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Study: Girl’s arrhythmia linkedtomosaicism Girl’sStudy: percent defective. composed ofamosaiccells,92percent healthyand8 conducted, touncover ofherillness:aheart themystery fastest andmostcutting-edgegenomesequencingever group ofresearchers, andacombinationofsomethe inside baby Astrea’s It heart. took a huge and diverse genetic mutationcausingtheproblem washiddenaway arrhythmia calledlongQT syndrome. But thedeadly happy,”and I was very she said. hoped forthebest.“All wasthatIgave Iknew birth, said she had no idea how bad things were and just livery. They waited, puzzled to hear how she was. Tsoi babyseen theirnew aftertheemergencyC-sectionde- scrambled to save her life. into cardiac arrest hours, few doctors every and nurses Packard Children’s Hospital Stanford begangoing obvious source. identify whatmightbecausinggeneticdiseaseswithno Medicine. studynew by researchers at the School of ecules calledcytokines,according toa toxic levels ofimmunesignalingmol- tosecretedeveloping neuro embryo - population of cells in the cranium of a author. ences. Priest is the lead author, and Ashley is the senior Sept. 26inProceedings oftheNational Academy ofSci- wethe test.” started and therest of the team, collected a blood sample and testing. So that night I went and talked to the parents prehensive diagnosisthantheavailable clinicalgenetic quencing —thatcouldmakeafasterandmore com- “and wetool—rapidwhole-genomese- hadanew could help. diatric cardiology, heard they aboutthecaseandknew of genetics,andJames Priest, inpe- MD,aninstructor Euan Ashley, FRCP, DPhil, aprofessor ofmedicineand Medicine’s CenterforInherited Cardiovascular Disease, Volume 8, No.18Volume 8, abnormally smallheads,abnormally aconditioncalledmicrocephaly. Women infected with the Zika virus can give birth to babies with By KristaConger affects cranial precursor cells Scientists findhow Zikavirus Getting onthecase A By JennieDusheck The doctorssoondiagnosedthebaby withaheart Her parents, Sici Tsoi andEdison Li,hadnoteven Three years ago, when a newborn baby at Lucile Although thestudywasconducted Infection by theZika causesa virus While Astrea Libeganasix-week stayinthehospi- A paper describing the case was published online “We realized how sick this child was,” Priest said, At a regular weekly clinical meeting of Stanford sick babywayfordoctorsto andopeninganew cine hassolved ageneticmystery, diagnosinga team ledby researchers attheSchoolofMedi-

Normal inside Stanford medicine Alil October 10, 2016 October a Medi Microcephaly ca l Medi a /Shutter “Cells inthecranialneuralcrest give rise medicine CatherineBlish, MD,PhD. small skulls,” saidassistantprofessor of small heads. fect calledmicrocephaly, orabnormally de- cansuffer from abirth with thevirus for whybabiesborntowomeninfected it mayprovide onepossibleexplanation solely incellsgrowndish, inalaboratory s t oc “Affected babieshave smallbrainsand k. com Nicholas Bayless andRachel author. Graduate students & Microbe. Blish isthesenior online Sept. 29inCell Host development.” formation andaltered neural ing risetodeficitsinskull neural crest cells,perhapsgiv- Zika couldinfectcranial virus ing brain. We wondered ifthe nicheforthedevelopportive - sup- also formanimportant the skullandface,they ofto thebonesandcartilage PublishedbytheOfficeofCommunication&PublicAffairs The studywaspublished a broadteamofphysicians andresearchers tounderstandthereasons behindthegirl’s heartproblem. Astrea Li, pictured here withfatherEdisonLiandmotherSici Tsoi, begangoingintocardiac arrest soonafterherbirththree years ago. Ittook related cells marked for a separate fate. within hoursafterconception,leavingasmalllineageof when hercellswere firstdividingasanearlyembryo, cells. It waspossibleforamutationtohave occurred wondered if Astrea might be a mosaic of two kinds of variants was unusual. Because ofthat oddratio, Priest problems. the mutationwascapableofcausingsuchseriousheart up againsttwoproblems. First, hewasn’t positive that found asuspicious mutation, but heimmediately ran gene variants known tocauselongQT syndrome. He tal, Priest looked in her blood cells for any of several Second, theratiobetween normal andmutatedgene See Zika, page6 requires adaptability. How canyou rec- we alsoknow success that evolutionary fully passed on to future generations. But genetic codeandtoassure thatit’s faith - that existtoprotect theintegrityof number of mechanismsextraordinary of thestudy. “We know thatthere are an velopmental biology, whoisleadauthor chemical and systems biology and of de- Daniel Jarosz, PhD, assistant professor of lieved, andcouldplayarole inevolution. is more widespread thanpreviously be- humans —protein-based inheritance and possiblyotherorganisms,including issue ofCell, indicatesthatinyeast ­ of Medicine. studybynew researchers attheSchool down to their offspring, according to a times and pass the advantageous traits cow hard disease,canhelpyeast survive agents of deadly brain disorders like mad By RosanneSpector can passonbeneficialtraits Prions, proteinswithabadrap, “In evolution there’s aparadox,” said The study, publishedintheOct. 6 Prion proteins, bestknown asthe sequencing of Astrea outin-depth cameinweekends, tocarry everything, other Stanford faculty. Personalis “The teamdropped firm calledPersonalis thatAshleyhadco-foundedwith They did this by turning to colleagues at a sequencing Service. co-directs Stanford Health Care’s Clinical Genomics ford CenterforInherited Cardiovascular Disease and dramatic asitgets,” saidAshley, whodirects theStan- two tothree weeks ofhigh-intensitywork andaboutas Connecting thedots Connecting all the dots was a huge hurdle. “It was First theyhadtoconfirmthatthevariant wasreal. — suggests this could be the case. oftheanswer.be part studyThe new limited?” raw materialforthatinnovation isreally oncile thatneedwiththefact of kids it rosz. “Once itcatchesonwitha couple fashion trend amongteenagers,” saidJa- a template. its kindfollow suit,usingtheoriginalas a chain reaction Other of sorts. prions of and foldthemintoashapethat kicksoff These chaperones wraparound prions or proteins thathelpotherproteins fold. proteins calledmolecularchaperones — they begin producing large quantities of stressed, inthiscaseby theblazingsun, of theyeast cellsfloatinginyour beerget beer onahotsummerday: When some Let’s considerthisscenarioinabottleof to know abitabouthow prionswork. How prionswork Jarosz had a hunch that prions might “I sometimes liken it to a spreading To understandhishunch,you need See norbert v See Page 4 ceremony. medical school at a traditional white lab coats received crisp, biosciences dents in the graduate stu- First-year prions, page5 mosaic, page7 on der gr oeben A conversation from space with astronaut, Stanford alumna

steve castillo By Holly Alyssa MacCormick lected to be a flight engineer for the ISS Expedition 48-49. On July 6, when she “Hello, Houston? This is George.” launched into space aboard the Soyuz George Mauro, the lead audio-video MS-01 with crewmates Anatoly Ivan- technician at the Li Ka Shing Center for ishin of Russia and Takuya Onishi of Learning and Knowledge, cupped a hand Japan, she became the 60th woman in over his cellphone’s mic and whispered, space. “I’ve always wanted to say that.” On detecting life, colonizing Mars Mauro was setting up a video feed from the center’s Berg Hall to the In- “What do you think is the best proxy ternational Space of life that we Station, via the could search for?” Johnson Space “It’s pretty fun to be a asked Zinaida Center in Hous- Good, a gradu- ton, for a question- scientist in space.” ate student in and-answer session immunology. with astronaut and “Any instru- Stanford alumna Kate Rubins, PhD, ment we send to another planet, or on who was aboard the space station. crewed missions outside of lower Earth Suddenly, two giant video screens orbit, would definitely have a suite of came to life in the hall. On them, a small tools to try to detect life,” Rubins said. dot, indicating Rubins’ position in low This would likely include some way to Earth orbit, glided past Australia. The detect antibodies and nucleic acids, she space station was traveling nearly five added. miles per second. “The thing is, we don’t exactly know A little before 1:15 p.m. on Sept. 29, what we are looking for. Nucleic acids the Johnson Space Center patched the off the Earth may be different than what room through to the video feed, and we are looking for on the Earth,” Rubins Rubins’ smiling face, framed by a fan of holly alyssa maccormick blonde, gravity-defying hair, filled the two screens. The packed lecture hall erupted in ap- plause. Moderator David Relman, MD, a professor of medicine and of microbiol- ogy and immunology, beamed. He was Rubins’ thesis co-adviser when she was a PhD student at Stanford. ‘Greetings from Earth’ “Kate, this is David. It’s good to see you!” Relman said. “I have to say this — because how often do you get to say this? — greetings from Earth.” Rubins laughed. “I have to say this, because I don’t get to say this often: Greetings from space.” “Kate spent a significant fraction of her graduate career in a spacesuit,” Rel- man quipped, referring to her studies of smallpox and Ebola, for which she at times wore a positive-pressure-supplied- (Top) David Relman served as the moderator for a Sept. 29 question-and-answer session with astronaut and Stanford alumna Kate Rubins, who is aboard the International Space Station. (Above) During the Q&A, a live video of Rubins was projected onto two screens in Berg Hall at the Li Ka Shing Center for Learning air protective suit. and Knowledge. (Below) Postdoctoral scholar Andrew Hryckowian speaks with Rubins. After receiving a PhD in cancer bi- ology from Stanford in 2006, Rubins became a Whitehead Fellow at MIT. said. “So, I think [we should] employ a taining life off the planet.” in the audience: “It’s pretty fun to be a Then, in 2008, NASA issued a call for variety of tools, basically everything in Relman asked, “Looking back at grad- scientist in space, but it’s also incredibly applications for the Astronaut Candi- our arsenal … to look for life elsewhere.” uate school, is there something you think fun to be a scientist on Earth. I hope that date Program, and Rubins told Relman “What do you think are the biologi- helped prepare you for what you are do- some days when the experiments get a of her childhood dream to travel into cal challenges of colonization on Mars?” ing now?” little grinding, you think about how in- space. “She asked if I would provide a asked Gustavo Catao Alves, a PhD stu- Rubins replied, “Getting the chance credibly lucky we all are to be able to ob- letter of recommendation,” Relman said. dent in geophysics. to be at Stanford, to do work there, to serve the world around us.” “It was one of the easiest letters I’ve ever “I think we are driving toward living train under you and Pat [Brown, MD, The event was made possible by the written.” on Mars. The space station is an example PhD, professor emeritus of biochem- Dean’s Office at the School of Medicine; In 2009, NASA chose her from more of where we are taking our first steps to- istry] and all of the associated mentors, the Stanford Medicine Alumni Associa- than 3,500 applicants to be one of 14 wards that,” Rubins said. “We take our friends and colleagues there, taught me tion; and NASA, in particular astronaut members of NASA Astronaut Group 20. coffee in the morning and we turn it into to be a scientist. I put this to use every Christina Koch and her colleagues in As the Q&A session began, Rubins tomorrow’s coffee, as we often say up day.” the Astronaut Office at NASA’s Johnson described what it was like to transition here. We take every bit of water from the Rubins then addressed the students Space Center. ISM from being a viral disease researcher to an system and we recycle it. … We take wa- astronaut, saying, “Astronauts don’t spe- ter molecules, split them and make oxy- steve castillo cialize anymore. Scientists are trained to gen for us to breathe. We scrub the CO2 fly and pilots are trained to be scientists.” out of the environment. We are making Rubins, already an experienced scien- our own atmosphere. … That, I think, is tist, learned to fly a T-38 jet and was se- a proving ground for technology for sus-

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2 October 10, 2016 Inside Stanford Medicine Researchers receive NIH grants for ‘high-risk’ work

Seven researchers at Stanford have received awards totaling $10.25 mil- lion from the National Institutes of Health to explore bold approaches to major research challenges. The Stanford recipients are among 88 scientists nationwide to receive Pioneer, New Innovator, Transformative Research and Early Independence awards through the NIH’s High-Risk, High-Reward program. The awards total about $127 million and are supported by the NIH’s Common Fund. “The program continues to support high-caliber investigators whose ideas stretch the boundaries of our scientific knowledge,” said NIH director Francis Collins, MD, PhD. “We welcome the newest cohort of outstanding Jason Andrews Sean Bendall Alia Crum scientists to the program and look forward to their valuable contributions.” Six Stanford scientists received New Innovator Awards, and one received an Early Independence Award. Six of the recipients are from the School of Medicine, and the seventh is from the School of Humanities & Sciences.

New Innovator Award different, their blood The New Innovator Award provides up to $1.5 hormone states reflect million over five years to fund innovative research their expectations — by an investigator who has not yet received a re- not their meals. People search project grant or the equivalent from the who thought they were NIH. getting a low-calorie Elizabeth Egan Polly Fordyce Anshul Kundaje Jason Andrews, MD, assistant professor of in- snack had hormone lev- fectious diseases, plans to use his award to study els indicating that they weren’t done eating. Those Fordyce is a mem- a new way of detecting tuberculosis by testing air who expected to be full felt full. ber of Bio-X and Stan- samples in public spaces. She carried out similar work with exercise. ford ChEM-H. Tuberculosis affects 9.6 million people every Simply by telling hotel maids their work counted Anshul Kundaje, year and causes 1.5 million deaths annually, mak- as exercise was enough to elicit some of the ben- PhD, assistant profes- ing it the No. 1 cause of death by infectious dis- efits of an active lifestyle. Women who considered sor of genetics and of ease. Resource-limited countries have traditionally their work exercise lost weight, had lower blood computer science, will tried to control TB by waiting until people show pressure and had smaller hip-to-waist ratios. use his New Innovator up in in a hospital, clinic or doctor’s office with Elizabeth Egan, MD, PhD, assistant professor Award to harness the symptoms, and to then test them for the disease. of pediatrics, will use her grant to study genetic power of vast biologi- Aashish Manglik But infected individuals may be capable of trans- characteristics that influence human susceptibil- cal data sets to under- mitting TB to others for as much as a year before ity to malaria. Malaria drugs are losing effective- stand how gene expression is regulated in healthy they’re diagnosed. Early screening of individuals ness as the malaria-causing parasite, P. falciparum, and diseased cells. In particular, he is working to would be ideal, but individual screening is costly develops resistance to them. Instead of targeting develop new machine-learning approaches based and not sustainable in poor countries where the vulnerabilities of the parasite, which can evolve on deep neural networks to decode the noncod- TB burden is greatest. to avoid attack, Egan’s team wants to understand ing portion of the human genome and identify More than 80 percent of transmissions can- how host factors influence the parasite’s biology. disease-associated genetic variation. not be linked to close contacts among household Findings from these studies may ultimately lead “The deluge of functional genomic data pro- members. Andrews intends to use custom-built to the development of drugs that strengthen hu- vides a unique opportunity to leverage new, deep- air-sampling devices and highly sensitive molec- mans’ inherent defenses against malaria. learning approaches to decode cellular function,” ular diagnostic techniques to study the utility of The malaria parasite causes illness when it in- said Kundaje. “The methods we develop will be testing for TB in the air in public settings, such as vades red blood cells, and physicians know that highly generalizable to several problems in ge- schools, churches and public transit, in the hope some people with certain genetic traits — such nomics and will contribute to the foundation for of locating the “hot spots” where TB transmission as those who carry one copy of the gene for the a paradigm shift in computational genomics.” occurs. blood disease sickle cell anemia — are naturally Kundaje is a recipient of the 2014 Alfred Sloan Andrews is a member of Stanford Bio-X. more resistant to malaria. However, because red Fellowship and was the lead computational ana- Sean Bendall, PhD, assistant professor of pa- blood cells lose their genome and nucleus before lyst for the Encyclopedia of DNA Elements, or thology, will focus his grant on single-cell pro- they mature, it is difficult to study the genetics of ENCODE, project and the Roadmap Epigenom- teomics — an approach that provides a snapshot the cells. ics Project. He is also a member of Bio-X and of of a cell’s protein profile that can yield valuable To avoid this problem, Egan’s team will use a the Stanford Neurosciences Institute. information about its identity and function. concept known as forward genetic screening: They He will use the technique to study some of the will generate many blood-forming stem cells with Early Independence Award earliest precursors of our blood and immune sys- different genetic changes, induce them to mature tem cells in an effort to identify those that can into red blood cells, and test how well the various Aashish Manglik received an Early Indepen- customize and broaden hematopoietic stem cell cells can be infected by the malaria parasite. Their dence Award, which supports promising young therapies. Currently, about 20,000 such trans- studies will then explore exactly what mechanisms investigators with up to $1.25 million over five plants are performed each year to reconstitute the in the red blood cells enable infection by the para- years. The awards are meant to allow exceptional immune systems of cancer patients who have re- site, ultimately aiming to provide insights for cre- early career scientists to more quickly assume in- ceived lethal doses of chemotherapy or radiation ating new antimalarial medications. dependent research positions by eliminating or to treat their disease. Only about 1 percent of all Egan is a member of the Stanford Child Health shortening the traditional postdoctoral training cells transplanted, however, are true multipotent Research Institute. period. stem cells. Polly Fordyce, PhD, assistant professor of ge- Manglik, MD, PhD, instructor of molecu- “Leveraging single-cell proteomic technologies netics and of bioengineering, specializes in devel- lar and cellular physiology, focuses on decoding that we have pioneered, we can capture cell iden- oping new instrumentation and assays for making the molecular basis of transmembrane signal- tities and functional information on millions of quantitative, systems-scale biophysical measure- ing and transport in order to understand how individual cells in a single experiment,” said Ben- ments of molecular interactions. cells recognize and respond to their extracellular dall. “This will allow us to comprehensively char- She will use the funds from her award to build environment. acterize the nature of these most primitive cells upon a method her lab recently developed for He intends to direct his NIH funding toward and their function in human regenerative medi- producing small beads with unique color char- the study of ferroportin, the key transporter in cine, health and disease.” acteristics. A goal is to expand this palette to en- the body responsible for regulating iron levels in Bendall is a member of Bio-X and of the Stan- compass thousands of easily differentiated color the blood. Ferroportin, in turn, is regulated by a ford Cancer Institute. codes. These beads can be linked to different types hormone called hepcidin, which previous research Alia Crum, PhD, assistant professor of psychol- of molecules in a way that uniquely associates a has shown binds to and degrades ferroportin in ogy, will use her award to continue examining given type of attached molecule to a particular the presence of high serum iron levels. Ferroportin the ways in which a person’s mindset alters their color code, allowing myriad molecules and their or hepcidin dysfunction can result in hemochro- physiology and behavior. Her work is inspired by interactions to be simultaneously tracked by im- matosis, also known as iron overload, or various the placebo effect and looks at the ways in which aging tiny amounts of material with a microscope anemias. a person’s mental state can elicit physical changes. in the same amount of time it takes to measure a There are no approved therapeutics that work One example is in work she did examining single interaction. by altering ferroportin or hepcidin levels, activi- nutrition labels. She took identical vanilla milk- By linking thousands of different, short protein ties or interactions. Manglik’s work aims to un- shakes and labelled them in two different ways — pieces, or peptides, to the beads, Fordyce hopes derstand how ferroportin works at the most basic one low calorie and healthy, the other indulgent to learn more about how proteins interact with level in order to produce new knowledge and new — then examined blood levels of a hormone that one another inside cells. Similarly, attaching thou- reagents that may lead to drugs capable of treating signals satiety. sands of small nucleotide sequences to these beads hemochromatosis or anemia by inducing favor- What she found is that if people eat the same should permit the development of new ways of ex- able changes in the ferroportin-hepcidin pathway. thing but think they are eating something very tracting information from single-cell sequencing. ISM

Inside Stanford Medicine October 10, 2016 3 New bioscience students welcomed as ‘partners in discovery’ photos by norbert von der groeben By Tracie White

Dirk Spencer, future plant scientist, sat grinning nervously with his new white lab coat draped carefully across his knee, waiting for his life as a Stanford gradu- ate student in biology to officially begin. “We are here to celebrate a very important mile- stone,” said Will Talbot, PhD, professor and chair of developmental biology, and the School of Medicine’s senior associate dean for graduate education and post- doctoral affairs. Talbot addressed the crowd of first-year bioscience students, their families, friends and col- leagues, seated in Berg Hall at the Li Ka Shing Center for Learning and Knowledge. “We are here to welcome our new partners in discovery.” Spencer, a 22-year-old from Brooklyn, was one of 122 new bioscience students chosen from an applicant pool of 1,959 who began classes Sept. 26. On Sept. 28, the students were awarded crisp, white lab coats during an annual ceremony welcoming them to their graduate- level studies at Stanford. “All I know about the ceremony is I’m not supposed to put on the lab coat until I walk across the stage,” said Spencer, chatting before the start of the event about how his research interests in plant biology could have relevance for human health by solving problems related to nutrition and food security. He just wasn’t quite sure how yet. ‘A formal start’ “It’s like a formal start to everything,” said another new graduate student, Ron Shanderson, an Atlanta na- tive whose childhood love of dinosaurs morphed over time into an interest in cancer biology. The students, who sat grouped together according to their departments, listened as Talbot welcomed them and introduced Lloyd Minor, MD, dean of the School of Medicine. “The key is this: Don’t become discouraged,” Minor said. “This is a game of the long haul. … What may seem like a small advance later may be one of the most impactful things that you’ve done in your life.” Minor shared a quote by School of Medicine faculty member Michael Levitt, PhD, reflecting on his career after winning the Nobel Prize in chemistry in 2013: New graduate students in the biosciences pose for a group photo with Gregory Frank, a former member of the Stanford Medicine Alumni “‘You never really have a single “Eureka” moment. Association’s board of governors; Theodore Leng, president of the alumni association; Will Talbot, the medical school’s senior associate dean There are a lot of small steps. Each time you solve a for graduate education and postdoctoral affairs; and Lloyd Minor, dean of the medical school. step, that’s great — but there’s another step. It’s really important not to give up.’” ysitter, weren’t able to make it to the ceremony. Both join the dean for a reception and dinner on the Alumni Minor added, “In fact it was only in looking back at his parents, who immigrated to the United States from Lawn. his science in his early years that he could understand the West Indies, were back home in New York. He said They adjusted their new coats, some too big, some how every step mattered. ... His research in the early his grandfather made him promise he’d visit him in the too small, some just right. 1980s directly led to a $40-billion industry in anti- West Indies when he graduated. “We’re in now,” one student said as she walked out- cancer drugs.” “When I told my parents I might be a plant scientist, side. “They can’t take it back, right?” ISM Receiving lab coats my father wasn’t quite sure about it,” Spencer said. He said he’s both excited and overwhelmed by the op- As the speeches ended, the students lined up to re- portunity to improve the future of human health ceive their coats. Biochemistry students came first, fol- through plant research. lowed by those in bioengineering, then biology, and As each of the various faculty members intro- so forth. Like all the other students, Spencer folded duced their new students, and watched them put his white coat across his left arm and got in line, then on their coats, they offered words of welcome. walked across the stage, put on his new coat with help “We look forward to seeing what you can do,” from Talbot, and shook the dean’s hand. said Tony Ricci, PhD, professor of otolaryngol- The crowd cheered as each student walked across the ogy, who introduced the neurosciences students. stage. Family members and friends took photos. Students chatted and laughed as they left the The new graduate students — 56 women and 66 building, heading out to take a group photo and men — are entering 14 different bioscience programs, such as biochemistry, neurociences and genetics. Eigh- (Clockwise from right) Minor shakes hands with new MD-PhD teen already have advanced degrees, and 26 are consid- student Binbin Chen at the Sept. 28 lab coat ceremony for ered underrepresented minorities in the biosciences. first-year students in the biosciences. New graduate students Twenty-six were born in countries outside the United prepare to go onstage at the ceremony, which was held at States, including Panama, Hong Kong and Venezuela. the Li Ka Shing Center for Learning and Knowledge. Talbot Spencer’s father, a plumber, and his mother, a bab- helps Dirk Spencer into a lab coat as Leng looks on.

4 October 10, 2016 Inside Stanford Medicine Community advisory board new resource for Stanford researchers By Ruth Schechter one of only a handful of such enterprises in the country for reaching specific populations but also for strength- focused on clinical research engagement in the com- ening grant submissions since funders often look for Ryan Matlow, PhD, a Stanford instructor of psy- munity. Members were carefully screened and received community partnerships. chiatry and behavioral sciences, was conducting a study training in research fundamentals, as well as their roles Board member Ngoc Nguyen, a San Francisco on mental health education and interventions in local and responsibilities for their volunteer service. health journalist, said she thought the investigators school districts. But getting children to participate in “Researchers often struggle to engage diverse com- have found the group’s suggestions helpful and ap- the three-year project, as well as retaining them, was be- munities in their project. The solution is to encourage preciated the input. “Health interventions come from coming a challenge. He also was having trouble devel- them to participate as partners, which also means go- research,” she said. “Identifying relevant interventions oping a way to keep numerous administrators, teachers ing back to them with results or resources,” said board requires asking questions that make connections so and families up to date on his study’s progress. member Nancy Brown, PhD, a clinical investigator and more people will benefit. The process is just as mean- So Matlow decided to present his study to the Com- education projects manager at the Palo Alto Medical ingful as the results.” munity Advisory Board for Clinical Research for feed- Foundation. “The idea norbert von der groeben back and guidance. here is to bring together “The board had some really good ideas on engage- different people to ment and retainment, and gave me some specific share different perspec- recommendations on how to manage the multiple tives. It’s a resource to partnerships of the project,” he said. “Presenting to an help researchers think impartial audience also helped confirm to me that my about their stakeholders basic approach was on the right track.” so both parties get what Help reaching diverse participants they need.” At one recent pre- The board is made up of 23 Bay Area residents sentation, for example, from diverse backgrounds and communities who are board members sug- involved in health care, education, law, public ser- gested that a research vice, community groups, business and religious orga- team include more nizations. Its goal is to provide insights and advice to detail about its meth- Stanford investigators on recruiting study participants odology. After further from a broad range of ethnicities, cultures, ages and discussion they recom- economic backgrounds. The board also offers advice on mended including in- Kathy Orrico, Jill Evans and Phil Dah are on the board, which aims to provide researchers with insights ways to appeal to those who might not normally sign centives for children to and advice on recruiting study participants from a broad range of ethnicities, cultures, ages and economic up for a research study. make them feel more backgrounds. Research has shown that gender, ethnicity and life- involved in the research, style play a role in incidences of certain diseases and providing travel vouchers to help with transportation Many of the board members are well-connected in health-related events. While research studies are de- costs and creating video testimonials for a registration their community and can network to help publicize signed to develop new protocols or gain insights into website. At another session, the board pointed out ways research recruitment efforts. “The goal is to get away medical conditions, minority populations tend to be to create a feedback loop to encourage a sense of team- from the standard population sample,” Brown said. underrepresented in them, and researchers often strug- work for members of the community. “We understand how difficult it is to get people to par- gle to find ways to recruit members from these groups. “CAB is a resource for investigators,” Prochaska said. ticipate in a study, and we really want to help.” “The board acts as a bridge between Stanford and “Study design involves all phases, from concept to dis- Prochaska and the board co-chairs plan to evaluate the community, helping researchers be more respon- semination. Refinements can be incorporated at any the board’s role on a regular basis, using feedback from sive to the kinds of questions and concerns the public stage.” both researchers and board members after each session, may have,” said Judith Prochaska, PhD, MPH, asso- Giving presentations and surveying presenters to determine what kind of ciate professor of medicine in the Stanford Prevention feedback would best aid their projects. Research Center and the board’s faculty co-chair. “It’s Investigators are asked to provide a project overview In the meantime, Matlow has incorporated some of a partnership to help researchers inform their science to board members in advance of meetings and discuss the board’s suggestions on how to better coordinate the to meet community needs. CAB members are able their current strategy and concerns during their presen- multiple administrators, schoolteachers and families in- to share their perspectives, and researchers receive tations, which are followed by extensive question-and- volved in his three-year research project. guidance on ways to improve protocols, design and answer sessions. Currently, researchers in most clinical “They’re the perfect group to go to, and they are a recruitment.” fields and at any stage of development are welcome to great resource for Stanford Medicine researchers,” he Uncommon enterprise submit their study for board review. They’re under no said. “It’s a neutral and confidential setting to process obligation to incorporate the board suggestions. (Can- how to manage some of the complexities of designing The board was established in March by the Stanford cer protocols are excluded because of the deep resources and refining a research project. And there’s a founda- Center for Clinical Research, in partnership with the available through the Cancer Clinical Trials Office.) tion there if I want to go back.” Office of Community Engagement in the Stanford Prochaska said the process is an important step not More information is available on the Stanford Cen- Center for Population Health Sciences. The board is only for refining recruitment methods and incentives ter for Clinical Research website. ISM

norbert von der groeben Prions genes they revved up, they found 46 most genetic mutations, prion traits are continued from page 1 made proteins that led to traits that re- dominant, and they don’t obey Mendel’s mained heritable many generations after laws. Rather than being passed to half spreads rapidly to other teenagers. But their expression had returned to normal. of all progeny in genetic crosses — as only teenagers.” The traits were generally beneficial, such Mendel saw with his peas — prion-based The upshot is that a single prion can as resistance to temperature stress and traits are transmitted to every cell. quickly convert many others to assume anti-fungal drugs, or enhanced growth at Additionally, when the researchers the same shape — and since a protein’s high temperatures. temporarily inhibited chaperone pro- shape dictates its behavior, that means When they analyzed the proteins’ teins, the prion-based traits were perma- the prion converts the other proteins’ shapes, they discovered that few of them nently eliminated. behavior as well. Furthermore, when a resembled what researchers had ex- For the ultimate test, the research- cell divides, both new cells are likely to pected prions to look like. Most previ- ers destroyed the DNA in the yeast cells carry prion proteins that will continue ously known prions fold in such a way carrying what they believed were prion- to spur conversions. That means the off- that they pack tightly together and form based traits, collected the remaining spring will also display the new behavior, long fibrils. The newly discovered prions cell contents and introduced it into or- a result of inheritance perpetuated not James Byers and Daniel Jarosz were part of a lacked that trait, but many had others in dinary yeast cells. They found the traits through the standard means of DNA but team that investigated how commonly traits in common: They were strongly attracted were transmitted even though the cell’s instead by way of proteins. yeast are passed down by way of prion proteins to DNA molecules and they featured DNA had been destroyed — indicating In the case of mad cow disease, a instead of DNA. long, floppy “arms” able to fold in a wide that proteins were transmitting the traits prion leads its normal brethren to fold variety of ways. instead. in a way that leads to tissue damage in sistant professor in 2013, he began what Non-Mendelian inheritance The researchers also found several the brain and spinal cord of cattle. A hu- would become a nearly three-year project human genes that would make proteins man version of the disease, called vari- to systematically assess an organism for Digging up unknown prions in yeast with similar characteristics. “These do- ant Creutzfeldt-Jakob disease, can result prion-based inheritance. He chose yeast, is less dangerous than you might think, mains have been widely conserved across from eating beef products from infected he said, because researchers around the said Jarosz. The efficiency of cross-spe- evolution, and several human homologs cattle. world have established the organism’s cies templating is very low for prion pro- had the capacity to fuel protein-based in- They’re not all bad genetics and have developed comprehen- teins. “This is probably one of the major heritance,” they wrote in the study. “Our sive tools to analyze them. reasons that mad cow disease wasn’t data thus establish a new and common But Jarosz knew that not all prions are “I wanted to know the breadth of more widespread,” he said. “There is a type of protein-based molecular memory bad. He had learned about a few benefi- protein-based inheritance across the safety concern with the human proteins. through which intrinsically disordered cial ones from his time as a postdoctoral yeast genome. Is it really so rare?” But luckily, simple procedures, like treat- proteins can drive the emergence of new scholar at the Whitehead Institute for With the help of several robots, his ing with bleach or soaking in sodium traits and adaptive opportunities.” Biomedical Research in the laboratory team overexpressed nearly every yeast hydroxide, can render these protein con- The work is an example of Stanford of Susan Lindquist, PhD, a co-author of gene, one by one, for 48 hours — trig- formations harmless.” Medicine’s focus on precision health, the the study who has pioneered investiga- gering each gene to create 10 to 100 The team also found that the traits goal of which is to anticipate and prevent tions of prions as a driver of inheritance. times more copies than usual of the pro- followed prionlike inheritance patterns. disease in the healthy and precisely diag- When Jarosz came to Stanford as an as- tein designated by its code. Of the 5,300 For example, unlike traits resulting from nose and treat disease in the ill. ISM Inside Stanford Medicine October 10, 2016 5 Air-bag helmet could reduce impact of head in bike crashes Saul Bromberger and Sandra Hoover

By Taylor Kubota at two different angles, simulating hits to the crown and the side of the head. David Camarillo knows all too well Researchers dropped the helmets from as that bicycling is the leading cause of low as 0.8 meters to as high as 2 meters sports- and activity-related concussion and measured the linear acceleration of and brain injury in the United States. the helmet as it struck the ground. He’s had two concussions as the result A crucial caveat of bicycling accidents. While he doesn’t doubt that wearing a helmet is better Camarillo said the large size of the than no helmet at all, Camarillo thinks air-bag helmet compared to foam bike that traditional helmets don’t protect rid- helmets is the likely source of its suc- ers as well as they could. cess. Being larger, it can also be softer, “Foam bike helmets can and have allowing for a more cushioned fall. How- been proven to reduce the likelihood ever, this cushioning also has a potential of skull fracture and other, more severe downside. In the testing, the air-bag hel- brain injury,” said Camarillo, PhD, an met was pre-inflated, and the researchers assistant professor of bioengineering at maximized the pressure of the air inside Stanford. “But I think many falsely be- the helmet before each drop in order to lieve that a bike helmet is there to protect get these results. against a concussion. That’s not true.” “As our paper suggests, although air-

Knowing what he does about tradi- bag helmets have the potential to reduce kurt hickman tional bike helmets, Camarillo, whose the acceleration levels that you experi- lab works on understanding and prevent- ence during a bicycle accident, it also ing concussion, decided to test a new suggests that the initial pressure that type of helmet that is starting to be avail- your air-bag helmet has is very critical in able in some European countries. reducing these acceleration levels,” Kurt A paper describing the results was said. published Sept. 27 in the Annals of Bio- Without the maximum amount of medical Engineering. Camarillo is the air, the air-bag helmet could bottom out, senior author, and postdoctoral scholar causing the head to hit the ground with Mehmet Kurt, PhD, is the lead author. much more force than if it were wear- Reduced acceleration ing a traditional foam helmet. In current versions of the air-bag helmet, a chemi- The helmet Camarillo tested comes cal process triggers expansion, which in a soft pocket worn around the neck. doesn’t seem to guarantee maximum air It pops up, like an air bag, around a pressure. person’s head when it senses a potential Linear acceleration and concussion collision. It was originally designed to address the fact that people don’t like to In this study, the researchers measured wear helmets for aesthetic reasons. The linear acceleration of a head upon impact David Camarillo (top) and Mehmet Kurt are co-authors of a study that evaluated a new type of bicycle researchers compared this air-bag helmet to determine the risk of skull fracture helmet for its potential to reduce concussions. directly to traditional foam bike helmets. and head injury. Linear acceleration does Their results were striking. not directly relate to risk for concussion. Better helmet testing “We conducted drop tests, which are Concussion is a rapidly evolving area of The drop test used in this study is cur- typical federal tests to assess bicycle hel- research, but experts currently think that rently the standard test for bicycle hel- The air-bag helmet is not available in mets, and we found that air-bag helmets, it may be related to angular stretching of mets. Testing the abilities of the helmets the United States but is sold in some Eu- with the right initial pressure, can reduce the brain, which is more likely caused by to reduce rotational forces would better ropean countries. head accelerations five to six times com- a twisting motion than linear motion. reveal how they could protect against “If our research and that of others pared to a traditional bicycle helmet,” “There are many theories as to why concussion, Camarillo said. However, begins to provide more and more evi- Kurt said. concussion happens, but the predomi- given the large advantage of the air-bag dence that this air-bag approach might The drop test consisted of putting the nant one is that, as your head rotates very helmet in this research, there is a good be significantly more effective, there will helmets on a dummy head containing quickly, the soft tissue within your brain chance it would reduce the likelihood of be some major challenges in the U.S. to accelerometers and dropping it, neck- contorts and, essentially, what you get is concussion compared to a foam helmet, legally have a device available to the pub- side up, from various heights onto a a stretching of the axons, which are the he said. lic,” Camarillo said. metal platform. The head form was tilted wiring of the brain,” Camarillo said. Even for See helmet, page 7

rapidly dying, as the neural precursors do, the cranial the fetus, causing devastating birth defects. Outbreaks Zika neural crest cells act as a reservoir for the virus by al- of the virus are currently occurring in multiple coun- continued from page 1 lowing it to replicate repeatedly. In addition, they begin tries and in three American territories: American Sa- to secrete high levels of cytokines, including leukemia moa, Puerto Rico and the U.S. Virgin Islands. Local Greenberg share lead authorship of the study. inhibitory factor and vascular endothelial growth factor, mosquito-borne transmission has also been identified A reservoir for the virus known to affect neural development. in two areas of Miami, and the World Health Organi- “The magnitude of altered cytokine secretion caught zation has designated the disease a public health emer- Cranial neural crest cells are cells that arise in hu- us by surprise,” said Blish. “These molecules are impor- gency of international concern. mans within about five to six weeks of conception. Al- tant for neurogenesis, and the infected cells are secreting “Our study brings attention to the possibility that though they first appear along what eventually becomes them at high levels.” other infected embryonic cell types in the develop- the spinal cord, the neural crest cells migrate over time Abnormally shaped cells ing head can influence Zika-associated birth defects, to affect facial morphology and differentiate into bone, including microcephaly, perhaps through signaling to cartilage and connective tissue of the head and face. When Bayless and Greenberg incubated neural pre- neighboring cells or by serving as a viral replication They also provide critical molecular signals that support cursor cells together with infected neural crest cells, the reservoir,” said Wysocka. “Formation of the cranial nearby developing neurons in the brain. neural precursors appeared abnormal and were more neural crest cells and a cross-talk between brain and cra- Bayless and Greenberg used a technique developed likely to initiate a program of cellular suicide. niofacial development occurs during the first three in the laboratory of study co-author Joanna Wysocka, They next exposed the neural precursor cells to leu- months of human fetal development, which is when PhD, a professor of chemical and systems biology kemia inhibitory factor and vascular endothelial growth epidemiological studies have suggested that Zika infec- and of developmental biology, factor at levels equivalent to tion correlates with poor birth outcomes.” to convert human embryonic those secreted by the infected The researchers said that although the findings are stem cells into cranial neural cells. After three days, they ob- intriguing and merit further study, their studies were crest precursors in the labora- served an increase in structures conducted only on cells grown in a laboratory and it is tory. Wysocka’s research focuses associated with cellular migra- possible that other factors related to Zika infection may on understanding how these tion and growth, as well as a affect brain size and outcomes in affected infants. cells affect the embryonic de- significant increase in the fre- Tomek Swigut, PhD, a senior scientist in Wysocka’s velopment of facial features, quency of cell death. lab, is also a co-author of the study. including those of humans and “At least in vitro, these el- The research was supported by the National Insti- chimpanzees. evated levels of cytokines appear tutes of Health, the Tashia and John Morgridge Fac- Recent research has focused Catherine Blish Joanna Wysocka to induce premature differentia- ulty Scholar Program from the Stanford Child Health on the effect of Zika virus infection of the neural pre- tion and migration,” said Wysocka. “This abnormal de- Research Institute, the March of Dimes Birth Defect cursor cells that give rise to neurons in the developing velopmental program then leads to cell death.” Foundation, the Howard Hughes Medical Institute, a brain. But Bayless and Greenberg found that not only The Zika virus, which is spread by the Aedes genus seed grant from the Stanford Center for Systems Biol- can cranial neural crest cells also be infected by the Zika of mosquito, has sprung into the public eye over the ogy and two Ruth L. Kirschstein awards. virus, they respond differently than their neighbor- past year as it has become increasingly apparent that Stanford’s Department of Medicine also supported ing neural precursor cells to the infection. Rather than pregnant women infected with the virus can pass it to the work. ISM 6 October 10, 2016 Inside Stanford Medicine norbert von der groeben Mosaic affect other parts of the body. continued from page 1 “And that really is a brand new phenomenon,” Priest added. Until recently, he said, no one had thought of and her parents,” said Ashley. The company’s scientists looking for mosaic gene variants as the cause of these established that the gene variant was real and present kinds of diseases. in Astrea but not her parents, indicating it was a new “What we are uncovering is a phenomenon that is mutation. much more common than we had ever anticipated,” To find out if the particular mutation they had iden- said Ashley. In fact, he said, “I think there’s enough tified could cause long QT syndrome, Priest and Ashley evidence now to suggest that a large number of people gave the sequence to a team of collaborators at Gilead, have some level of mosaicism,” although the genetic dif- a company that designs drugs to treat the disease. Gil- ferences are probably harmless in most of us. ead reported that the gene variant would cause long QT The team’s approach to this case is an example of syndrome. Moreover, they said, this mutation was espe- Stanford Medicine’s focus on precision health, the goal cially deadly. of which is to anticipate and prevent disease in the Next the Stanford team wanted to be sure that Astrea healthy and precisely diagnose and treat disease in the really was a mosaic individual; they needed to show that James Priest and his colleagues found that Astrea’s heart was ill. individual cells actually had different genomes, some composed of a mosaic of cells. Astrea’s mother said that when her daughter was first carrying the deadly mutation, some healthy. Each cell’s born, “we asked, ‘Is she safe now? Is she stable now?’ genome would have to be individually mapped. “That and one of the doctors told me, ‘We don’t know. But field was founded by Stephen Quake,” said Ashley, “so had been causing her long QT syndrome. even for your two older girls, there’s no guarantee they’ll having him here at Stanford, I called him and asked if The team still wondered, though, if a heart with 8 be healthy tomorrow. So treat Astrea like a normal kid he could help.” Quake, PhD, a professor of bioengi- percent mutant cells could really have caused Astrea’s se- and make every day count.’” neering and of applied physics who is also a co-author vere long QT syndrome. The team contacted colleagues Tsoi said this advice inspired her to become a differ- of the paper, and his team looked at individual cells in the Computational Cardiology Laboratory at Johns ent kind of mother. “I used to be very strict, but since from Astrea’s blood sample and showed that most of her Hopkins University, experts in computer modeling of that day whenever I want to do something with the cells had normal genes, but 8 percent carried the muta- cardiac electrical activity. The biomedical engineers’ kids, I just do it as soon as possible.” She advises other tion for long QT syndrome. Astrea’s blood cells were eventual computer model of a heart with a mosaic of parents, “Don’t think too much about the future, don’t definitely mosaic. healthy and mutant cells in the organ’s electrical tissue wait. Just do it.” But another question remained. It wasn’t yet clear if acted exactly the way Astrea’s real heart did. “It was an Earlier this month, Astrea celebrated her third birth- the baby’s heart tissue was also a mosaic of normal and important moment: a mosaic heart really could cause day. She does cartwheels with her older sisters and loves damaged cells. heart block and cardiac arrest,” said Ashley. to listen to the music from Frozen. Coming home in the Despite treatment with two drugs and the implanta- “We’d thrown everything we had at diagnosing the car with her mother recently, Astrea said, “I don’t want tion of defibrillator and a pacemaker, Astrea developed baby,” said Ashley, “but still we wanted to know, how to go home. I want to play outside.” an enlarged heart when she was about 7 months old. To common is this?” “And so we did,” said her mother. her parents, she looked healthy, but assessments showed Broader analysis Other Stanford-affiliated co-authors are former that she was in great danger; during a visit to the hospi- graduate student Charles Gawad, MD, PhD; assistant tal, her heart stopped again. Astrea needed a heart trans- To find out how often mosaicism might explain un- professor of pediatric cardiology Scott Ceresnak, MD; plant, and her name was quickly added to a waiting list diagnosed arrhythmia, the team partnered with a ge- postdoctoral scholar Frederick Dewey, MD, PhD; for- for a donor heart. “I thought it would be at least a year netic testing company with a database of arrhythmia mer pediatric electrophysiology fellow Lindsey Malloy- of waiting,” said Tsoi. But after just five weeks, someone cases. “We asked them, ‘How many cases of mosaicism Walton, DO, MPH; genetic counselors Kyla Dunn, from Stanford called and asked if she was driving. “Are have you seen when you looked at genes that cause ar- MS, and Megan Grove, MS; assistant professor of med- you in a safe place?” the voice asked. It was news of a rhythmia?’ The answer was about 0.1 percent,” Priest icine Marco Perez, MD; senior research scientist Norma donor. said. Neff, PhD; clinical associate professor of cardiothoracic On the day of Astrea’s transplant, her parents took The team’s work may offer a new way to finally de- surgery Katsuhide Maeda, MD; professor of pediat- their two older daughters and picnicked on the Stan- termine the cause of arrhythmias that previously had rics Anne Dubin, MD; and professor of cardiovascular ford campus, waiting patiently to hear how the surgery been a mystery, said Priest. About 30 percent of heart medicine Thomas Quertermous, MD. went. In the evening, they went to see Astrea. “The first arrhythmia patients don’t have a genetic diagnosis. This work was supported by grants from the Na- thing I saw was the monitor,” said Tsoi. “That was the “Maybe,” he said, “there are additional mutations that tional Institutes of Health. first time I’d ever seen the green line — the heart beat are in the heart only. Genetic tests are nearly always Stanford’s Department of Medicine also supported line — so stable and regular.” done on blood or other easily acquired tissues. So it’s the work. The tissue from Astrea’s original heart allowed re- easy to imagine a mosaic gene variant that occurs only Co-authors Ashley and John West are co-founders of searchers to determine that, indeed, 8 percent of the in the heart and doesn’t show up in the blood. Really, Personalis Inc., which performs clinical genetic testing, heart cells carried the deadly mutation they believed the same reasoning could apply to genetic diseases that and performed sequencing for the study. ISM

Helmet norbert von der groeben continued from page 6 conventional foam helmets, the standard testing doesn’t address some elements that science indicates matter when it comes to brain injury and head trauma, includ- ing assessment of rotational forces and drop tests of parts of the helmet other than the crown. The air-bag helmet would raise additional testing issues, including the fact that helmets are generally tested on a head dummy with- out a neck, which couldn’t wear the air-bag helmet. Future air bag helmet research The researchers plan to test how the air-bag helmet affects rotational accelerations and forces on the head during impact, and how it could reduce tissue-level strains in the brain. The researchers also want to more closely investigate the bottoming-out weakness of this helmet type, dropping it from greater heights and seeing how the air cushioning holds up. They also intend to work on making this helmet smarter. It already expands when it senses a likely im- pact, but they want it to be able to predict the severity of the impact and compensate accordingly. Other Stanford co-authors of the paper are Calvin Kuo, MD, PhD, professor of medicine; postdoctoral scholar Kaveh Laksari, PhD; and Gerald Grant, MD, professor of neurosurgery. Camarillo, Kuo and Grant are members of Stanford Bio-X, the Child Health Research Institute and the Stanford Neurosciences Institute. The study was supported by the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering, the Thrasher Research Fund, the Eating, drinking and being merry at staff BBQ David and Lucile Packard Foundation and the Child Alberto Lovell, Nghi Le and Natalia Kosovilka attend a School of Medicine Staff Appreciation Barbeque, featuring a catered lunch Health Research Institute Transdisciplinary Initiatives and live music, on Oct. 4. This year, the barbecues were held at five different campus locations on five different days. At each, Lloyd Program. Minor, MD, dean of the School of Medicine, and Marcia Cohen, senior associate dean of finance and administration, thanked the Stanford’s Department of Bioengineering, which staff for all that they do to support students, advance research and keep the medical school humming. is jointly operated by the School of Medicine and the School of Engineering, also supported the work. ISM Inside Stanford Medicine October 10, 2016 7 Gene could help explain insulin resistance, researchers say norbert von der groeben By Jennie Dusheck than did regular mice, even though all the mice got the Health researchers have known for decades that Type same amount of food and 2 diabetes results from a phenomenon called insulin re- water. sistance, but what causes insulin resistance has remained The mice without Nat a mystery. 1 also had a decreased abil- Now, researchers at the School of Medicine and the ity to use fat for energy, University of Wisconsin-Madison have begun to untan- said Knowles, and they gle a web of connections that includes a gene; mitochon- were also pretty slow on dria, which produce energy for cells; insulin resistance; the exercise wheel. “When and how well the body’s metabolism functions. we put a mouse on a tread- “We’ve identified a mechanism for insulin resistance mill and make them exer- that involves a gene that ties insulin resistance to mito- cise really, really hard, the chondrial function,” said Joshua Knowles, MD, PhD, mice that lack this Nat1 an assistant professor of cardiovascular medicine at gene don’t have the ability Stanford. to keep up with normal A paper describing the work was published in the mice,” Knowles said. “And Oct. 4 issue of Cell Reports. Knowles is the senior au- that supports the hypoth- thor, and Indumathi Chennamsetty, PhD, a postdoc- esis that poorly function- toral scholar at Stanford, is the lead author. ing mitochondria are part Insulin is a hormone secreted by the pancreas that of the problem.” helps fat and muscle cells take glucose from the blood. Insulin resistance is a When a person’s cells stop responding to insulin, the known forerunner to Type person has insulin resistance and glucose builds up in 2 diabetes. But insulin re- the blood, signaling the pancreas to produce ever more sistance by itself — char- insulin. acterized by the decreased Insulin resistance severe enough to damage body tis- uptake of sugar by muscle sues is common. One 2015 study estimated that nearly and fat cells — can lead 35 percent of all U.S. adults are sufficiently insulin to cardiovascular disease, resistant to be at greater risk of diabetes and cardio- inflammation, polycystic A team led by Joshua Knowles has begun to untangle the cause of insulin resistance, which can increase vascular disease. The environmental causes of the sky- ovary syndrome, fatty liver the risk of developing Type 2 diabetes. rocketing rate of insulin resistance in the United States disease and other health include poor diet and sedentary habits, but the molecu- conditions, even in people who do not have Type 2 effects. lar mechanisms have been unknown, said Knowles. diabetes. Other Stanford co-authors of the study are instruc- Suspect gene A person who is insulin resistant but still making tor in pediatric cardiology Michael Coronado, PhD; plenty of insulin may not have diabetes, said Gerald visiting graduate student John Sandin; research associ- Previous work by Knowles and his team linked a Reaven, MD, professor emeritus of cardiovascular med- ate Giovanni Fajardo, MD; postdoctoral scholars Kévin variant of a human gene called NAT2 with insulin re- icine and a co-author of the paper. But the person will Contrepois, PhD, Ivan Carcamo-Orive, PhD, Andrew sistance in humans. In mice, suppressing a similar gene, have higher triglyceride levels; lower levels of high-den- Whittle, PhD, and Mohsen Fathzadeh, PhD; professor called Nat1, caused metabolic dysfunction, including sity lipoproteins — the “good” cholesterol; and higher of genetics Michael Snyder, PhD; professor of pediatric decreased insulin sensitivity and higher levels of blood blood pressure. All of these conditions increase the risk cardiology Daniel Bernstein, MD; and professor of car- sugar, insulin and triglycerides. of heart disease. diovascular medicine Thomas Quertermous, MD. The new study shows that suppressing the expression Mystery of the slow-going mice Researchers at the University of Wisconsin-Madison of the Nat1 gene in mice interferes with the function also are co-authors of the study. of mitochondria — cell structures that make ATP, the Exactly why the Nat1-free mice have trouble run- This research was supported by an American Heart energy currency of cells. Without ATP, cells cannot live ning is something Knowles and his colleagues are still Association Fellow-to-Faculty Transition Award, the and function. working out. “Is that physically an effect on muscle, LeDucq Foundation and the National Institutes of In addition, mice whose Nat1 gene had been elimi- skeletal muscle? Is that an effect on the heart? We don’t Health. nated gained more weight and had larger fat cells and know exactly yet,” he said. Upcoming work will focus Stanford’s Department of Medicine also supported higher levels of biomarkers indicating inflammation on identifying a factor that links all these metabolic the work. ISM

Carla Shatz, PhD, the Sapp Fam- of note ily Provostial Professor, the David Starr reports on significant honors and awards Jordan Director of Bio-X and a profes- Stanford and Intermountain award for faculty, staff and students sor of biology and of neurobiology, was awarded the more than $500,000 in seed grants Lawrence Chu, MD, was promoted 2016 António to professor of anesthesiology, periop- Champali- Stanford Medicine and Intermoun- fraction in the community — Francois erative and pain medicine, effective maud Vision tain Healthcare have announced the re- Haddad, MD, clinical associate profes- Aug. 1. He is Award, which cipients of more than $500,000 in seed sor of cardiovascular medicine; Kirk the founder recognizes grants focused on transforming health Knowlton, MD, Intermountain cardio- and executive groundbreak- care. vascular medicine. director of the ing research on Earlier this year, the two organi- • Translational approaches to the health-inno- how eyes send zations announced a collaboration mechanisms of septic cardiomyopathy vation confer- signals to the to enable joint clinical, research and — Euan Ashley, MRCP, DPhil, associ- ence Medicine Carla Shatz brain. Shatz education projects that are expected ate professor of cardiovascular medicine; X. His research shared the prize to benefit both — and possibly the Samuel Brown, MD, Intermountain focuses on edu- of 1 million euros (about $1.12 mil- U.S. health-care system at large. Inter- critical care medicine. cational infor- lion) with three other researchers. Her mountain Healthcare is a not-for-profit • Implementation and evaluation of Lawrence Chu matics and on research has clarified mechanisms of health-care system based in Utah. graduating from pediatric to adult care opiate-induced brain development, including an unex- The seed grants were awarded to — Korey Hood, PhD, clinical professor hyperalgesia in patients with chronic pected role for certain immune-related projects that will be jointly led by prin- of pediatrics; Aimee Hersh, MD, Inter- pain. proteins. cipal investigators from Stanford and mountain pediatrics. Michael Fredericson, MD, profes- Rodrigo Valderrabano, MD, a Intermountain. The one-year, $75,000 • Impact of donor-derived BK virus sor of orthopaedic surgery, was awarded postdoctoral scholar, received a Young grants will take effect on Nov. 1. infection and immune recovery in kid- a Pac-12 Conference Student-Athlete Investigator Following are the names of the grant ney transplant recipients — Benjamin Health & Well-Being Grant. Freder- Award from the recipients and their project titles: Pinsky, MD, PhD, assistant professor icson directs Stanford’s sports medi- American So- • Whole-genome DNA sequencing of pathology and of infectious diseases; cine fellowship and is the head team ciety for Bone of stage-3 colorectal cancer — James Diane Alonso, MD, Intermountain physician for the university’s track and and Mineral Ford, MD, associate professor of oncol- transplant services. field team. He Research. The ogy and of genetics at Stanford; Lincoln • Development and implementation plans to use award recog- Nadauld, MD, PhD, Intermountain ge- of a digital health-care program for pa- the $482,000 nizes junior nomics and health precision. tients with atrial fibrillation — Mintu award to inves- researchers • Baseline assessment of hand hy- Turakhia, MD, assistant professor of tigate methods who submit giene practices and ICU microbiology cardiovascular medicine; Jared Bunch, to improve outstanding — Arnold Milstein, MD, MPH, pro- MD, Intermountain heart-rhythm bone health abstracts. His Rodrigo Valerrabano fessor of medicine; Bill Beninati, MD, services. and reduce the research focuses on describing evidence Intermountain critical care medicine. More information about the grant incidence of of bone and hematopoietic cell interac- • Developing a precision-based ap- program is available by emailing inter- stress fractures tions in humans and their connection proach for the diagnosis and prognosis mountain-stanford-collab@stanford. in female dis- Michael Fredericson with clinically relevant outcomes, such of heart failure with preserved ejection edu. ISM tance runners. as fractures. ISM 8 October 10, 2016 Inside Stanford Medicine