and RNA stabilizing solutions, many of which work by inhibit- HOW DO YOU ACCOUNT FOR DIFFERENCES ing enzymes, do not help preserve proteins. This is an active area IN FLOW RATES? of work, Speicher says. To solve the protein problem, Wong’s Besides the stimulation of saliva, many different factors (such as group has come up with a stabilizing solution that is pre-added to age, exercise, smoking habits, alcohol use, time of day, and overall RNAPro•SAL collection tubes (Anal Chim Acta, 722:63-69, 2012). oral health) affect the flow rates of saliva. Accounting for differences in individuals’ saliva flow rates can be important if you’re collect- HOW LONG CAN YOU FREEZE IT? ing quantitative data. Some researchers directly measure a person’s A –80 °C freezer can preserve saliva for a long time, but for a given saliva flow rate: the volume of saliva collected (measured using a analyte, the limits are untested. Recent evidence from Speicher sug- pipette) divided by the time it took to produce the amount. gests a note of caution: salivary DNA with no stabilizing solution, Another way to circumvent differences in flow rates is to use stored at –80° for 14 months with no freeze-thaw cycles, is partially or a device aimed at collecting a fixed amount of fluid. Vivek Shetty completely degraded (Diagn Microbiol Infect Dis, 82:120-27, 2015). at UCLA and his collaborators developed such a device, which As a general rule, aliquot your samples to minimize the freeze- collects 100 μL, and are selling it through the Japanese company thaw cycles. “We always suggest that samples are kept cold after Nanbu Irika for $10 per device (or $280 for 30 devices). they’re collected and that the cold chain is managed very thought- Internal controls are also important when you’re adjusting for fully until they can be frozen,” Granger says. differences in flow rates or variations in sample quality. Total pro- And if, after reading the many reviews now available on saliva tein concentration is one approach; a small panel of RNA markers collection and processing, you’re still lost, then pick up the phone is another. Check to see if anyone has measured your analyte of and call someone who’s been doing what you aim to do. “Most sci- interest, and whether there are any validated references. entists are more than happy to talk,” Malamud says. g

07.2015 | THE SCIENTIST 59 LAB TOOLS

Breaking Down Barriers

Finding and recruiting diverse populations for clinical studies

BY CARINA STORRS

urveys of clinical research tell a bleak tale about diversity in study populations. A review of cancer treatment trials Spublished between 2001 and 2010 reported that 80 percent of participants were white and 60 percent were male (Can- cer, 119:2956-63, 2013). Another survey found that less than 5 percent of NIH-funded studies of respiratory diseases in the last 20 years included minority (nonwhite) participants (Am J Respir Crit Care Med, 191:514-21, 2015). This lack of diversity means that many questions go unan- swered about the benefits and risks of drugs in minorities, women, and the elderly—groups that are typically underrepresented. What’s more, different ethnic groups have different propensities toward certain diseases—Hispanic people are more likely than whites to be diagnosed with diabetes, for example—making the study of treatments for these groups even more important. Enrolling the necessary clinical trial participants from any demographic can be a challenge (see “Clinical Matchmaker,” The Scientist, June 2015), but there are special barriers to recruiting underrepresented groups. Minority groups often harbor a general distrust of the medical community, dating back to the infamous Tuskegee syphilis trial with African Ameri- can men in the 1930s. Practicalities also stand in the way: time commitment and transportation to the study site can be particularly challenging for women and the elderly, respectively. CTRC is building a nationwide registry of patients and Researchers are becoming increasingly aware of this prob- healthy individuals interested in participating in clinical trials. lem, but “there is clearly a long way to go” to fix it, says Romana Prospective trial participants sign up through the I’m In web- Hasnain-Wynia, program director for addressing disparities at site, which was created by the NMQF and the Pharmaceutical the Patient-Centered Outcomes Research Institute (PCORI), Research and Manufacturers of America (PhRMA) to increase a nongovernmental organization that supports and commu- awareness about the importance of diversity in clinical trials. nicates research, including research on health disparities, to As of April 2015, the registry included about 200 volunteers, patients. On the bright side, however, “there are more tools and but NMQF is working to increase numbers with a website rede- resources for working with disparate populations than there signed for user-friendliness and by holding events to promote were even 10 years ago,” she says. awareness. One-time access to search the registry generally Here, The Scientist takes stock of resources that aim to help costs $250; ongoing access runs from $50,000 to $250,000, researchers increase diversity in clinical research. depending on the study budget. Researchers can use CTRC’s “Map Datasets” function to Finding study participants view the location of registered volunteers across the U.S. Each in the general population volunteer is represented by a purple dot; clicking on a dot opens A growing number of Web-based tools can help clinical a window with an individual’s nonidentifiable information: researchers connect with underrepresented groups. One exam- unique CTRC ID number, gender, race, zip code, and the medi- ple is the Clinical Trial Recruitment Center (CTRC), which cal condition(s) that she would like to help researchers study. is hosted by the Clinical Trial Engagement Network (CTEN). (A feature that allows searching by specific demographics is in CTEN is a set of tools for researchers that was launched in the works.) Investigators provide the ID numbers of volunteers March 2014 by the National Minority Quality Forum (NMQF), that fit their study to NMQF, and NMQF provides those volun- a nonprofit organization that aims to improve health care for teers with information about the trial and the option to enroll. ISTOCK.COM/MICHAELJUNG

60 THE SCIENTIST | the-scientist.com for other network users who may want to collaborate and who across the U.S. focusing on conditions ranging from arthritis to focus on underrepresented groups. Crohn’s disease to sleep apnea. Joe Selby, the executive director “We are helping the investigator understand the full land- of PCORI, encourages researchers to contact a network’s princi- scape of where patients are and where potential investigators pal investigator, listed on each network’s page, to inquire about might be found,” says Gary Puckrein, president and founder of working with its patients. Some networks, such as the one for NMQF. The map also displays hospitals that focus on minority muscular dystrophy, are already connecting researchers and populations, sites of other clinical trials, and the prevalence of patients, but all should be ready to offer this assistance by the certain medical conditions in each zip code. end of 2015. ResearchMatch is another tool that lets investigators working at member research institutions, of which there are cur- Broadening recruitment strategies rently 105, look through its registry of de-identified patients Patient registries can hook up investigators with people who and healthy individuals (Acad Med, 87:66-73, 2012). Research- already want to participate in clinical research. But these reg- ers working at one of these institutions can sign up using their istries do not always have enough participants in the right geo- institution name and institutional e-mail address. This allows graphical areas, so researchers end up having to do their own them to search the database for free by criteria such as age, race, and body mass index (BMI) range. ResearchMatch, which was developed at Vanderbilt University School of Medicine and A comprehensive model where researchers launched in 2009, has been used by more than 2,600 research- are actively involved in improving community ers and has signed up more than 77,000 volunteers inter- health can rebuild trust in black and Hispanic ested in participating in clinical studies or taking clinical sur- communities. veys. Research institutions must be not-for-profit to join the Stephen Thomas, ResearchMatch network. University of Maryland Center for Health Equity Beyond such networks, some academic medical centers allow outside researchers to query their de-identified electronic medical records for patients who fit a certain profile, includ- outreach to inspire interest in their study—not to mention in ing age, race, and disease. Tips on how to query these data- the notion of clinical research itself. bases are often available through clinical translational science Often, this involves creating recruitment materials such as offices. Many institutions have such offices, including all 62 flyers or other types of ads that are posted in hospitals, clinics, that are funded through NIH Clinical and Translational Sci- or elsewhere in the community. Thinking carefully about how ence Awards (CTSA). those materials are designed is key to encouraging enrollment of underrepresented groups and to overcoming barriers such as Connecting with specific disease groups distrust and concern about being treated fairly, says Consuelo Some disease groups work with researchers to help them con- Wilkins, executive director of the Meharry-Vanderbilt Alliance, nect with underrepresented patients. For example, the North which supports translational research at Vanderbilt University American Research Committee on Multiple Sclerosis (NAR- and Meharry Medical College. COMS), which was established in 1993, maintains the world’s In one case, Wilkins and her colleagues were able to boost largest registry of adults diagnosed with MS who provide vol- enrollment of African American women in a study by rede- untary information about their age, sex, race, and details about signing the recruitment flyer to include a photo of an African their disease. Researchers can apply for recruitment assistance American woman and colorful text blocks instead of a simple to have NARCOMS notify participants who meet demographic black-and-white layout (Clin Transl Sci, doi:10.1111/cts.12264, or other requirements for a study and solicit their participation. 2015). The language in the flyer or ad is also important; words The Cystic Fibrosis Foundation (CFF) also collects age, sex, such as “obese” and “qualify (for a study)” can have especially race, and other demographic and health data for people who negative connotations among minority groups. For example, have the disease. Investigators can apply for access to de-iden- Wilkins says that African American men did not respond to tified information about patients with particular demographics one particular study about prostate cancer because the flyer for observational studies, and can also connect with one of the prominently featured the word “profiling” (referring to genetic more than 110 CFF-accredited care centers to find patients who profiling), which some associated with racial profiling. Wilkins meet their study criteria. recommends that researchers ask members of their target com- In the last two years, PCORI has been supporting the cre- munity to look over recruitment materials to ensure the lan- ation of disease-specific patient groups, called Patient-Pow- guage is not insensitive. ered Research Networks (PPRNs), which help advance health Vanderbilt University’s Institute for Clinical and Transla- research by connecting members with clinical trials and com- tional Research developed an approach for getting this type municating health information. There are currently 18 PPRNs of feedback, called the Community Engagement Studio (Acad

07.2015 | THE SCIENTIST 61 LAB TOOLS African American Women Needed for Research Study

African American Women Needed for Research Study You can help with this important clinical study that will test if a drug improves blood sugar This study will look at how muscles absorb glucose (sugar) and how the body regulates your blood pressure. levels and blood pressure.

You may qualify if you: 1. Are an African American, and 2. Have high blood pressure or borderline high blood pressure, This study is conducted 3. Are overweight, and 4. Are between the ages of 18-60 years, and at Vanderbilt University Medical Center. 5. Have high triglycerides, high cholesterol, or high blood sugar, and 6. Do not smoke. You may qualify if you are : OOverwweigheight t Requires a screening visit, study medication, 3 This study will require a screening visit, four clinic visits, two AAgeg 18-60 years study days, study medications, and blood and urine collections. study days, and blood and urine collection. HavHaee borderline or high blood Participants will be compensated for their time. ppress ure Participants will be compensated. If you would like to learnGinnie more Farle abouty this study, contact HHighg cholesterol [email protected]. HHighg blood sugar levels Vanderbilt University AAndddo d onot smoke Date of IRB Approval: 7/6/2011

For more information PLEASE CALL 615-689-1033 (Davalynn Johnson) [email protected]

Date of IRB Approval: 8/10/2010

6/2/10 TRIAL BY FLYER: Customizing flyers for women and minority groups, such as by using wording and photos tailored to them, may enhance enrollment of these underrepresented groups in clinical research.

Med, in press). Researchers spearheading a particular study cates In-Reach and Research (HAIR), to offer people the hold a workshop for community stakeholders such as health- opportunity to participate in clinical studies. advocacy groups, members of neighborhood centers and Indeed, several studies have demonstrated that barber- churches, and patients to explain various aspects of the study shops and beauty salons can help recruit community mem- including recruitment strategies. This type of effort makes sense bers into studies, such as prostate cancer screening (Am J Prev for investigators or centers that are creating an ongoing research Med, 47:77-85, 2014). There is a “realization that barbershops program around a population, Wilkins says. She and her col- and beauty salons have been underutilized as trusted venues to leagues have developed an online toolkit to help researchers reach people,” Thomas says. implement this approach for their own studies. The center’s Maryland Community Research Advisory Many of the clinical research offices at CTSA-funded institu- Board (MD-CRAB) is made up of community members who tions also help researchers design their flyers and ads to ensure give feedback to researchers about recruitment strategies, study the language is appropriate and easy to understand. Some design, and other study aspects. Several other places have simi- offices, such as the University of North Carolina’s TraCS Insti- lar groups, such as the University of Pittsburgh and the Mayo tute, have templates that researchers can start with. Recruit- Clinic in Rochester, Minnesota. The Maryland Center for Health ment specialists in these offices also advise about the best Equity provides technical assistance to anyone interested in set- locations in the community for posting flyers or ads and help ting up a CRAB, Thomas says, adding that it is not difficult. researchers connect with outlets for posting. However, according to Stephen Thomas, director of the Funding research with a focus on diversity University of Maryland Center for Health Equity and a pro- PCORI can be a good source of funding for clinical studies that fessor in the university’s School of Public Health, this kind make an effort to include underrepresented groups. Although of marketing can only take researchers so far. “A comprehen- PCORI’s main focus is on research that compares outcomes sive model where researchers are actively involved in improv- between two clinically acceptable treatments, it also priori- ing community health can rebuild trust in black and Hispanic tizes research that could reduce health disparities. “You get a communities,” Thomas says. His center partners with health lot of points for focusing your questions on minority or other groups that regularly go into the community—for example, to underserved, understudied, or disparate communities,” says the center’s network of 11 barbershops in Maryland and DC— Selby, executive director of PCORI. Researchers can apply for where they offer basic health services such as blood pressure funding for individual studies through one of PCORI’s tar- screening, smoking cessation assistance, and health insurance geted announcements in specific study areas or through a broad registration help. Investigators who collaborate with the cen- announcement in an area the researchers propose. Funding

g ter work with this same network, known as the Health Advo- opportunities are available through at least 2018, Selby says. SHIBAO OF DR. CYNDYA COURTESY

62 THE SCIENTIST | the-scientist.com CAREERS

Staying Active in the Lab

Retiring as a professor, and even shutting down your own lab, doesn’t necessarily mean quitting research.

BY JENNY ROOD

ohn Dowling never did a postdoc. In what was a fairly typical career tran- Jsition in 1961, he went directly from Harvard graduate student to Harvard assistant professor, and, after a few institutional moves, eventually settled at the university as a full professor in 1971. (See “An Eye for Detail,” The Scientist, October 2014.) Now retired at the age of 79, the vision researcher plans to make up for skipping what has become a critical part of every new scientist’s career by joining the labs of his younger colleagues, neuroscientists Jef- frey Lichtman and Joshua Sanes, as a postdoctoral fellow. Dowling believes that older researchers can still be “quite creative and contribute substantially to the effort. . . . I always loved doing experiments and wanted to stay active the field.” Retirement has not been mandatory for professors in the U.S. since 1994, but many still choose to give up their teaching a goal he finally reached in the summer of CONTINUING TO MENTOR: Joseph Lambert, and administrative duties—and their sala- 2014, as he turned 79. Similarly, organic a retired researcher formerly of Northwestern ries—while continuing to spend time in the chemist Joseph Lambert, who retired five University, discusses research results with Alli- son Levy, an undergraduate student at Trinity lab. Some, like Dowling, choose to take a years ago after 45 years at Northwestern University, where Lambert continues research step down the academic ladder by pursu- University in Illinois, stopped taking new on a volunteer basis. ing post-retirement postdocs; others find graduate students five years before his themselves able to start or continue leading planned retirement age of 70. small labs. While doing research in retire- A second consideration is location. Knowing he wanted to move back to his ment is unconventional, options and sup- Many researchers, like Dowling, choose hometown of San Antonio, Texas, where he port systems for many professors contem- to stay at their own institution, and sim- had recently purchased his childhood home, plating their research future are out there ply move down the hall to the lab of a Lambert spent his final years at Northwest- and growing more plentiful. Some univer- colleague. Plant biochemist and pho- ern tailoring his research group to match a sities have even set up special associations tosynthesis expert Andre Jagendorf, hoped-for position at local Trinity University. for retired faculty members. Here, The Sci- who retired from Cornell University in He shifted his lab to one rich in undergrad- entist speaks with a handful of researchers 1996, didn’t even have to go that far: he uates and postdoctoral fellows to prepare entering retirement but not quite ready to remained in his own longtime labora- for a similar composition at Trinity, which walk away from science altogether. tory space as a member of Robert Tur- does not have graduate programs in chem- geon’s group, which moved in upon Jag- istry. He also changed his research focus Preparing for retirement endorf’s retirement. “The standard model from wet-lab chemistry to a less resource- For researchers who plan to retire, the first of retire, no longer teach, no longer draw intensive side project he’d been pursuing step is crafting an exit strategy. Dowling a salary is quite viable at your home insti- on and off since the 1970s: investigating the aimed to cut his lab in half by the time he tution,” Lambert says. “But moving to chemical properties of amber. Meanwhile,

UNIVERSITY, JENNIFER GOODRICH BALREIRA TRINITY UNIVERSITY, was 70, and at 75, to shut it down entirely— another place is a bit more unusual.” he and then Trinity chemistry department

07.2015 | THE SCIENTIST 63 CAREERS

chair Steven Bachrach negotiated with the One can do wonders when Johns Hopkins University in 2012 after 50 administration to set up a unique position you say, “Oh, by the way, years as a professor of biochemistry there. for Lambert: research professor of chem- I don’t want any money, Moreover, even those supported by their istry. The nonsalaried role doesn’t take up hosts’ funding can encounter problems all I need is an office.” lab space or take away a hiring position obtaining research materials, as employ- from a younger colleague, but it still allows —Joseph Lambert, Trinity University ees not specifically listed on grants some- Lambert to mentor students and conduct times cannot order their own supplies. research. He continues to publish three or has his own office,” Turgeon says of Jag- For this reason, Lambert negotiated his four articles a year on the nuclear magnetic endorf, who comes in five days a week to position at Trinity to be on the tenure track, resonance spectroscopy of amber, for exam- conduct his own research as well as help allowing him to apply for grants, such as ple, and has already written two books. “I’m out with washing dishes or running the one he has received from the Dreyfus Foun- a member of the Trinity staff, and I feel like high-performance liquid chromatography dation. (In two years, at age 77, he will be I’m contributing to their objectives,” he says. machine. “You can work in the lab and do up for tenure for the second time.) At Johns Nancy Mills, who retired this year from things you enjoy, but you’re not faced with Hopkins, Brand has another option: the the chemistry department at Trinity Uni- a lot of bureaucracy or teaching.” Johns Hopkins Academy. Established the versity, also knew she wanted to relocate It can also simplify the funding situa- year Brand retired, the academy provides after retirement, but she didn’t know where tion. Most late-career postdocs work on a retired Johns Hopkins faculty with access exactly. So she used her last sabbatical, in volunteer basis and don’t draw a salary, and to facilities, including offices if their home 2008, to work in Mike Haley’s group at the the same is true of Lambert, even though he departments don’t have space, and a few University of Oregon to test out the town is running his own group at Trinity. “One thousand dollars a year to enable them to of Eugene. She found it to be a good fit, so can do wonders when you say, ‘Oh, by the continue their research, travel to confer- Mills and her husband began planning their way, I don’t want any money,’” Lambert ences, and organize symposia. move, and Mills began strategizing how jokes. “All I need is an office.” “The academy is a win-win situa- she’d continue her research once outside the “It’s a lot easier,” agrees Jagendorf, who tion . . . both for the university and the comfort of her Trinity lab. While her work is also not paid. “I don’t have to write grant faculty,” says Brand, who in 2013 pub- had long relied on both computational and applications; I don’t have to worry about lished a paper on protein dynamics and wet-lab experiments, she realized that the salaries; just work.” latter would be hard to conduct after her For those in charge of their own proj- retirement, due to a lack of access to the ects, however, funding can be an issue. MILLS’S MILIEU: Nancy Mills brainstorms with members of her Trinity University lab necessary space and equipment. So she “The main problem is that the granting before retiring to Eugene, Oregon, where she started focusing her last years at Trinity on agencies don’t look kindly on old people,” remains active in research as a part of Mike experiments in the lab. “I began to take all says Ludwig Brand, 83, who retired from Haley’s group. the computational projects I was envision- ing and just put those on the back burner,” she says, saving them for her retirement. Then, as luck would have it, Haley got in touch to tell Mills that the computational scientists in his group had gradu- ated and to ask if she would be willing to fill that role. Mills jumped on the opportunity. Not only had she found a location for retirement, but her time in Haley’s lab ended up landing her a job. “The connections I made on sabbatical meshed nicely with my goals for retirement,” she says.

Finding funding One of the advantages of integrating into a younger faculty member’s lab—the retirement research approach taken by Jagen- dorf, Mills, and Dowling—is an ability to focus on the science. “He works more

or less like a postdoc would, except he DON HAMERMAN/TRINITY UNIVERSITY

64 THE SCIENTIST | the-scientist.com MASTER NAVIGATOR: Circa 1992, Johns Hop- kins University’s Ludwig Brand, now retired but still active in research, gives a sailing lesson FOLLOW to graduate student Martha Brown on Middle River, Maryland. THE SCIENTIST to the fact that most retired professors Engage in the broader conversation work on a volunteer basis, contributing to on our Facebook, Twitter, YouTube, and Pinterest sites. the output of a lab while not requiring a salary, the wisdom of the older lab member can be a real benefit to the group, says Turgeon. “[Jagendorf] just has a lot of insight,” he says. “He often has some pretty knowledgeable and inspirational things to say.” David Weiner, a pathologist at the University of Pennsylvania who hosted retired clinical dermatologist Henry Maguire as a full-time postdoc in his lab has a second in press with the academy’s from 1997 to 2011, couldn’t agree more. support. He also continues to serve on Earlier in his career, Maguire had worked graduate board exams, teach freshman with Martha Chase, one of the research- seminars, and work with students and ers who conducted the storied 1952 Her- young faculty. “One advantage of not shey-Chase experiment that helped con- writing grants is you have a little more firm DNA as the hereditary material of time to mentor,” Brand says. modern organisms. In retirement, Magu- A handful of other institutions, such ire’s expertise was an invaluable asset to as Emory University and Arizona State the group, Weiner says. “He always chal- University, have organizations known as lenged us: What is the importance of this “emeritus colleges” that provide intellec- work? What is the point of doing this? . . tual programs for retired faculty. While . He made things kind of slow down, took some institutions may provide offices you out of the rat race, and gave you time or small research grants, most are pri- to think about things in an elegant and marily focused on providing intellec- important way.” tual engagement for retired professors Maguire’s experiences were also an on a shoestring budget. Arizona State’s inspiration to the next generation of sci- emeritus college, for example, even runs entists, Weiner adds. He recalls a group an academic journal for its members. As of students gathered around the 80-year- of October 2013, there were eight emeri- old Maguire as he slowly and methodi- tus colleges or equivalent institutions at cally explained testing for delayed-type American universities, and their ranks hypersensitivity, a procedure he had first continue to grow. championed half a century earlier to study inflammatory responses and com- Finding the right fit pare in vivo immune reactions in the skin Although Mills is nervous about retirement to a visual readout. “They will always because it’s a “one-way path” and you can’t remember how they learned how to do “unretire,” she is excited that her future those experiments,” Weiner says. collaboration will continue to engage her When looking for a lab to retire to, mind. “It’s potentially a godsend to be able Lambert says it’s all about personalities. to work with Mike Haley’s group,” Mills “The most important thing is finding a says. “Intellectual stimulation is harder friendly environment.” when you work all by yourself.” “Labs are like families,” agrees Weiner. Retired researchers can also be a boon “Henry really contributed to that rich fabric

g OF LUDWIG BRAND OF LUDWIG COURTESY to the younger faculty hosts. In addition and made it so much more wonderful.” READING FRAMES

The War Rages On

Conflict between science and religion continues, with effects on health, politics, and the environment.

BY JERRY A. COYNE

he battle between science and reli- But while science and religion both gion is regularly declared over, claim to discern what’s true, only sci- Tended with an amicable truce. ence has a system for weeding out what’s Accommodationists on both sides assure false. In the end, that is the irreconcilable us that the disparate pursuits occupy non- conflict between them. Science is not overlapping spheres of inquiry (science just a career or a body of facts, but, more deals with the natural world; religion with important, a set of cognitive and practi- meaning, morals, and values). After all, cal tools designed to understand brute there are many religious scientists (two reality while overcoming the human notables are evangelical Christian Francis desire to believe what we like or find Collins, director of the National Institutes emotionally satisfying. The tools include of Health, and Brown University biologist observing nature, peer review, indepen- Kenneth Miller, an observant Catholic), so dent replication of results, and above Viking, May 2015 how can there be possibly be a conflict? all, the hegemony of doubt and critical- But despite these claims, the dust ity. The best characterization of science I hasn’t settled. Why do 55 percent of know came from physicist Richard Feyn- 50 US states, for instance, have codified Americans aver that “science and religion man: “The first principle is that you must legal protections for parents who harm are often in conflict”? Why are less than not fool yourself—and you are the easi- their sick children by rejecting science- 10 percent of all Americans agnostics or est person to fool. So you have to be very based medicine in favor of faith healing. atheists, yet that proportion rises to 62 careful about that.” Forty-eight of our 50 states allow reli- percent of all scientists at “elite” universi- In contrast, religion has no way to gious exemptions from vaccination. The ties, and to 93 percent among members adjudicate its truth claims, which rest results are predictable: children need- of the National Academy of Sciences? I on ancient scripture, revelation, dogma, lessly become sick, and some die. And consider these questions and more in my and above all, faith: belief without strong we in America are familiar with religious latest book, Faith vs. Fact: Why Science evidence. The problem, of course, is that incursion into the public sphere, such as and Religion Are Incompatible. faith is no way to decide what’s true. It is, the persistence of creationism in schools. My conclusion: the conflict between à la Feynman, an institutionalized way In the end, in both science and every- science and religion is deep, endemic, of fooling yourself. The toolkit of science day life, it’s always good policy to hold and unlikely to be resolved. For this con- is—and will remain—the only way to dis- your beliefs with a tenacity proportional flict is one between faith and fact—a bat- cover what’s real. Religion can offer com- to the evidence supporting them. That is tle in the long-fought war between ratio- munality and can buttress morality, but the foundation of science and the oppo- nality and superstition. has no purchase on truth. site of religion. As the philosopher Wal- The friction exists because science and But even if science and religion are ter Kauffman noted, “Belief without religion are both in the business of deter- incompatible, what’s the harm? Most evidence is not a virtue, but opens the mining what is true in the universe— of the damage comes from something floodgates to every form of superstition, although religion has other concerns as inherent in many faiths: proselytizing. prejudice, and madness.” g well. Science’s ambit is well known, but If you have a faith-based code of con- it’s important to realize that religion also duct attached to beliefs in absolute truths Jerry A. Coyne is a professor of ecology depends heavily on claims about what is and eternal rewards and punishments, and evolution at the University of Chi- true: claims about the existence, number, you’re tempted to impose those truths cago. His 2009 best-seller, Why Evolu- and nature of gods, what behavior one’s on others. The most obvious subjects tion Is True, was one of Newsweek’s “50 god commands, the occurrence of mira- are children, who are usually indoctri- Books for Our Time.” Read an excerpt of cles, and whether there are eternal souls, nated with their parents’ brand of faith. Faith vs. Fact: Why Science and Religion untrammeled free will, and afterlives. That can cause real physical harm: 43 of are Incompatible at the-scientist.com.

66 THE SCIENTIST | the-scientist.com CAPSULE REVIEWS

Stoned: according to New York University of just four letters, they don’t make for a A Doctor’s Case for Medical Marijuana neuroscientist Joseph LeDoux in his sexy history-of-science tale. Nonetheless, David Casarett new book, Anxious. understanding those processes is crucial Current, July 2015 By considering anxiety in tandem to putting the genetic code to work with its evolutionary partner, fear, in science, medicine, industry, and The science (or lack researchers and physicians can agriculture. Parrington’s book serves thereof) behind the use develop a better understanding of as a good primer on the subtlety and of medical marijuana is the conditions under which anxiety complexity of the genome, especially a hotly debated topic in stops being adaptive and starts being the human genome, new facets of which scientific circles these disruptive. By contextualizing anxiety emerge on a regular basis from labs days. As more states disorders in the study of conscious vs. around the world. legalize marijuana unconscious emotions in the human for therapeutic or recreational use, brain, LeDoux argues, science will Testosterone: it’s never been more urgent to fully glean crucial information about how to Sex, Power, and the Will to Win understand the health effects of the better treat the increasingly prevalent Joe Herbert drug, which the federal government malady. Meditation, deep-brain Oxford University Press, July 2015 still considers a compound that is stimulation, and gene therapy are all on devoid of any medicinal virtue. Such the table, according to the author. “For It is the best of hormones, is the quest that propels University therapy to have maximally beneficial it is the worst of hor- of Pennsylvania researcher/physician and persistent effects, it may well be mones. In Testosterone, David Casarett in Stoned. necessary to change both conscious and Cambridge University With a flair for narration, Casarett nonconscious memories that contribute neuroscientist Joe Her- seeks clarity on the issue of medical to distress,” LeDoux writes. bert leads a guided tour marijuana, traveling around the world through human evolu- to labs, clinics, and patients’ homes. The Deeper Genome: tion using the multifaceted hormone The author even experiments with Why There is More to the Human as his lens and vehicle. “Testosterone,” different marijuana-laced products Genome Than Meets the Eye he writes, “has only one function— using himself as subject. Although John Parrington to enable a male to reproduce.” But in Casarett clearly favors the use of Oxford University Press, July 2015 humans (and other animals), the potent medical marijuana, Stoned gives chemical exerts its effect all over male a reasonably balanced account of By now everyone knows bodies, including brains. The fuel for the benefits and risks of marijuana the tale of how Watson antler growth, aggression, and inven- as far as research has been able to and Crick, Franklin and tiveness, testosterone plays a crucial role determine. Uplifting and heartrending Wilkins worked together in mammalian reproduction, was cen- in turns, the book stays in a narrative (or not) to discover the tral to early human evolution, and con- groove that makes reading it as structure of DNA. The tinues to shape the social landscape of pleasurable as it is informative and more contemporary today’s world. thought-provoking. story of the race to sequence the human Lest his perspective on testosterone genome is equally familiar. But these be deemed too male-centric, Herbert Anxious: Using the Brain to Under- days, a new story about the genome is explains that the chemical’s effects reach stand and Treat Fear and Anxiety emerging: a more complicated one about far outside the male body. “The tendrils Joseph LeDoux how the genetic code is controlled. In of its powerful actions creep into much Viking, July 2015 The Deeper Genome Oxford University of what we do,” he writes. “By ‘we’ I do researcher John Parrington gives a nice not simply mean men: the dramatic, Anxiety is on the rise. overview of the regulatory elements, but often unrecognized, influence it Nearly 20 percent of RNA varieties, and epigenetic changes has on men is reflected in . . . the lives Americans experience that play crucial roles in translating of women. Testosterone has important some form of anxiety genetic information into palpable, roles in women, too, . . . though these disorder. And the key biological material and behaviors. are less often recognized than those in to understanding and Because these insights represent a men, and thus on another dimension of stemming the modern steadily building body of knowledge that the formation and structure of the world tide of agita may lie deep in the continues to uncover complexities buried we all live in.” very brains from which it emanates, deep within a deceptively simple string —Bob Grant

07.2015 | THE SCIENTIST 67 Cell Sorter S3e™ Measure Autophagic Flux Using Cyto-ID® ® ® • Incorporates the fluorescence wavelengths and Lyso-ID with ImageStream X Mark II commonly used by immunologists Guide (488/640 nm) • Offers a hands-free startup sequence that automatically aligns the stream to optics and optimizes the droplet/side stream The • Ability to prevent tubes from running dry or overfilling ensures that precious sample is never lost • Allows scientists to use one or two lasers and up to four detectors to sort two defined populations simultaneously

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68 THE SCIENTIST | the-scientist.com The

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07.2015 | THE SCIENTIST 69 SURVEYTAKE NOW! THE

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Half Mile Down, 1934 BY JENNY ROOD

n August 15, 1934, two tall, lanky men squeezed through the tiny Ohatch of a 57-inch-wide steel ball that was then dropped into the deep sea off the coast of Bermuda. Naturalist William Beebe and the orb’s inventor, Otis Bar- ton, were already familiar with the damp, uncomfortable quarters inside the sphere. Despite the danger of being suspended by a single cable, Beebe and Barton had made numerous dives during the previous four years observing marine life and mapping the contours of the underwater volcano beneath the islands from inside the capsule. On that summer day, however, the two would descend 3,028 feet, deeper than any human had been before or would be again for nearly 30 years. In a 1926 article in The New York Times, Beebe, a noted American ornithologist- turned-marine biologist had outlined his wish to go deeper than the 60 feet his diving suit would allow. In response, Bar- ton, an engineer studying natural history in graduate school at Columbia Univer- sity, designed the bathysphere to protect against the high pressure of the ocean depths. By the 1930 summer research season, the 5,400-pound sphere made of inch- and-a-half-thick steel was ready for its inaugural dive. The first manned descent WCS. lasted 15 minutes and only reached 45 and flew through life with a pair of flap- BEEBE IN THE BATHYSPHERE: Naturalist feet below the surface, but after testing ping, fleshy wings.” Beebe’s vivid descrip- William Beebe peers out of the access hatch unmanned descents to greater depths and tions inspired underwater explorers like of the bathysphere, a metal capsule he used to probe the contours of the ancient volcano under working out some kinks, Beebe and Barton Jacques Cousteau for decades to come, says Bermuda and to study how light and marine life progressed to depths of a quarter of a mile. Beebe biographer Carol Grant Gould. changed at ocean depths previously inaccessible On September 22, 1932, Beebe con- These days, visitors can see the bril- to human explorers. “There’s an amazing sense ducted the first-ever international live liant blue bathysphere, which belongs to of wonder and awe when he’s looking through broadcast from the U.S., speaking to radio the Wildlife Conservation Society, the suc- the bathysphere window,” says Carol Grant Gould, author of a biography of William Beebe. listeners from the bathysphere 2,200 cessor of the New York Zoological Society “He never, ever lost that.” feet down. Peering out of a single three- that funded Beebe’s first expeditions, at inch-thick window of fused quartz, Beebe the entrance to the New York Aquarium, described the strange, unknown life- where it was placed last year in honor of in terms of . . . deepening our realization forms he saw. In Half Mile Down, his book the 80th anniversary of Beebe and Bar- of how diverse and odd a lot of that life describing the bathysphere’s journeys, he ton’s record-setting dive. was,” says the Aquarium’s vice president wrote of siphonophores “lovely as the finest “His meticulous and careful descrip- and director Jon Dohlin. “The idea of tak- lace” and “pteropods, or flying snails, each tions and the illustrations that came out ing the bathysphere down a half mile . . .

 of which lived within a delicate, tissue shell, of those descriptions were really valuable was so far ahead of its time.” © SOCIETY ARCHIVES. IMAGE WILDLIFE CONSERVATION COURTESY

72 THE SCIENTIST | the-scientist.com ®

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