ISSUE No.2 April-May 2020

Health& Plus MEDICAL RESEARCH Medicine IN THE TWITTER AGE RESULTS FROM THE FIRST CRISPR CLINICAL TRIALS

FOODS THAT FIGHT ALZHEIMER’S Anatomy of an Outbreak The new coronavirus raises questions about how pathogens evolve—and if

we’re ready to face them WITH COVERAGE FROM FROM THE Health& EDITOR Medicine

Your Opinion Matters! Help shape the future of this digital magazine. Let us know what you think of the stories within these pages by emailing us: [email protected]. LIZ TORMES Warfare in Wonderland In Lewis Carroll’s Through the Looking-Glass, the Red Queen tells Alice that “it takes all the running you can do, to keep in the same place.” This passage inspired the name of one of the principal concepts of evolution: in its broadest sense, the Red Queen hypothesis describes the evolutionary arms race between two species—say, predator and prey—who evolve side by side in response to each other, both vying for survival by adapting to the pressure of coexis- tence. In the past several weeks of covering the new global coronavirus outbreak, the Red Queen has certainly been running around my mind. Whenever a new virus emerges in the human species, scientists rush to quickly understand its unique structure and, hopefully, devise a vaccine to counteract, or at least contain, it. In this issue’s cover story, Simon Makin describes what researchers know so far about the structure of coronaviruses and what tools we may have to disable them (see “How Coronaviruses Cause Infection—from Colds to Deadly Pneumonia”). As case num- bers pile up in this country and others, epidemiologists must work swiftly. As the queen says: “If you want to get somewhere else, you must run at least twice as fast.”

Elsewhere Nicole Wetsman reports on how social media offers doctors and researchers a new way to share their research findings (see “How Twitter Is Changing Medical Research”). And Heidi Ledford updates readers on the progress of clinical applications of the CRISPR-Cas9 gene-editing complex, some of which are inching closer to real disease treatments (see “Quest to Use CRISPR against Disease Gains Ground”). Curiouser and curiouser. On the Cover The new coronavirus raises Andrea Gawrylewski questions about how pathogens Collections Editor evolve—and if we’re ready

[email protected] to face them GETTY IMAGES

2 April-May 2020 WHAT’S Volume 2 • Number 2 INSIDE OPINION 24. Novel Coronavirus Is a Reminder: The Best Defense against a New Viral Outbreak Is Early Detection Infectious disease surveillance networks already exist, but they can be highly porous 27. Doctors and Suicide The rate among students, residents and physicians GETTY IMAGES GETTY IMAGES is significantly higher NEWS FEATURES than the average—but 4. 8. 10. 14. so-called wellness Bacteria “Tolerant” Are Human Body Invisible Ink Could How Coronaviruses Cause Infection— initiatives can help of One Antibiotic Temperatures Reveal Whether from Colds to Deadly Pneumonia 29. Are More Likely to Cooling Down? Kids Have Been The outbreak of a novel coronavirus raises Calling an Illness Develop Resistance A new study finds that Vaccinated questions about how such pathogens evolve and “Psychosomatic” Even combination they have dropped The technology embeds what makes infections mild or severe Doesn’t Mean therapies do not prevent on average over the immunization records 17. It’s Imaginary such pathogens from past century and a half into a child’s skin How Twitter Is Changing Medical Research Recent experiments becoming resistant 6. From online journal clubs to “tweetorials” to have begun mapping Virus Spread by 9. conference updates, social media is changing the neuronal connections What’s in Kale Shrews Linked the dissemination and discussion of biomedicine between mind and body (or a Pear) That to Human Deaths 21. like never before from Mysterious Seems to Lower Quest to Use CRISPR against Brain Infections Alzheimer’s Risk? Disease Gains Ground The pathogen has been Particular antioxidants As the first clinical trial results trickle in, newly identified in eight in fruits and vegetables researchers look ahead to more sophisticated cases of encephalitis in may lower chances medical applications for genome editing Germany over the past of getting the disease 20 years

3 NEWS Vaccinated The technology embeds immuniza world, and even in many developed world, andeveninmany developed Keeping trackofvaccinationsremains tion records into achild’s skin a major challenge in the developing a majorchallengein thedeveloping countries paperwork gets lost and countries paperwork getslost and Kids HaveKids Been Invisible Could Ink Reveal Whether Reveal Whether

- five years, according to tests on pig five years, accordingtotests onpig would be injected with a bit of dye that would beinjectedwithabitofdyethat way toaddressthisproblem:embed- ter combined with an app that shines ter combinedwithan appthatshines up todate.NowagroupofMassa- ily seenwithaspecial cell-phonefil- is invisibletothenakedeyebuteas- parents forget whether their child is parents forgetwhethertheirchildis near-infrared light onto the skin. The near-infrared lightonto theskin.The researchers hasdevelopedanovel dye would be expected to last up to dye wouldbeexpected tolastup ding therecorddirectlyintoskin. chusetts InstituteofTechnology Along with the vaccine, a child Along withthevaccine,achild where medical records may not be where medicalrecords maynotbe the study, publishedlastDecember vide quickandeasyaccesstovacci- in mation directly associated with a mation directly associatedwith a risk of the procedure, according to risk oftheprocedure,accordingto nation history, avoidtheriskofcleri- been testedinchildren—wouldpro- as complete or as accessible, there as completeoraccessible, there and ratskinhumaninadish. can bevalueinhaving medicalinfor- cal errors and add little to the cost or cal errorsandaddlittletothecostor “Especially in developing countries “Especially indeveloping countries The system—which has not yet The system—whichhasnotyet Science Translational Medicine. think, is a pretty interesting “This, I think,isaprettyinteresting Jaklenec and their colleagues, uses a Jaklenec and theircolleagues, usesa way toaccomplish those goals.” Institute ofTechnology, whowasnot involved inthenewstudy. Sucha bioengineers Robert Langer and Ana bioengineers Robert LangerandAna health informationisbeingrecorded mation mustbeextremelydiscreet system ofrecordingmedicalinfor- person,” saysMarkPrausnitz,abio- and tohisorherfamily, hesays. and acceptabletothepersonwhose engineering professor at the Georgia engineering professorattheGeorgia The research,conducted byM.I.T. vaccine, byamicroneedlepatch.The under theskin,usingaquantumdot dye, whichisinvisibletothenaked M.I.T. engineershavedevelopeda dye thatisdelivered,alongwitha way tostoremedicalinformation specially adaptedsmartphone. eye, canbereadlaterusinga 4 SECOND BAY STUDIOS NEWS

A close-up microscope image of the microneedle array, which could deliver quantum dots into skin (left). The quantum dots after being administered in the skin of rodents (right).

been vaccinated and who had not, Jaklenec says. “But obviously we didn’t want to give people a scar,” she says, noting that her team was look- ing for an identifier that would be invisible to the naked eye. The researchers also wanted to avoid technologies that would raise even more privacy concerns, such as iris scans and databases with names and identifiable data, she says. The work was funded by the Bill & Melinda Gates Foundation and came patch of tiny needles called micronee- came in the project,” Jaklenec says, ter for Drug Design, Development about because of a direct request dles to provide an effective vaccina- adding that the team tested a num- and Delivery. “There may be other from Microsoft founder and philan- tion without a teeth-clenching jab. ber of off-the-shelf dyes that could concerns that patients have about thropist Bill Gates himself, who has Microneedles are embedded in a be used in the body but did not find being ‘tattooed,’ carrying around per- been supporting efforts to wipe out Band-Aid-like device that is placed on any that endured when exposed to sonal medical information on their diseases such as polio and measles the skin; a skilled nurse or technician sunlight. The team ended up using a bodies or other aspects of this unfa- across the world, Jaklenec says. “If is not required. Vaccines delivered technology called quantum dots, tiny miliar approach to storing medical we don’t have good data, it’s really dif- with microneedles also may not need semiconducting crystals that reflect records,” he says. “Different people ficult to eradicate disease,” she says. to be refrigerated, reducing both the light, which were originally devel- and different cultures will probably The researchers hope to add more cost and the difficulty of delivery, oped to label cells during research. feel differently about having an invis- detailed information to the dots, such Langer and Jaklenec say. The dye has been shown to be safe ible medical tattoo.” as the date of vaccination. Along Delivering the dye required the in humans. When people were still vaccinated with them, the team eventually wants researchers to find something that The approach raises some privacy for smallpox, which has since been to inject sensors that could also was safe and that would last long concerns, says Prausnitz, who eradicated worldwide, they got a visi- potentially be used to track aspects enough to be useful. “That’s really helped invent microneedle technol- ble scar on their arm from the shot of health such as insulin levels in dia-

the biggest challenge that we over- ogy and directs Georgia Tech’s Cen- that made it easy to identify who had betics, Jaklenec says. K.J. MCHUGH ET (2019) AL., MEDICINE TRANSLATIONAL SCIENCE

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This approach is likely to be one of many trying to solve the problem Virus Spread by of storing individuals’ medical infor- mation, says Ruchit Nagar, a fourth- Shrews Linked to year student at Harvard Medical Human Deaths from School, who also was not involved in Mysterious Brain the new study. He runs a company Infections called Khushi Baby that is also try- ing to create a system for tracking The pathogen has been newly identified in eight cases of such information, including vaccina- encephalitis in Germany over tion history, in the developing world. the past 20 years Working in the northern Indian state of Rajasthan, Nagar and his team have devised a necklace, Borna disease virus 1 (BoDV-1) resembling one worn locally, that causes a bizarre and deadly neuro- compresses, encrypts and pass- logical infection in horses, sheep word-protects medical information. and other domesticated mammals in The necklace uses the same tech- parts of Germany, Switzerland, Liech- Bicolored white-toothed shrew in its natural environment nology as radio-frequency identifica- tenstein and Austria. Borna disease tion (RFID) chips—such as those was named after a city in eastern which can live in hay and secrete or be present in people with psychiatric employed in retail clothing and ath- Germany where it once killed excrete fluids containing the virus. disorders such as depression, schizo- letes’ race bibs—and provides health numerous horses in the late 19th About 14 years ago researchers phrenia and bipolar disorder. It was care workers with access to a moth- century. Infected animals have been identified the bicolored white-toothed later shown, however, that the viral er’s pregnancy history, her child’s known to engage in strange behav- shrew as a reservoir host—an organ- RNA sequences detected in these growth chart and vaccination history, iors such as smashing their heads ism in which a virus replicates but studies were likely the result of labo- and suggestions on what vaccina- into things and “pipe smoking”—an does not usually cause illness—for ratory contamination, and research tions and other treatments may be informal term for when animals are BoDV-1. Horses and sheep are con- on human infections subsided. needed, he says. But Nagar acknowl- eating hay and suddenly stop chew- sidered “dead-end hosts” that cannot But in 2015 a related type of bor- edges the possible concerns all such ing mid-mouthful, with the uneaten spread the pathogen. For decades, navirus found in exotic squirrels was technology poses. “Messaging and portion protruding like a pipe. But scientists had debated whether the implicated in at least four human cultural appropriateness need to be the disease does not appear to virus is zoonotic, or capable of jump- deaths. Then, between 2018 and considered,” he says. spread between horses; they are ing from animals to humans. Several 2019, scientists detected the classi-

—Karen Weintraub thought to acquire it from shrews, studies even suggested that it might cal bornavirus, BoDV-1, in five peo- GETTY IMAGES

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ple in Germany who suffered serious state of Bavaria between 1999 and them to their owners. Beer and his part of the group that discovered or fatal encephalitis (brain inflamma- 2019. The samples were tested for team hypothesize that the patients shrews were a reservoir host for the tion caused by infection)—three of genetic material from BoDV-1, which were exposed to BoDV-1 this way or virus. “This Borna disease is really whom were recipients of organ the researchers verified by additional perhaps by inhaling dust containing a strange disease—it’s not like a flu,” transplants and were taking drugs to testing for antibodies to it. Seven out dried shrew urine. Future research will he adds, noting that it does not suppress their immune system. Now, of nine patients who died of enceph- be needed to determine the exact cause epidemics. “It’s a single-ani- in a study published in January in alitis of unknown cause at one diag- infection route, he says. mal disease, and it seems to be the Lancet Infectious Diseases, nostic center later tested positive for Once in a human or horse host, the same in humans.” researchers have reported eight addi- the virus (one of these cases had virus is thought to cross the blood- The virus itself is somewhat tional cases of BoDV-1 infection in been reported previously). An addi- brain barrier into the central nervous unusual in that it has a very short humans who died of encephalitis. The tional two cases with positive tests system, where it triggers the host’s genome and makes only a few pro- pathogen appears to have flown were also included in the analysis. immune system to attack brain tissue. teins. It does not seem to infect under the radar for decades, but the The results confirmed that the “It’s not the virus killing the brain cell or many individuals—but when it does, researchers say doctors should be virus had caused eight new enceph- nerve tissue,” Beer explains. “It’s the it kills them very efficiently. Numer- considering it a potential cause in alitis cases; two of the patients were [host’s] own immune system recog- ous other zoonotic viruses infect such deaths. immune-compromised individuals nizing the infection and starting to kill many people but are seldom deadly. “We now have eight more cases, who had received organ transplants, parts of brain.” Previous research has found that and these provide additional material and six were not. Because other There is no known treatment for humans and most mammals actually for a better understanding of the dis- recipients of organs from the same the disease, but researchers are have bornavirus sequences in their ease,” says Martin Beer, head of the donor did not test positive for the exploring whether antivirals such as genomes, which may help organisms Institute of Diagnostic Virology at virus, researchers think the transplant ribavirin—which has been shown to protect themselves against infection, the Friedrich Loeffler Institute in recipients who died from the virus kill a range of bornaviruses in cells some hypothesize. Germany, who was co-senior author probably acquired it because they grown in a dish and in animal stud- Fortunately, the virus does not of the new study and also was part were immune-compromised, not from ies—could be effective in treating appear to be transmitted between of the team that reported the squir- the donor. The patients suffered BoDV-1 infections in humans. Beer humans. “I think we are all happy rel bornavirus infections. The find- symptoms including headache, fever and his colleagues have plans to that this is not a virus that can ings confirm that the virus can infect and confusion that later progressed test newer antivirals against the virus spread easily,” Beer says. But in light humans and cause deadly encepha- to coma and ultimately death. in animal studies. of these new findings, doctors litis. “But the risk is, to our opinion, All of the patients lived in rural “I think it’s an excellent paper,” should consider BoDV-1 as a possi- pretty low,” Beer says. areas and worked or spent a lot of says Norbert Nowotny, a professor ble cause of encephalitis in areas Beer and his colleagues analyzed time outside. Most had also been of virology at the University of Veter- where it has been known to infect postmortem brain tissue from 56 around cats, which are known to inary Medicine, Vienna, who was not humans and horses. patients in southeastern Germany’s catch shrews and sometimes pre­sent involved in the new study but was —Tanya Lewis

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Colored transmission electron micrograph of a deadly cluster of methicillin-resistant Staphylococcus aureus (MRSA) bacteria. own patients are [probably] going to Bacteria “Tolerant” be treatable,” Laxminarayan says, although the killing action of the anti- of One Antibiotic biotic may kick in more slowly. “It’s Are More Likely to really a public health problem, not a Develop Resistance clinical problem” for a single patient. Even combination therapies “We agree that judicious use and do not prevent such pathogens proper antimicrobial stewardship is from becoming resistant critical to preserving the longevity of our antibiotics,” say Andrew Berti, an assistant professor at Wayne State One way to address the growing University’s Eugene Applebaum Col- problem of antibiotic resistance has lege of Pharmacy and Health Sci- been to use multiple drugs. Give ences, and Elizabeth Hirsch, an assis- patients two antibiotics, the thinking tant professor at the University of goes, and even if the microbes are Minnesota’s College of Pharmacy. resistant to one of them, the other Neither Berti nor Hirsch was involved will work. But a new study suggests in the study, but they co-wrote a that drug combinations can actually related Perspectives piece in the speed the development of resistance. same issue of Science. “However,” In a paper published in January in they say, “in the absence of a rapid, Science, Israeli researchers showed ence of an antibiotic. But this was in Washington, D.C., who was not validated means to determine antibi- that when a patient develops toler- the first study to demonstrate the involved in the work. “Our entire otic tolerance, we continue to see a ance to a single antibiotic in a combi- process in people, according to its approach to antibiotics is going to clear role for combination antibiotic nation—meaning it kills bacteria senior author Nathalie Balaban, a have to be rethought,” says Laxmina- therapy in cases of documented more slowly—outright resistance to biophysicist at the Hebrew University rayan, who is also a senior research staphylococcal infection, [where such] the second drug becomes more likely. of Jerusalem. scholar at Princeton University. “We combinations maintain their ability to Previous work by the same team and The study, although small, reveals can’t do this ‘give to everybody and suppress resistance development others had already shown the same a major threat to the way doctors kumbaya’ [approach], which is what against typical, nontolerant bacteria.” effect in a lab dish: they found that currently think about combination we’re following now.” Every year in the U.S. more than slowing the killing rate can lead to antibiotics, says Ramanan Laxmina- Clinicians tend not to focus on tol- 35,000 people die, and more than resistance such that the bacteria rayan, director of the Center for Dis- erance, because it may not have 2.8 million get sick, from antibiot-

continue to grow even in the pres- ease Dynamics, Economics & Policy much impact in the short term. “Their ic-resistant infections, according to GETTY IMAGESKARI LOUNATMAA

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the U.S. Centers for Disease Control mycin was not any more effective Balaban says the same evolution- and Prevention. The challenge is than the single agent. ary processes involved in the devel- What’s in Kale that tolerance cannot be measured The researchers also showed that opment of antibiotic tolerance and in the clinic, so doctors cannot tell such resistance develops in some resistance are likely to be at play in (or a Pear) That whether a patient has developed it. other dangerous bacteria and with cancer as well and might be used to Seems to Lower This will not make much difference other antibiotic combinations. They inform treatment. Tumor cells might Alzheimer’s Risk? in an otherwise healthy person next plan to study whether the effect become tolerant of chemotherapy Particular antioxidants in fruits who just needs a little help to fight occurs in more types of bacteria, Bal- first and then develop resistance and vegetables may lower chances off an infection, Balaban says. But aban says, and to examine antibiotic that spreads to other drugs. She of getting the disease it could be life-threatening in an combinations that could effectively does not plan to conduct such already weakened patient with treat life-threatening infections with- research herself, however. a blood infection. out promoting resistance. The new study points to the need A number of studies in recent years Balaban and her colleagues at the Theoretically, the second drug in for a laboratory test to detect whether have shown that clean living—exer- Hebrew University of Jerusalem and a combination is expected to kill any the bacteria infecting a patient are cise, sleep, a Mediterranean diet—low- Shaare Zedek Medical Center in of the microbes left alive by the first tolerant of the planned antibiotic ers one’s prospect of being diagnosed Israel looked at the evolution of antibiotic. But the new study demon- treatment before starting therapy, with Alzheimer’s. Some of these rec- potentially deadly methicillin-resis- strated that when a patient is already says Bruce Levin, a biology professor ommendations sound a little like a tant Staphylococcus aureus (MRSA) tolerant to the first drug, adding a at Emory University. Levin, an evolu- parent’s entreaty to a child to eat the in two patients with blood infections second one spurs resistance by pro- tionary biologist who studies infec- daily apple or finish broccoli left on a that lasted for more than two weeks moting the reproduction of bacteria tious disease and drug treatment plate. What does it really mean, even though they were on antibiot- that were not killed immediately. and was not involved in the study, though, to say that eating greens or ics. One patient was first put on the As a patient’s serum level of anti- adds that he was intrigued and berries diminishes risk? How much antibiotic vancomycin. After four biotic drops between daily doses, the impressed by the results. The ques- do such changes lower your chances days rifampicin was added to that bacteria that “went to sleep” in the tion is, he says, “Will this study serve of Alzheimer’s? And which specific person’s regimen. Then, from day presence of the drug can reawaken as a warning, [and] will people chemicals help to ward off the most eight to day 14, vancomycin was and reproduce enough to evolve re­ respond to it? Or will it be just common type of dementia? replaced with daptomycin. sistance, Berti says. Hirsch says the another academic exercise?” A study by researchers at Rush When the team tested bacteria new study’s major contribution was Editor’s Note (1/13/20): This arti- University Medical Center, published taken from the patient, the microbes finding in patients what had already cle was updated to include addi- in January in Neurology, tries to pin that had developed tolerance been seen in the lab. Berti agrees: tional comments from Andrew Berti down some specifics—and in doing against vancomycin were also killed “It’s been assumed for a long time,” and Elizabeth Hirsch on the use so, it demonstrates the benefits of more slowly by daptomycin. And the he says. “This is the first time it’s of combination antibiotic therapy. using dietary measures to stay cog- combination of rifampicin and dapto- been shown” definitively in patients. —Karen Weintraub nitively intact. The team took 921

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participants without dementia from olive oil, wine and tomato sauce— Rush's Memory and Aging Project, achieved a 38 percent risk reduction a large ongoing study that began compared with members in the low- more than 20 years ago. The recruits, est quintile. Kale, beans, tea, spinach who had a mean age of 81, were and broccoli were the sources of the tracked for an average of six years. most kaempferol, which furnished a Study members who followed a 51 percent drop in risk. Tea, wine, kale, regimen with the highest flavonol oranges and tomatoes provided lots levels—the top fifth—had a 48 per- of myricetin, along with a 38 percent cent lower risk of receiving an Alz- lower Alzheimer’s incidence. Toma- heimer’s diagnosis than those in the toes, kale, apples and tea are loaded bottom quintile. (Flavonols are a with quercetin, but no health benefit class of antioxidant and anti-inflam- was registered for that flavonol. matory molecules found in foods.) As The biochemical composition of the study progressed, 28 people in flavonols (part of a larger antioxidant the top flavanol group of 186 study class known as flavonoids) appears members, or 15 percent, went on to to enable them to quell inflammation an overall healthy diet.” and well educated, and three quarters develop Alzheimer’s. Meanwhile 54 and to scavenge free radicals in the Also, getting your kaempferol from were women. of the 182 participants in the lowest blood and the gut to help prevent kale may be better than searching The senior author of the study was quintile, or 30 percent, received such cellular damage. “This study adds online for a supplement that contains Martha Clare Morris, who developed a a diagnosis. The study’s takeaway is to our understanding of which ele- the molecule. “There’s a multitude of diet called the Mediterranean–DASH that “a healthy diet that contains vari- ments of a healthy diet may be vitamins, minerals, and bioactive sub- (Dietary Approaches to Stop Hyper- ous fruits and vegetables is critical important in reducing dementia risk,” stances in individual foods that you tension) Intervention for Neurodegen- for continued health—but especially says Keith Fargo, director of scien- may not get if you’re taking multiple erative Delay, or MIND, which has brain health,” says Thomas M. Hol- tific programs and outreach at the supplements,” Holland says. been linked to lower Alzheimer’s risk. land of Rush, who led the research. Alzheimer’s Association, who was The Neurology study did not include Morris is now heading an effort to do In the paper, the researchers dug not involved in the new paper. “At a control group, so it was not able to a randomized controlled trial to con- deeper into the issue, analyzing the this point,” he adds, “people should establish a cause-and-effect relation- firm, with hard evidence, whether this risk reduction for the four flavonols not put too much stock in specific ship between dietary patterns and diet really does serve as a preventive surveyed: isorhamnetin, kaempferol, nutrients—including subsets of lowered risk. Future investigations measure. When the results are in, it myricetin and quercetin. People in flavonols—for reducing dementia also need to look at a more diverse might actually be possible to counter the top quintile who ingested the risk until more research is done. group. Most of the new paper’s partic- jokes about kale with real data.

most isorhamnetin-rich foods—pears, Rather they should focus on eating ipants were highly motivated, white —Gary Stix RON LEVINE GETTY IMAGES

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temperatures that make it unneces- Are Human Body sary to rev up the metabolic system to stay warm or to cool off, she says. Temperatures That perpetually 72-degree-F office Cooling Down? may feel cold to some, but it does A new study finds that they have not stress out the human body the dropped on average over the past way it would to spend the night in century and a half a 40-degree-F cave. It is unclear whether those who live closer to the way people did in the 1800s—with It is one of those facts of life that we more infection or less climate con- learn early and don’t forget: normal trol—have higher body temperatures. body temperature is 98.6 degrees Research on the Tsimané, indige- Fahrenheit. But a new study in eLife nous people who live in lowland argues that that number is outdated. Bolivia, suggests that infections can The figure was probably accurate in boost average body temperature. A 1851, when German doctor Carl Rein- 2016 paper showed that responses hold August Wunderlich found it to be to infection accounted for about the average armpit temperature of and women of 97.5 degrees F. the cause of the apparent tempera- 10 percent of resting metabolism in 25,000 patients. Times have changed, The study suggests that in the ture drop, but Parsonnet thinks it that population and that lower metab- though, according to the recent paper: process of altering our surroundings, could be a combination of factors, olism was associated with slightly the average American now seems to we have also altered ourselves, says including warmer clothing, indoor lower body temperature, says Michael run more than a degree F lower. senior author Julie Parsonnet of temperature controls, a more seden- Gurven, an anthropologist at the Uni- Stanford University researchers Stanford. “We’ve changed in height, tary way of life and—perhaps most versity of California, Santa Barbara, looked at data from Civil War sol- weight—and we’re colder,” she says. significantly—a decline in infectious who conducted that study but was diers and veterans and from two “I don’t really know what [the new diseases. She notes that people not involved in the new one. Yet even more recent cohorts to confirm that measurements] mean in terms of today are much less likely to have in healthy members of the Tsimané body temperatures among American health, but they’re telling us some- infections such as tuberculosis, population, temperatures appear to

men averaged around 98.6 degrees thing. They’re telling us that we are syphilis and gum disease. have dropped between 2004 and GETTY IMAGES F back then but have steadily fallen changing and that what we’ve done In places like the U.S., people also 2018, he adds—a phenomenon he over time and that temperatures in the last 150 years has made us spend more time in what scientists plans to investigate further. among women have fallen as well. change in ways we haven’t before.” call the thermoneutral zone—an Parsonnet says she suspects that

Their data reveal an average for men The researchers did not determine environment of climate-controlled it might be healthier to have a lower SARINYA PINNGAM

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Normal body temperature is 98.6 de­­grees Fahrenheit, right? Not so. There is no baseline for humans ●A , and even if there were, it would be closer to 97.7 °F. Goodbye, 98.6 Temperature also varies across the day, peaking in late afternoon and bottoming out in early morning ●B . It is slightly higher for women than for men as well ●C . For two decades research has debunked the benchmark, set way back in 1868, yet it persists. One important ramification, says Jonathan S. Hausmann, a Healthy body temps are surprisingly lower rheumatologist at Boston Children’s Hospital, who led the latest study, is to redefine fever. Most doctors use 100.4 °F or higher, but if “normal” is lower, then the fever threshold should be, too. It also should vary with the daily pattern and be tailored to each individual, Hausmann says: “A child at 99.0 °F at 4 a.m. may By Mark Fischetti | Graphic by Nadieh Bremer be highly abnormal but at 4 p.m. could be within normal limits.”

●A Less Than . ●B Daily Cycle ●C Women and Men A 2002 analysis of 20 studies showed that mean body A landmark investigation in 1992 found that temperature for In the newest study, published in August 2018, 329 people temperature in healthy women and men varies, depending 148 men and women hit a low each day of about 97.5 °F took their temperatures, logged on smartphones. The overall on whether it is taken in the mouth, rectum or ear, and is around 6 A.M. and peaked at about 98.4 °F between 4 and mean was 97.7 °F. Women were 0.2 °F higher than men, on often well below 98.6 °F. 6 P.M. It defined the upper limit of the normal range as fever: average. Fever was found to be 99.5 °F or above. Tempera- 98.9 °F at 6 A.M. and 99.9 °F at 4 P.M. tures varied across the day. They also decreased, on Each dot is the mean body average, with rising age (not shon). temperature from one study Each orange dot is one measurement Each dot is one measurement Male (temperature taken in mouth) (temperature taken in mouth) Female Median 98.6 °F 37.0 °C Male Gender combined or not specified 36.0 36.5 37.5 38.0 Female 96 97 98 99 100 Circle size indicates study Gender combined or not specified size, from 12 to 1,532 98.6 °F Midnight participants Approximate mean 37.0 °C Approximate temperature (male) 36.0 36.5 37.5 38.0 mean Approximate mean 96 97 98 99 100 temperature temperature (female) 98.6 °F across 24 37.0 °C 6 A.M. Temperature hours 36.0 36.5 37.5 38.0 taken in ... 8 A.M. 96 97 98 99 100 Mouth Midnight Noon 3 A.M. Rectum 4 P.M. 12 participants 6 A.M. 6 P.M. Ear 9 A.M. 1,532 Noon participants Midnight 3 P.M.

6 P.M. R.I.P. German physician Carl Wunderlich put the mercury thermometer and temperature charts into widespread clinical use. 9 P.M. His 1868 book set normal body temperature at 37.0 degrees Celsius, or 98.6 °F. Time to let it go. Midnight SOURCES: “NORMAL ORAL, RECTAL, TYMPANIC AND AXILLARY BODY TEMPERATURE IN ADULT MEN AND WOMEN: A SYSTEMATIC LITERATURE REVIEW,” BY MÄRTHA SUNDLEVANDER ET AL., IN SCANDINAVIAN JOURNAL OF CARING SCIENCES, VOL. 16, NO. 2; JUNE 2002 (A); “A CRITICAL APPRAISAL OF 98.6 °F, THE UPPER LIMIT OF THE NORMAL BODY TEMPERATURE, AND OTHER LEGACIES OF CARL REINHOLD AUGUST WUNDERLICH,” BY PHILIP A. MACKOWIAK ET AL., IN JAMA, VOL. 268, NO. 12; SEPTEMBER 23–30, 1992 (B); “USING SMARTPHONE CROWDSOURCING TO REDEFINE NORMAL AND FEBRILE TEMPERATURES IN ADULTS: RESULTS FROM THE FEVERPRINTS STUDY,” BY JONATHAN S. HAUSMANN ET AL., IN JOURNAL OF GENERAL INTERNAL MEDICINE. PUBLISHED ONLINE AUGUST 13, 2018 (C) 12 NEWS

metabolism and body temperature. but you just don’t know,” he says, “We’ve changed in research. “Human body temperature And she hopes to explore that con- because there are so many variables data going back that far—roughly nection more in the future. that could not be controlled for in height, weight—and 150 years—is very interesting,” he For the eLife study, she and her the data set, such as whether sol- we’re colder.” says. “It allows us to see short-term colleagues compared temperatures diers and veterans were healthy —Julie Parsonnet alterations of physiological traits in from three different data sets: a when tested, where the thermometer humans, which is quite rare.” total of 83,900 measurements from was placed and what kind of instru- All the experts agree on one thing: the Union Army Veterans of the ment was used. were careful or simply filled in 98.6 a fever is still a fever. Lowering the Civil War (UAVCW) cohort collected Even Wunderlich’s established degrees F because that is what they average for normal body tempera- between 1862 and 1930; 15,301 1851 result is questionable, Macko- knew normal temperature was sup- ture does not mean that the stan- measurements from the National wiak says, because although he had posed to be. Those concerns were dard for a fever—generally consid- Health and Nutrition Examination a large database of patients, it is tempered, she says, by the fact that ered to be higher than 100 degrees Survey I (NHANES I) collected hard to know whether he measured she and her team found a similar F for adults—should be changed, between 1971 and 1975; and temperature consistently or how he annual drop in temperature between Mackowiak says. “Temperature can 578,222 measurements from the analyzed such a volume of informa- the 1970s cohort and the current be helpful in determining whether or Stanford Translational Research tion long before the invention of one. The effect was still present not you’re ill and, based on its level, Integrated Database Environment computers. And “the body is com- when they looked at soldiers’ and how ill you might be,” he says. For (STRIDE) collected between 2007 posed of a whole host of tempera- veterans’ year of birth rather than patients, a bacterial infection plus and 2017. Figures for women were tures,” Mackowiak adds. The liver is when the temperature was obtained, a lower-than-normal temperature not available from the earliest data the hottest part, and the surface of suggesting that the type of ther- could be an even more ominous sign set but were collected from the two the skin is the coldest. Plus, he says, mometer or the caregiver’s attitude than one higher than normal, he later cohorts, and the research “there’s no ‘normal’ temperature; could not explain the change. And says. A rise or fall in temperature showed that body temperature for there’s a range of temperatures,” within the data set, the researchers can also indicate whether you are men and women decreased steadily with people running hotter later in found the expected variation by age, getting better or how you are across the time periods. the day than they do in the morning. weight and height, suggesting that responding to medication, he adds, Philip Mackowiak, an emeritus Women also have higher tempera- the values were not random. though “how you feel is the most professor of medicine at the Univer- tures on average than men, in part Even with the data’s limitations, the important thing.” sity of Maryland School of Medicine, because their temperatures rise with findings are compelling, according to The new study probably should not who was not involved in the new ovulation. Frank Rühli, founding chair and direc- change the definition of fever, Rühli study, says data from as far back as Parsonnet agrees that the Civil tor of the Institute of Evolutionary says. “But the variety of what is the Civil War are inherently suspect. War data set has some limitations, Medicine at the University of Zurich, looked at as being normal should “That’s not to say that what [the new such as where caregivers took the who says he reviewed the paper for probably be adjusted.” study] found is not valid. It could be, temperatures and whether they eLife but was not involved in the — Karen Weintraub

13 How Coronaviruses Cause Infection— from Colds to Deadly Pneumonia The outbreak of a novel coronavirus raises questions about how such pathogens evolve and what makes infections mild or severe By Simon Makin GETTY IMAGES

14 Simon Makin is a freelance science writer based in London.

THE 2019 NOVEL CORONAVIRUS (2019-nCoV) ticle is wrapped in a protein “envelope.” Viruses all do behind the ongoing outbreak—which the World Health Organization has declared an inter- basically the same thing: invade a cell and co-opt some national public health emergency—was named after the family of viruses it belongs to. The of its components to make many copies of themselves, term “coronavirus” may have initially been unfamiliar to many, but most everyone has which then infect other cells. But RNA replication typi- cally lacks the error-correction mechanisms cells employ encountered milder forms of such viruses, of which four strains cause about a fifth of com- when copying DNA, so RNA viruses make mistakes during mon cold cases. Other types cause diseases that are endemic in certain animal populations. replication. Coronaviruses have the longest genomes of But until less than two decades ago, all known human varieties caused illness so mild that any RNA virus—consisting of 30,000 letters, or bases— coronavirus research was something of a backwater. and the more material a pathogen copies, the more oppor- tunities there are for mistakes. The upshot is that these That all changed in 2003 when the pathogen behind mals, says microbiologist Stanley Perlman of the Univer- viruses mutate very rapidly. Some of these mutations may the SARS (severe acute respiratory syndrome) outbreak sity of Iowa. But there were no bats being sold at the ani- confer new properties, such as the ability to infect new in China was identified as a coronavirus. “Everybody in mal market in Wuhan, China, where the current outbreak cell types—or even new species. the field was shocked,” says microbiologist Susan Weiss is thought to have begun, suggesting that an intermedi- A coronavirus particle consists of four structural pro- of the University of Pennsylvania. “People started really ate host species was likely involved. This situation seems teins: nucleocapsid, envelope, membrane and spike. The caring about this group of viruses.” That outbreak is to be a common feature of these outbreaks. Such hosts nucleocapsid forms the genetic core, encapsulated in a believed to have started when a coronavirus jumped from may increase the viruses’ genetic diversity by facilitating ball formed by the envelope and membrane proteins. The animals—most likely civet cats—to humans, resulting in more or different mutations. spike protein forms club-shaped protrusions that stick a type of disease called a zoonosis. These viruses’ propen- But what is a coronavirus? What determines whether, out all over the ball, making it resemble a crown or the sity for such jumps was underlined in 2012 when a differ- when and how it jumps to humans and how infectious it sun’s corona—hence the name. These protrusions bind to ent virus jumped from camels to humans, causing MERS will be? And what makes the difference between a case of receptors on host cells, determining the cell types—and (Middle East respiratory syndrome). That illness has the sniffles and a deadly disease? In the years since these thus the range of species—that the virus can infect. killed 858 people to date, primarily in Saudi Arabia, rep- viruses first emerged as a severe global health threat, The major difference between coronaviruses that cause resenting approximately 34 percent of those infected. researchers have been studying their molecular biology a cold and those that cause a severe illness is that the for- SARS, MERS and the new coronavirus almost certainly in an effort to answer such questions. mer primarily infect the upper respiratory tract (the nose all originated in bats. The most recent analysis of the and throat), whereas the latter thrive in the lower respi- 2019-nCoV genome found that it shares 96 percent of its ANATOMY OF A CORONAVIRUS ratory tract (the lungs) and can lead to pneumonia. The RNA with a coronavirus previously identified in a specific Coronaviruses are enveloped, single-stranded RNA SARS virus binds to a receptor called ACE2, and MERS bat species in China. “These viruses have been floating viruses, which means that their genome consists of a binds to one called DPP4—both are found in lung cells, around in bats for a long time” without sickening the ani- strand of RNA (rather than DNA) and that each viral par- among other places. Differences in the distribution of

15 these receptors in tissues and organs may account for dif- receptors, or co-receptors, are also involved,” says molec- have different accessory proteins,” Weiss says, adding that ferences between the two diseases, such as the fact that ular biologist Burtram Fielding of the University of the they “have evolved to shut down various aspects of that MERS is deadlier than SARS and features more promi- Western Cape in South Africa. The virus binding to a [innate immune] response.” Some researchers think bats nent gastrointestinal symptoms. MERS is not hugely receptor is only the first step in the cell-entry process. harbor coronaviruses because they do not mount the infectious, however, which may also be a receptor-related When a virus binds to a host cell, the two start morphing intense immune response humans do. “A lot of the sig- trait. “DPP4 is expressed [highly] in the lower bronchi together, and other viral proteins may bind to other recep- naling molecules that alert our immune system are sup- [airways leading into the lungs], so you have to have a tors. “For the efficiency of entry, it’s not just the one main pressed in bats, so they don’t get sick,” Tait-Burkard says. large number of viruses coming in, because our airways receptor,” Fielding says. “There could be others as well.” Rather than reacting, bats maintain a constant low-level are very good at filtering out pathogens,” says virologist response, which may contribute to the viruses’ evolution. Christine Tait-Burkard of the University of Edinburgh. IMMUNE SYSTEM ARMS RACE “[Bats] have a constant expression of interferons, which “You need prolonged, intense exposure [to reach the Another important feature of coronaviruses is their selects for viruses that are good at evading that response,” lungs], which is why we see people who work closely with “accessory” proteins, which appear to be involved in evad- Tait-Burkard says. “So bats are very good selection vessels camels getting sick.” ing the host’s innate immune response—the body’s front for viruses that are very good at hiding.” Conversely, because pathogens can get in and out of the line of defense. The response is initiated when a cell Accessory proteins are far from fully understood, how- upper airways more readily, viruses that replicate there detects an invader and releases proteins called interfer- ever. “They can be taken out of some viruses without any are more infectious. In addition, “the ability to replicate ons, which interfere with the pathogen’s replication. The effect on the ability of the virus to grow,” Perlman says. in different temperatures makes a big difference, because interferons trigger cascades of antiviral activity, from “You would think: if you had a protein that was key for the upper respiratory tract is cooler,” Tait-Burkard says. shutting down host protein synthesis to inducing cell countering the immune response, if you took it out, the “If the virus is more stable at those temperatures, it doesn’t death. Unfortunately, most of these processes are also bad immune response would win—and it’s not necessarily so.” go to the lower respiratory tract.” The lower airways are for the host. “A lot of the disease that’s caused is actually Some researchers believe accessory proteins influence also a more biochemically and immunologically hostile the immune reaction—inflammation—and destructive how deadly coronaviruses are. There have been studies environment, she adds. Analysis of 2019-nCoV strongly things induced by viruses,” Weiss says. “That will also with SARS in which removing an accessory protein did suggests that the new virus, like SARS, uses ACE2 to gain determine how virulent a virus is: how much of a destruc- not change the virus’s replication efficiency but did make entry to cells. This observation would fit with the fact that tive immune response does it induce, as opposed to just it less pathogenic. “Lots of virus would still be made, but it appears, so far, to be less deadly than MERS (the cur- a protective one?” This aspect is also why underlying it seemed to be less harmful,” Fielding says. rent estimated mortality rate for the new coronavirus is medical conditions are so important. Most of the people Coronaviruses do possess some ability to correct genetic about 2 percent, but that figure may change as the out- who have died from the new coronavirus so far “had errors, but it neglects certain regions of their genome, break unfolds and more cases are detected). comorbidities, like autoimmune diseases, or secondary Tait-Burkard says. Consequently, two sections in particu- The picture quickly becomes complex, though, because infections, which can become much more prevalent once lar are especially prone to mutations: those that encode viruses that use the same receptor can result in drasti- our innate immune systems are busy fighting a virus,” the spike protein, and accessory protein regions. “In those cally different illnesses. One human coronavirus called Tait-Burkard says. “That’s why the important thing is to two areas, coronaviruses allow a lot of mistakes, which NL63 binds to the same receptor as SARS but only causes treat people for comorbidities and give them antibiotics drives their evolution, because they manage to bind to upper respiratory infections, whereas SARS primarily to stop bacterial infections taking hold.” new receptors and evade the immune response of new infects the lower respiratory tract. “Why that is, we don’t Of course, the immune response’s purpose is to elimi- systems,” Tait-Burkard says, “which is why coronaviruses know,” Perlman says. Another curiosity is that the ACE2 nate invaders, so viruses possess countermeasures. This are so good at jumping from species to species.” receptor is prevalent in the heart, but SARS does not trait seems to be what differs most among various coro- Related Video infect heart cells. “That was a clear indication that other naviruses. “These viruses are closely related, but they

16 How Twitter Is Changing Medical Research Medical “tweetorials” toconferenceupdates, dissemination anddiscussion social mediaischanging the From onlinejournalclubsto By Nicole WetsmanBy Nicole of biomedicine

17 GETTY IMAGES Nicole Wetsman is based in New York.

sther Choo only had a few thousand followers on Twitter IMMEDIATE ANALYSIS before August 2017. Choo, an emergency physician at the Before Twitter, researchers had limited ways to respond Oregon Health & Science University, interacted mostly with to and critique new research in their field. They could write a letter to the editor or an opinion piece in a journal, other doctors. But when she tweeted one day about the but that response would be published only if editors of racism she had endured while practicing medicine, her posts that journal agreed to it. Even if it was published, it would went viral—and her follower count shot up to 20,000 almost often not appear for weeks. They could conduct their own overnight. Now she has nearly 80,000 followers. experiments and publish their own papers, but that ave- nue is also subject to the same gatekeeping and time “The professional benefits have been so concrete,” Choo helps level the scientific playing field, says Janet Han restrictions. Blogs allow self-publishing, but it is hard to Esays. Twitter, for her, has helped her meet new profes- (@netta_doc), a cardiologist with the Veterans Affairs direct people to them, and the PubMed Commons—which sional colleagues and friends and has offered opportu- Greater Los Angeles Healthcare System and the Univer- offered a way for researchers to comment directly on arti- nities for advocacy around racial and gender equity in sity of California, Los Angeles, and an author on papers cles—never caught on and was discontinued in 2018. medicine. “It’s hard to imagine what my career would be about social media in medicine. “Anybody can be on Twit- Twitter sidesteps those roadblocks and allows conver- like without it.” ter,” she says, from first-year students to department sations about new papers to happen immediately and As a high-profile physician on the platform, Choo chairs. “Anyone can interact with anyone.” publicly, says Jordan Gauthier (@drjgauthier), a fellow (@choo_ek) is an outlier in the medical community in The platform is also fundamentally reshaping the way at the Fred Hutchinson Cancer Research Center. “On the terms of her number of followers—but she is part of a scientists and academic physicians can discover, discuss day of publication, people can react to it,” says Gauthier, large and growing community of doctors and scientists and share research. It is not an extracurricular endeavor an active Twitter user with around 2,000 followers. who use Twitter as part of their professional lives. A to those who participate—it is a critical communication Comments on Twitter remove the journal from the Nature survey conducted in 2014 found that 13 percent of tool, says Vinay Prasad (@VPrasadMDMPH), a hema­ equation, allow anyone to discuss scholarship and have scientists use Twitter, and in 2017 an analysis published tologist-oncologist at Oregon Health & Science Univer- high visibility, Prasad says: “It’s a tremendous democra- in PLoS One identified over 45,000 scientists with accounts. sity and an active Twitter user with over 30,000 follow- tization of critique of science.” The open platform allows Most scientists and physicians do not reach as wide an ers. But that change comes with growing pains, and for the possibility that some of the criticism or comments audience as Choo does, but they find that it has been everyone from individuals to major institutions is strug- might be inaccurate, he adds. “But I trust that the com- helpful for their careers. “Twitter lowers the boundaries gling to figure out the best way to incorporate social munity is smart enough to draw attention to what is of our institutional silos,” says Ankeet Udani (@ankeetu- media into traditional metrics around achievements. “It’s accurate. Inaccurate comments don’t get the same dani), an anesthesiologist and medical-education spe- probably one of the most disruptive—and net beneficial— retweets.” cialist at the Duke University School of Medicine, who things that has happened in academic medicine,” Sometimes feedback given on Twitter can be more started a Twitter-based journal club for residents. It also Prasad says. pointed and critical than what might be given in person

18 or in a formal op-ed. “You can see sharks gathering in Rochester, Minnesota. She was the senior author on a ter “celebrity” status that was not grounded in academic around a paper to tear it apart,” Gauthier says. But while 2017 paper that found, for the first time, that female doc- success and therefore was not justified. they can bite, the trend might help push the quality of tors were significantly less likely to be introduced with The index was broadly criticized, including by those research. “I think about it—am I going to get panned by the professional title “Doctor” than were their male col- who took issue with the idea that citations are the most one of the statisticians online?” he says. “Maybe it’s driv- leagues during grand rounds, when clinicians describe important metric of scientific expertise—which penal- ing excellence and improving methods and asking peo- patient cases to other physicians—male physicians intro- izes junior researchers, for example, who will automati- ple to think about what the community in the field thinks, duced their female colleagues using formal titles only cally have a lower citation count. “It’s critical of people rather than just in your own office.” around half the time. The team submitted their results who seek to communicate more broadly, as if that’s a bad to three high-impact journals but were rejected. thing,” Prasad says. GOING CLUBBING “The main sense I got from reviewers was that they Choo says that mentality has faded within the scientific Online discussion of papers is sometimes facilitated by didn’t think [the findings] were actually a thing,” Hayes community. “A few years ago it was a very different land- Twitter journal clubs. Journal clubs, where researchers says. The paper was eventually published in a lower-im- scape,” she says. “You don’t hear much anymore that you’re get together and critically examine new papers or pieces pact women’s health journal, but she pushed the paper out wasting your time on Twitter and should be writing a paper.” of literature, are important forums for the exchange of on social media and wrote a blog post describing the find- Some institutions are starting to consider social media ideas and continuing education. But they traditionally ings. That helped the paper reach a wider audience even activity in hiring and promotion decisions, which is a happen in person, and participants are usually limited out of a less widely read journal. “As a result, my co-au- positive step, says Eric Topol (@EricTopol), a cardiolo- by location. On Twitter, however, journal clubs can thors have been quoted in Time and the Washington Post.” gist and geneticist at the Scripps Research Institute and expand beyond those boundaries. Udani, for example, The scientific community is still trying to figure out a high-profile figure (with over 177,000 followers) in sci- started one for anesthesia residents. Anesthesiologists how to integrate social media into traditional bench- entific Twitter. “Increasingly, this is going to be the way are often isolated, but using Twitter to talk about papers marks of success. Hayes herself says that the number of the science community does exchange ideas, and it com- exposes them to approaches from all over the world. “It’s retweets and likes a paper gets should not be a surrogate plements the typical story of a person’s citations,” he says. a change to the traditional journal club, which is a bit for the value of the science itself. However, it should be included in only a small way, says outdated,” he says. Hayes. “Being popular should not be the reason someone A formal analysis of the educational potential of Twit- UPENDING POWER STRUCTURES becomes a full professor.” Organizations have to grapple ter journal clubs, centered on a medical-radiation jour- Social media offers an alternative to traditional power with how much weight they give social media use and nal club, concluded that the flexibility and accessibility structures in science and research, which give high-im- how they determine what types of usage are relevant to of the digital environment offer benefits that in-person pact journals, tenured professors and prestigious insti- a person’s scientific work. “We need to systematize the clubs do not—including the opportunity for more peo- tutions the most weight. On Twitter, people who do not way we assess validity,” Hayes says. “It’s still a bit of a ple to observe without pressure to participate, global have tenure, who have more limited publications to their Wild West out there.” engagement and fewer hierarchies based on seniority. In name or who are early in their career have opportunities Choo did not initially think that social media should this particular journal club—the #MedRadJClub meet- to demonstrate their expertise. But displays of knowl- be incorporated into career-advancement decisions, but ing—one hour of conversation could have up to 245 par- edge on social media, rather than in traditional forums she’s been won over. “I was sold on the quality and rigor ticipants and 4,559 tweets, the analysis showed. such as journals, are sometimes criticized as less rele- of some of the educational information people are put- Twitter can offer a second chance for papers that might vant or rigorous. In 2014 a researcher created a metric ting out on social media. People do tweetorials, which not have been accepted in high-impact journals, says Sha- called the “Kardashian index” to measure scientists’ Twit- are really rigorous. It’s incredible medical education.” ronne Hayes (@SharonneHayes), cardiologist and ter followings against the number of citations their Choo says, however, that rigorous, quantitative measures founder of the Women’s Heart Clinic at the Mayo Clinic papers receive—with the implication that some had Twit- need to be developed to assess people’s social media use.

19 ESTABLISHING A PRESENCE With so many conversations about science and medicine happening on Twitter, people who do not use it at all are missing out on an important forum for conversations about science and medicine, Hayes says. They do not have to be as active as Prasad or Choo—or even tweet at all—but they should keep an eye on the discussion. “I think it has reached the point where academic physicians for sure should have a presence, if nothing else, just so they can see what’s going on. It’s like reading journals,” she says. “You can’t put your head in the sand. It’s another source of information.” People who resist often have common concerns, includ- ing the brevity of tweets and the time it takes away from other work. Reshma Jagsi (@reshmajagsi), deputy chair in the department of radiation oncology at the Univer- sity of Michigan, shared many of those concerns before she started using Twitter this summer. “I was a Twitter resister,” she says. She saw her concerns upended quickly, noting that threading tweets and linking out to articles allow for robust conversations. Social media can eat up a lot of time, but it is possible to use it productively and in moderation. Good science, Choo says, often takes time and space, so time manage- ment is key. “Some days I can get really caught up in it,” she says. “I definitely do think you need safeguards in place to make sure you’re staying productive.” Sorting through the volume of information on Twitter and identifying the best ways to use it can take time as well. Ignoring it entirely is not the right solution to that problem, however, and it is possible to see a slice of the information even if someone cannot see everything, Jagsi says. “The sorting of the wheat from the chaff is, so far, worth it.” This article is reproduced with permission and was first published in Nature on December 9, 2019.

20 QUEST TO USE CRISPR AGAINST DISEASE GAINS GROUND As the first clinical trial results trickle in, researchers look ahead to more sophisticated medical applications for genome editing By Heidi Ledford GETTY IMAGES A scanning electron microscope image of a sickle-cell red blood cell.

21 Heidi Ledford works for Nature magazine.

phia. “But I think we’re starting to see some of the results three people to treat some forms of cancer—showed no The prospect of of that work.” signs of clinical improvement. It has been only seven years since researchers discov- using the popular ered that a molecular defense system called CRISPR– SIGNS OF PROGRESS Cas9, which microbes use to fend off viruses and other In both cases the transplanted cells flourished in the genome-editing tool invaders, could be harnessed to rewrite human genes. bone marrow of recipients without any serious safety Since then gene editing has attracted attention for its concerns, but they did not produce a clear medical ben- CRISPR potential to modify embryos—an application that is eth- efit. In the man treated for HIV, the researchers attempted ically and legally fraught if those embryos are destined to use CRISPR to disable a protein that many strains of to treat a host of to become human beings. But in parallel, scientists have HIV use to enter cells. But only 5 percent of the trans- been testing CRISPR’s much less controversial ability to planted cells were edited—not enough to cure disease, diseases in people disable or correct problematic genes in other cells in the researchers reported in September. The study has order to treat a host of diseases. been placed on hold while researchers explore ways to is moving closer In 2016 Chinese researchers announced that they had boost that percentage, says Hongkui Deng, a stem-cell treated the first person with a CRISPR–Cas9 therapy researcher at Peking University in Beijing and a lead to reality. designed to fight cancer. In cells extracted from a partic- author of the work. Medical applications of CRISPR–Cas9 had a banner ipant’s blood, the researchers disabled the gene that There are early hints that another trial might meet with year in 2019. The first results trickled in from trials test- codes for a protein called PD-1, which holds the immune more success. CRISPR Therapeutics in Cambridge, Mass., ing the tool in people, and more trials launched. In the system in check but can shield cancer cells in the pro- and Vertex Pharmaceuticals in Boston, Mass., have treated coming years researchers will be looking ahead to more cess. The scientists then reinjected the cells. two people with the genetic disorders sickle-cell anemia sophisticated applications of CRISPR genome editing By 2019 the U.S. government’s clinicaltrials.gov data- and β-thalassemia. Both deplete oxygen-carrying hemo- that could lay the foundation for treating an array of dis- base listed more than a dozen active studies testing globin molecules in the blood; the idea is to use CRISPR eases from blood disorders to hereditary blindness. CRISPR–Cas9 as a treatment for a range of diseases from to disable a gene that otherwise shuts off production of But although the results of clinical trials of CRISPR cancer to HIV and blood disorders. another form of hemoglobin. Early results suggest that genome editing so far have been promising, researchers So far too few people have been treated in these trials the treatment might have eased some symptoms of the say that it is still too soon to know whether the technique for any firm conclusions to be drawn about the safety of disorders, but the participants will need to be followed will be safe or effective in the clinic. CRISPR–Cas9 therapies or how well they work. Prelim- for a longer period to be sure. “There’s been a lot of appropriate caution in applying inary results from two trials—one in which gene-edited Other researchers are already itching to move beyond this to treating people,” says Edward Stadtmauer, an blood cells were transplanted into a man to treat HIV editing cells in a dish. The challenge is in finding ways oncologist at the University of Pennsylvania in Philadel- infection and one in which they were transplanted into to transport the gene-editing machinery to where it is

22 needed in the body, says John Leon- “Can you imagine Intellia is looking for a way around ard, chief executive of Intellia Thera- the viruses. The company has part- peutics, a biotechnology company in a future without nered with Swiss pharmaceutical giant Cambridge, Mass., that is focused on gene editing?” Novartis to develop fatty nanoparticles CRISPR–Cas9 genome editing. “The that can protect genome-editing mol- —John Leonard delivery approach is so important.” ecules as they travel through the Last July the pharmaceutical com- bloodstream but also can pass through panies Editas Medicine in Cambridge, Mass., and Aller- the membranes of target cells. gan in Dublin launched a trial to treat the genetic disor- These particles tend to accumulate in the liver, and der Leber congenital amaurosis 10, which can cause researchers are working to develop particles that infil- blindness, by editing eye cells. Researchers will inject trate other tissues, such as muscle or the brain. But for into the eye a virus containing DNA that encodes the now Intellia will focus on liver diseases, says Leonard, CRISPR genome-editing machinery, bypassing the need and the company plans to launch its first trial of the tech- to guide those tools through the bloodstream to the spe- nology this year. “It’s crawl before you walk, so to speak,” cific tissues. The virus will be responsible for carrying he says. the genome-editing tools into cells. It is the first trial to None of the technologies currently being tested is what attempt CRISPR–Cas9 gene editing inside the body, and researchers envision for the long-term applications of early results could be reported this year. genome editing, says Gersbach. “The approaches that That would be a landmark moment for the field and people are taking are the things that we can do today,” he could pave the way for future trials targeting other says, “but not what we would do if we could design the organs, says Charles Gersbach, a bioengineer at Duke ideal drug.” University in Durham, N.C. But he and others say that Leonard says that when he meets with investors, they they hope researchers will eventually move away from often demand to know what medical advances will be using viruses to shuttle genome-editing machinery into made in the next six months. “We do our best to describe cells. Deactivated viruses can still sometimes provoke that, but I always end it by saying, ‘Can you imagine a immune responses and can carry only a limited amount future without gene editing?’” he says. “I have yet to meet of DNA. the person who says yes.” This article is reproduced with permission and was first SHRINK TO FIT published in Nature on January 6, 2020. What’s more, some gene-editing tools are currently too large to fit inside commonly used gene-therapy viruses, says chemical biologist Andrew Anzalone at the Broad Institute of M.I.T. and Harvard in Cambridge, Mass. These include the souped-up CRISPR systems called prime editors that were first reported in late 2019 and which might prove to be more precise and controllable than CRISPR–Cas9.

23 Seth Berkley is CEO of Gavi, the Vaccine Alliance. Opinion

Visitors to the Temple of Heaven, Beijing, during the outbreak in January 2020.

PUBLIC HEALTH Novel Coronavirus Is a Reminder: The Best Defense against a New Viral Outbreak Is Early Detection Infectious disease surveillance networks already exist, but they can be highly porous

he current outbreak of a new coronavirus, 2019-nCoV, has quickly escalated to become Ta serious global problem that has now been declared a Public Health Emergency of Interna- tional Concern by the World Health Organization. As of this writing the disease has spread to more than 100 countries, including more than 300 confirmed cases in the U.S. But in some ways, outbreaks such as this should come as no surprise. Deforestation and the sale of live wild animals or bushmeat, such as bats and monkeys, make the emergence of new viruses

inevitable, and population growth, dense urbaniza- KEVIN GETTY FRAYER IMAGES

24 Opinion tion and human migration make their spread There are no guaranteed solutions to ensure infectious diseases are easier. What is surprising is that, although we are better able to respond to such threats than always detected early, before they reach densely populated areas. ever before, we are still not fully prepared. Screening at airports is likely to be of limited use in preventing its further spread, but we now as possible, before they spread, and why good to know how virulent it is—but with a rising death at least have the ability to rapidly identify and disease surveillance is so important. toll, we have to be worried. We also do not know genetically sequence new pathogens, to help Infectious disease surveillance networks how easily it can be transmitted from human to minimize the time it takes to develop treatments already exist across the globe to do precisely this. human, although we now have confirmation that and vaccines. We also have mechanisms in place, They can, however, be highly porous and of vary- this is occurring. such as through the Coalition for Epidemic Pre- ing effectiveness. In some ways we are lucky that Nor do we know exactly where it originated. It paredness and Innovation and Gavi, the Vaccine 2019-nCoV emerged in China, where there exists is possible that the first transmission of the virus Alliance, to help stimulate the development of a strong public health system. During the West from animal to human took place at a market vaccines and make them available quickly once Africa Ebola epidemic, it took three months in Wuhan where live wild animals were sold. But we have them. But despite this, our ability to before the very first case, patient zero, was con- if other people were infected in rural areas before swiftly detect threats in the first place is seriously firmed by a laboratory, because that community the infected animal was brought to market, that wanting, and that is worrying. was outside of an efficient disease surveillance means that with good surveillance it might have Infectious disease knows no borders, so when network. Also, new threats are more common been possible to detect the threat before it it comes to controlling outbreaks, timing is every- than perhaps most people realize. Since 1940 reached densely populated areas. thing. The speed with which this outbreak was more than 330 emerging infectious diseases There are no guaranteed solutions to ensure identified and communicated and the fact that have been identified. If deforestation and the that infectious diseases are always detected early, 2019-nCoV has been genetically sequenced are unregulated sale of bushmeat continue, then we before they reach densely populated areas. But positive steps, and there is more than one vac- should expect to see more. we do have one cost-effective way of widening cine now already in development. But even Deforestation runs the risk of exposing human- the net: increased government investment in pri- though vaccines for coronaviruses are far simpler ity to as yet unencountered viruses—often mary health care, particularly in lower-income to develop than those for diseases such as through contact with wild animals such as bats, countries. Primary health care is typically the first malaria and HIV, it will still be months before the exotic canine species and monkeys or with vec- point of contact people have with medical and first clinical trials take place and at least a year tors such as mosquitoes—increasing the risk of health services when they get sick and so is ideal before a vaccine could possibly be available for outbreaks of both new and existing diseases. for early detection of diseases. But in many parts use. As context, the Ebola vaccine Ervebo, which Indeed, genetic analysis of 2019-nCoV suggests of the world it is still very limited or even nonexis- is now being used in the Democratic Republic of that it most likely came from a bat. tent. Even in middle-income countries, where the Congo, is one of the fastest vaccines to get With 2019-nCoV, the third new severe out- health care provision can be relatively good, there regulatory approval, and that took five years. That break of novel coronaviruses in the past two can exist large clusters of communities that are is why it is so important to detect threats as early decades, we still do not have enough information missing out. When it comes to new emerging

25 Opinion infectious diseases, people in rural areas, those close to forests and those consuming bushmeat are our biggest concern, because these are essentially our underserved blind spots. National immunization programs can help change that. With 90 percent of the world’s chil- dren now receiving at least one routine vaccina- tion, childhood immunization already has a larger reach than any other medical intervention. In addition to this, immunization provides an impetus for other vital health components that not only are essential to vaccination but can help strengthen primary health care. These include supply chains, trained health workers, data systems and, crucially, disease surveillance and in some cases basic laboratory testing. Extending routine immunization systems to that last 10 percent not only will make those communities healthier and save lives but also will put in place the basics of a health care warn- ing system. No matter how we achieve it, primary health care must be strengthened at a global level to reach every community if we are to widen the surveillance and response net and be fully pre- pared for these kinds of outbreaks. Until we have a resilient and universal primary health care sys- tem, we will be leaving some communities out. And when the next emerging infectious disease strikes, that may simply not be enough. Related Video

26 Jeannie Aschkenasy is a clinical psychologist and assistant professor Opinion in the department of pediatrics at Rush University Children‘s Hospital and is a Public Voices fellow through the OpEd Project.

MENTAL HEALTH Doctors and Suicide The rate among students, residents and physicians is significantly higher than the ave- rage—but so-called wellness initiatives can help

“First, do no harm,” is what medical students in the U.S. declare when they take the Hippocratic oath at the white-coat ceremony symbolizing their entry into the medical profession. It refers to the patients they will be taking care of. But perhaps it should also refer to themselves. As a psychologist embedded in the depart- less demanding schedules. for medical students and residents. ment of pediatrics at a major medical center, Yet many health care professionals do not Compared with those among the general popu- I have worked closely with pediatric residents often discuss a major occupational hazard in lation, however, the rates of death by suicide are since 1995. In addition to meeting with first-year medical training: the high suicide rate among much higher in physicians, especially physicians residents during the first week of orientation, medical students, residents and physicians. who are women. In the U.S. an estimated 300 to I facilitate a monthly support group where resi- The rates of death by suicide in the general 400 medical students, residents and practicing dents have protected time to share concerns in public in the U.S. are increasing. The National physicians die by suicide annually. Physician a nonthreatening, confidential environment. Institute of Mental Health reported in 2017 that deaths impact not only the families and friends of These monthly groups have spurred many suicide was the 10th leading cause of death for the doctors who end their lives but also thousands positive changes, including trying to ensure males and the 14th for females. It was the sec- of patients, nurses, support staff and others. that rotations with the most demanding sched- ond leading cause of death for young people In January 2019 the Accreditation Council for

ules are now staggered with rotations that have aged 10 to 34, a common age bracket Graduate Medical Education sent out an e-com- GETTY IMAGES

27 Opinion munication to members wishing everyone a “joy- Clinic’s Program on Physician Well-Being, Stan- in December 2018, physician Bryant Adibe ous, happy and healthy New Year.” The note also ford’s WellMD, and the Pediatric Resident Burn- moved to Rush University Medical Center as its included a reminder that the third quarter of the out-Resilience Study Consortium. first chief wellness officer. academic year, beginning in January, is the sec- Indeed, many of the concerns and challenges To reduce rates of burnout at Rush University ond highest period of risk for resident and fellow of residency—debt, moving to a new location, Children’s Hospital, a four-week wellness rotation suicide. time management, impostor syndrome—have not was launched in 2017 for the second year of For 2020, the third quarter for the academic changed over the past two decades. Many con- training. Many were skeptical about this four- year begins shortly. Recognizing that physicians cerns have intensified, however, such as the week rotation, yet the most salient component of are at increased risk for burnout and depression, demands of electronic record keeping, the this rotation provides residents with the time to the council introduced new standards and, in their increased burden of non-MD chores such as schedule appointments with their own health care updated Common Program Requirements, insurance pre-authorizations, and the intrusion of providers, in addition to covering their peers, so defined “well-being” of physicians to include that 24-7 access. that they too may schedule health care appoint- they “retain the joy in medicine while managing The American Academy of Pediatrics empha- ments. Residents are also encouraged to eat their own real-life stresses.” sizes the need to address the social-emotional healthy meals, exercise, check in with the staff The ACGME guide states: “Residents and fac- lives of physicians, as well as the need to help psychologist, catch up on sleep and socialize with ulty members are at risk for burnout and depres- them sustain their work-life balance and avoid friends and family. sion. Programs, in partnership with their Spon- burnout. In 2015 six institutions founded the Prior to the launch of the four-week wellness soring Institutions, have the same responsibility to 2016–2019 Pediatric Resident Burnout-Resil- rotation in 2017, the burnout rate reported by address well-being as other aspects of resident ience Study Consortium. Rush’s second-year pediatric and internal medi- competence.” The World Health Organization defines burnout cine/pediatric, or med/peds, residents was Historically there have been many mixed mes- as an “occupational phenomenon.” According to 80 percent. In 2018 residents reported that rates sages in residency training, noting that it is insuf- the WHO, burnout is a “syndrome conceptualized of burnout fell from 80 percent to 30 percent, ficient to provide a wellness curriculum without as resulting from chronic workplace stress that and they remained there in 2019. including, as I wrote about the problem in 1992, has not been successfully managed” and refers To be sure, a four-week wellness rotation is not "the larger working environment … involving the specifically to the occupational or workplace con- the answer to the epidemic of physician burnout, hospital and/or training programs, and the con- text and not to experiences in other [personal] depression and suicide. But it is a start. stantly changing health care system.” areas of life.” Burnout is a symptom; it is not the problem. Medical schools, residency training programs Some leading institutions are addressing and Medical students and physicians need time to and hospitals throughout the country are imple- recognizing the need to address the issues of engage in self-care activities and seek mental menting “wellness initiatives” of varying degrees. burnout and work-life balance at the institutional health assistance without jeopardizing their And many medically affiliated organizations have level. In 2017, moving from the Mayo Clinic to license, reputation and ability to practice medicine. programs dedicated to addressing wellness, such Stanford Medicine, physician Tait Shanafelt Yes, residents learn that to be ethical doctors, as the American Medical Association’s Steps For- became the first chief wellness officer at a U.S. they must first do no harm. They can also learn to ward: Preventing Physician Burnout, the Mayo academic medical center. At my own institution, first help themselves.

28 Richard Dum is a research associate professor of neurobiology Opinion at the University of Pittsburgh. David Levinthal is the director of the Neurogastroenterology and Motility Center and assistant professor of medicine at the University of Pittsburgh. Peter Strick is the scientific director of the University of Pittsburgh Brain Institute, as well as Thomas Detre Professor and chair of neurobiology.

THE BODY Calling an Illness “Psychosomatic” Doesn’t Mean It’s Imaginary Recent experiments have begun mapping the neuronal connections between mind and body like never before

lacebo effects, exercise highs, getting sick when you’re stressed out—the popular P press and the scientific literature alike are replete with examples of how the mind or mental processes influence our health and well-being. This “mind-body connection” is essential for nor- mal organ function and also is viewed as the basis for psychosomatic disorders. Yet the concept that our thoughts can influence the function of a vari- primates are different from those of other ani- nervous system. We know a great deal about the ety of organ systems is often viewed with some mals—a reality that has important implications neural connections that link autonomic output skepticism, in part because it has lacked a firm for research into the causes and treatment of from centers in the brain stem and spinal cord to biological basis. neurological disorders. specific organs. That’s changing. We are now starting to provide The connection between the central nervous Yet the neural circuits that link higher brain the scientific evidence to reveal the important system and internal organs is mediated by sym- function and central sites, such as the cerebral dynamic between our brains and our bodies. And pathetic (fight-or-flight) and parasympathetic cortex, to autonomic output and organ function

in the process we are learning how the brains of (rest and digest) subdivisions of the autonomic have not been clearly defined. That’s because JUAN GARTNER GETTY IMAGES

29 Opinion most conventional tracers are capable of defin­- “central commands” from the cerebral cortex. of cortical areas and is influenced by a more ing only the direct inputs to and outputs from This general experimental paradigm is one that diverse set of behaviors. Each network found in an organ and not the background web of con­ can be applied to reveal multisynaptic circuits in the monkey has a human equivalent. Taken nections that provide indirect, but meaningful, a wide variety of networks. For example, rabies together, these observations suggest that nonhu- neural signals. tracer injections into limb muscles can reveal the man primate models are essential for examining Our research team has overcome this chal- networks involved in the voluntary control of the influences of higher-order aspects of move- lenge by using neurotropic viruses, which specifi- movement; tracer injections into laryngeal mus- ment, cognition and mood on sympathetic cally target neurons, as transneuronal tracers. cles can reveal the central circuits responsible function. In the Proceedings of the National Academy of for vocalization; tracer injections into the heart Modern medicine has generally viewed the Sciences we recently described using a rabies and stomach can reveal circuits responsible for concept of psychosomatic disease with suspicion. virus tracer to reveal the areas of the cerebral the central control over the cardiovascular and This attitude is partly the result of a lack of infor- cortex that influence the adrenal medulla of the gastrointestinal systems; and tracer injections mation about the neural networks that connect monkey and rat, as well as rabies transport from into the spleen can reveal the central neural cir- the “mind,” conceptually associated with the cere- the kidney in the rat. cuits that influence immune function. bral cortex, with autonomic and endocrine sys- In our nonhuman primate studies we injected The adrenal medulla can be considered as our tems that regulate internal organs. As a conse- the rabies tracer into the adrenal medulla, a gland “first responder” in situations requiring fight or quence, some definitions of psychosomatic at the top of the kidney, and tracked its path back flight. Thus one might expect the input to it to disorders include dismissive descriptions such as to brain regions involved in movement, cognition be highly conserved across species. Indeed, the “all in the mind,” “irrational” or “subconscious.” and mood. These cortical areas represent key cortical motor areas are a major source of input Our findings should correct this perspective nodes in a “stress and depression connectome.” to the adrenal medulla in both the rat and the because they provide a concrete neural substrate In the rat, descending influences over the adrenal monkey. But here the similarities end. The primary for cortical areas involved in movement, cognition medulla, as well as the kidney, originate largely motor cortex, the primary somatosensory cortex and affect to influence a major sympathetic from cortical motor areas. In fact, the cortical and a single secondary motor area account for effector, the adrenal medulla. We suggest the areas that are the major source of cognitive con- about 93 percent of the cortical input to the adre- adoption of the view reflected in the dialogue at trol in the monkey appear to be absent in the rat. nal medulla in the rat. In contrast, the monkey’s the end of Harry Potter and the Deathly Hallows, Thus the mind-body connection in primates is adrenal medulla receives input not only from cor- where Harry says, “Tell me one last thing, is this more widespread and complex than that in rats. tical motor areas (about 53 percent) but also real? Or has this been happening inside my These observations provide a new perspective from cortical areas involved in cognition and head?” Professor Dumbledore replies, “Of course on the neuroanatomical organization of the corti- affect (about 35 percent). it is happening inside your head, Harry, but why cal influences over the sympathetic nervous sys- Furthermore, in the monkey the adrenal on earth should that mean that it is not real?” tem. The power of transneuronal tracing with medulla receives substantial input from motor rabies virus is that it reveals the entire extent of areas on the medial wall of the hemisphere that the cortical influence over this system. In this way don’t exist in the rat. Thus the monkey’s adrenal it identifies the potential origins of the elusive medulla is the target of output from a broader set

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