Multigene testsforbreastcancerontherise in mice usingatypeofseaweed Scientists manipulategutbacteria tions, the researchers said. tumor. This timelagmaylimitapatient’s treatment op- toremovetesting tobedelayed until aftersurgery the multigene testingwasmore likelythantheBRCA-only associated geneticvariants, thestudyfound.However, as thetestsforBRCA1 andBRCA2 toidentifydisease- fected relatives, the researchers said. clinically usefulinformationforpatientsandtheirunaf- clinicians thatmultigenepaneltestscanyieldmore associated with testing more genes. current studydidnotshow anincrease inmastectomies cers —outofanabundancecaution.However, the which bothbreasts are removed toprevent future can- in to considerprophylactic mastectomies—asurgery clinicalsignificance,wouldleadmorecertain women testing, which may identify genetic mutations of un School of Medicine and five other U.S. medical centers. associated mutations,according toresearchers atthe clining infavor ofteststhatcandetectmultiplecancer- grows intheintestineby calibrating the sible to control how much a bacterium The researchers also have shown it’s pos- others by manipulating themice’s diet. engraftment ofonebacterial strainover have shown thatit’s possibletofavor the Medicine, mice, working withlaboratory ecology has hampered this task. disease. But thesheercomplexityofgut our healthorhelpfendoff there inwaysthatenhance thousands of bacterial species manipulate themakeupof help scientists learn how to are quicklyevicted,could large intestine, while others take upresidence inthe we ingestcansuccessfully why somebacterialstrains immune responses. gens and even help guide our trients thatkeepushealthy, repel patho- eat. In turn,theyprovide essentialnu- is the senior author. management andpolicyattheUniversity ofMichigan, Katz, MD,MPH, professor of medicineandhealth . Kurian istheleadauthor.10 inJAMAOncology Steven timely manner.” experienced clinician,suchasageneticcounselor, ina to discussgenetictestinganditsimplicationswithan testing. They shouldalsoadvocate fortheopportunity whether theymaybeappropriate candidatesforgenetic “Newly diagnosedwomenshouldasktheirdoctors cine and of health research and policy at Stanford. said AllisonKurian, MD, associateprofessor ofmedi- cally usefulresults andare rapidlybecomingthenorm,” Volume 10, No.10 By KristaConger ‘Becoming thenorm’ T By KristaConger Overall, multigenepanelswere abouttwiceaslikely The shiftreflects agrowing acknowledgement by Some researchers had wondered whether multigene Now, researchers at theSchoolof Understanding how and Gut bacteriathrive onthefoodwe A paper describing the research was published May “In general,multigenepaneltestsyieldmore clini- genes in women with breast cancer is rapidly de ence ofmutationsintheBRCA1 andBRCA2 he use of genetic tests aimed at detecting the pres INSIDE STANFORD MEDICINE May 21, May 2018 Justin Sonnenburg PhD, is the lead author. graduate student Elizabeth Shepherd, nenburg is the senior author. Former published onlineMay 9 inNature. Son- disease.” in achaoticmannerduringourfirst community inourgutsthatassembled each mouse’s water or food. amount ofaspecificcarbohydrate in Giving bacteriumalegup ics —live, A paperdescribingtheresearch was “We’re allendowed withamicrobial The burgeoning field of probiot - - - PublishedbytheOfficeofCommunication&PublicAffairs enhance healthandfight in adeliberatemannerto to reshape ourmicrobiome suggests it could bepossible derstood process. This study chestrated andnot-well-un- acquisition isapoorlyor- strains throughout life,this we continuetoacquire new and immunology. “Although professor ofmicrobiology Sonnenburg, PhD, associate yearsfew oflife,” saidJustin “In general, multigenepaneltestsyieldmore clinicallyusefulresults andare rapidly becomingthenorm,” Allison Kuriansaid. cer between 2013and2015. They askedthewomenif had beendiagnosedwithstage-0tostage-2breast can- of cascade testing.” to improvederway and success rates upon the delivery effective, and there are currently several initiatives un that this‘cascade testing’ ofunaffectedrelatives iscost- relatives,” Kurian said.“Some priorresearch hasshown cancerprevention inunaffected cally targeted,primary for geneti- becauseitofferstheopportunity important isveryriers ofdisease-associatedmutations.“This and herfamilymembers,whomaybeunwittingcar- only tests to yield information about both a patient The researchers over surveyed 5,000women who Multigene paneltestsare more likelythanBRCA- See SEAWEED , page7 - therapy; they’ll sometimesshow T cells tients who’ve yet toreceive animmuno - specific enough. I could image tumor pa veloped, isthatthey’re sometimesnot including oneswe’ve previously de- problem thatoccursinotherapproaches, and chairofradiologyatStanford. “The “Sam” Gambhir, MD,PhD, professor are going to kill the tumor,” said Sanjiv T cellsbecausethoseare theonesthat need toimageactivated just imageall T cells;you poised to kill tumor cells. T cells,assumewhenthey’re immune cells, in particular activated —thestatusthat immune cellswhenthey’re tive tracer that latches onto vised cancer therapy. effectiveness de- of a newly invented a litmustestforthe scientists at the School of Medicine have immunecellsinthebody,track certain of cancer ‘vaccine,’ study reports PET scantracer predicts success By HanaeArmitage “It’s notgoodenoughto The moleculeisaradioac- By engineering a special molecule to - steadily over time,from about tion whoreceived multigenepaneltestingincreased riod. However, ofthosewhowere tested,thepropor- stayed relatively constantthroughout thetwo-year pe- women hadreceived anygenetic testing. This number studies. and accuracyofgeneticinformationthaninprevious This datalinkageprovided substantiallygreater depth were data. linkedtopopulation-basedcancerregistry results camedirectly from thetestinglaboratoriesand Anovelderwent. feature ofthisstudywasthatgenetic andwhattypeof teststheyun- when itwasperformed they’d hadgenetictesting, and,ifso,whoordered it, They found that only about one-quarter oftheThey foundthatonlyaboutone-quarter Sam Gambhir - thorship ate studentAaron Mayer share leadau- scholar Israt Alam,PhD, andgradu- of ClinicalInvestigation. Postdoctoral published online May 14 inthe T cells to attack healthy tissue. the immunesystemerroneously activates autoimmune diseases,whichoccurwhen also makesforapowerful tooltodetect done that here.” cells more specifically, and I think we’ve — sowe needawaytotrackactivated T always activated andkillingtumorcells in theirtumors,butthose T cellsaren’t A studydescribingthetracer was of the flags anyactivated T cell,it latches ontoamoleculethat added. Because the tracer cancer therapies,Gambhir pabilities aren’t limitedto mice. The PET tracer’s ca- this studywasexclusively in the research conductedin a protective state,though fully galvanized T cellsinto a cancer vaccine has success- tors cantheoretically seeif With thetracer, doc- See See MULTIGENE, page7 Page 4 becoming ill. people from healthy to prevent Center aims Diagnostics Integrated Health and The Precision TRACER, page7 STEVE FISCH Journal

Student research symposium showcases curiosity and scholarship

By Julie Greicius “Their projects reflect close collabora- driven from perhaps lack of knowledge, of your world in a new and possibly ex- tions between our students and our fac- a belief that you can’t get pregnant when panding way. And that’s also an exciting In his last year as an undergraduate ulty, because typically on each poster the you’re breastfeeding, or other ideas about thing for me to see.” student in bioengineering at Washington student is first author, and the faculty suppressed fertility.” “Just seeing and helping Stanford University in St. Louis, Missouri, Sheun mentor and sponsor of the work is senior Most student research is financially bring to bear what it can do for students Aluko took a contemporary dance class author.” supported by the Medical Scholars Re- is rewarding,” Baker said, “because of the and two yoga classes. Inspired by the ‘At the edges of science’ search Program, a grant program that way the students use it and run with it, intersection of movement and bioengi- has been active at Stanford for nearly 40 and because of the things they can do neering, Aluko was drawn to the pos- This year’s posters represented just a years. “Altogether, we fund something on when they get these chances.” sibility that technology could provide sampling of work by Stanford’s medical the order of 200 quarters of research by Winning poster presentations: real-time feedback for physical therapy. students, many of whom present their medical students each year,” Gesundheit On May 16, at the 35th Annual research at other national and interna- said. “That’s in addition to other sources • Alvaro Amorin, “Stereotactic ra- Stanford Medical Student Research tional conferences instead of, or in ad- of funding. And that’s what makes it diosurgery in the multimodal manage- Symposium, Aluko, now a third-year dition to, presenting at the symposium. remarkable.” ment of pituitary adenomas: a single medical student at Stanford, discussed Their research interests span an enor- Generous financial support is just center’s experience.” Mentor: Justin his research project, “Development of a mous range. part of what makes Stanford medical stu- Moore, MD, PhD, surgical neuro-on- wearable gait-training device for children “Our students are constantly inter- dents’ research projects happen. “Stan- cology skull base fellow. with cerebral palsy.” He is conducting ested in being at the edges of science and ford has a long history of being a real • Jacqueline Aredo, “Impact of con- the research under the guidance of a fac- finding opportunities to get into those leader in this area, working very hard to current genetic mutations on KRAS- ulty mentor, Jessica Rose, PhD, profes- labs and do things, which I think is su- make it possible for mutant non-small sor of orthopaedic surgery and director per exciting,” said Laurence Baker, PhD, students not just cell lung cancer

PAUL SAKUMA to get money from “We fund something on outcomes and tu- the grant program, the order of 200 quarters mor PD-L1 ex- but to have entrée pression.” Mentor: to faculty projects of research by medical Heather Wakelee, and activities,” students each year.” MD, professor of Baker said. oncology. For faculty • Henry Bair, mentors like Baker, who has overseen “Patterns and factors associated with the symposium for 10 years, supporting inappropriate antibiotic prescription for students is uniquely rewarding. “We see respiratory tract infections: a systemic students who come here without a lot of review at Stanford Express Care.” Men- research experience sometimes, but who tor: Marisa Holubar, MD, clinical assis- really find a passion area,” Baker said. tant professor of infectious diseases. “We also have students who achieve at • Anita Chanana, “Targeting CCR1 high levels, so the idea that we can help expression in epithelial ovarian cancer.” them get their papers into Science or Na- Mentor: Oliver Dorigo, MD, PhD, as- ture, or work with people to create what sociate professor of obstetrics and gyne- may ultimately become major projects cology. for them in their careers, I just think • Jaclyn Konopka, “The influence of that’s super cool.” oral contraceptive hormones on anterior Kay Hung, a second-year medical cruciate ligament strength.” Mentor: Ja- student, investigated the feasibility of son Dragoo, MD, associate professor of producing flexible, 3-D-printed mod- orthopaedic surgery. els of the mitral valve for patient edu- • Anusha Kumar, “Interim findings cation prior to mitral valve repair, then from an open label phase 1B investi- measured the improvements in patient gator-initiated study of Secukinumab understanding and satisfaction, as com- in patients with moderate to severe pared with those who received tradi- papulopustular rosacea.” Mentor: Anne tional education before their procedure. Chang, MD, associate professor of der- She said her faculty mentor, Joseph Woo, matology. MD, the Norman E. Shumway Professor • Jeffrey Kwong, “Assessing the (Clockwise from top) Medical student Katherine Dickerson listened to fellow student Brigit Noon discuss and professor of cardiothoracic surgery, Fisher, Millard, and Mohler techniques her poster presentation May 16 at the 35th Annual Stanford Medical Student Research Symposium. was encouraging. of cleft lip repair surgery with eye-track- Sheun Aluko discussed his project, “Development of a wearable gait-training device for children with “He always asked questions I hadn’t ing technology.” Mentor: Rahim Naz- cerebral palsy.” Another presenter, Kay Hung, is investigating the feasibility of producing flexible, thought about, and got me thinking in erali, MD, clinical assistant professor of 3D-printed models of the mitral valve for patient education prior to mitral valve repair. new directions, especially when I was plastic and reconstructive surgery. stuck,” Hung said. “But he never did • George Liu, “Thyroid cancer risk of the Motion & Gait Analysis Labora- director of the Scholarly Concentration the work for me, and I really appreciated in airline cockpit and cabin crew: a tory at Lucile Packard Children’s Hospi- Program and professor of health research that.” meta-analysis.” Mentor: Chris Hols- tal Stanford. and policy. The scholarly concentration has been inger, MD, professor of otolaryngology- Aluko was one of 64 medical students Brigit Noon, a second-year medical a requirement for medical students at head and neck surgery. who presented posters of their research student, spent a quarter devoted to re- Stanford since 2003. Many students • Julia Ransohoff, “Discovery of dif- projects to a roomful of their peers, fac- search on a retrospective analysis of data say they are grateful for the way their ferential RNA binding and regulation ulty, staff and others at the symposium showing trends in the uptake of long- research efforts help them develop con- by the APOL4 protein to disease-linked in Berg Hall at the Li Ka Shing Center acting, reversible contraceptive methods nections with their peers, faculty mem- psoriasis CDSN gene variants.” Men- for Learning and Knowledge. Forty- — such as intrauterine devices or con- bers, graduate students and postdoctoral tor: Paul Khavari, MD, PhD, the Carl J. eight faculty and staff members served as traceptive implants — for women in the scholars, Baker said. Herzog Professor in Dermatology in the judges. They circulated, asking questions immediate postpartum period. “Often enough, someone will say, ‘I School of Medicine. of the presenters and taking notes. “This project was particularly in- wouldn’t have done this project, but I • Megan Roche, “A prospective mul- “This symposium is the one yearly teresting to me because it focuses on a had to. Then I found a group of people ticenter study optimizing bone health session where the students are the fo- forgotten population of women who are I like, and I found a mentor I can work and preventing bone stress injuries in cus,” said Neil Gesundheit, MD, MPH, actually very highly susceptible to be- with, and an area of research I’m really Division 1 distance runners.” Mentor: interim senior associate dean for medi- coming unintentionally pregnant after into,’” Baker said. “You meet people and Michael Fredericson, MD, professor of cal education and professor of medicine. delivering a baby,” Noon said. “That’s you find things and they become part orthopaedic surgery. ISM

Inside Stanford Medicine is published monthly in July and Memorial service for Gerald Reaven is set for May 24 STANFORD December and semi-monthly

INSIDE the rest of the year. Memorial services will be held for ers will include faculty, colleagues and MEDICINE Gerald “Jerry” Reaven, MD, professor members of the family. is produced by Paul Costello emeritus of medicine, from 4-7 p.m. In lieu of flowers, a memorial do- Office of Communication & Public Affairs Chief communications officer May 24 in McCaw Hall at the Arril- nation may be made to support “The Stanford University Susan Ipaktchian laga Alumni Center. Gerald M. Reaven Memorial Educa- School of Medicine Director of print & 3172 Porter Drive Web communications Reaven, whose decades of research tion and Research Fund” at https:// Palo Alto, CA 94304 John Sanford at Stanford as an endocrinologist makeagift.stanford.edu. Mail code 5471 Editor helped show that insulin resistance Checks may be made payable to (650) 723-6911 Robin Weiss could lead to Type 2 diabetes and Stanford University and sent to Stan- http://med.stanford.edu/news/ Graphic designer multiple other diseases, died Feb. 12. ford University Development Services, He was 89. PO Box 20466, Stanford, CA, 94309- Send letters, comments and story ideas to John The program will begin at about 0466. Please note online or in the Sanford at 723-8309 or at [email protected]. 4:15 p.m., followed by a reception memo of the check: “In memory of Please also contact him to receive an e-mail ISM version of Inside Stanford Medicine. at the Ford Alumni Gardens. Speak- Dr. Gerald Reaven.”

2 MAY 21, 2018 INSIDE STANFORD MEDICINE Reducing tapeworm infection could help academic performance By Rob Jordan JOHN OPENSHAW washing don’t work in many cases. “Schools appear to be hotbeds of transmission, as A Stanford-led study in China has revealed for the well as places for potentially effective intervention,” first time high levels of a potentially fatal tapeworm Openshaw said. infection among school-age children. The researchers Community education will be key to pushing down suggest solutions that could reduce infections in this infections: A third of parents who responded to a survey sensitive age range and possibly improve education out- believed intestinal worms have no adverse effects, and comes and reduce poverty. 19 percent thought less activity and drinking hot water “This disease invades the brain,” said John Open- or eating spicy food would help. shaw, MD, the study’s lead author and an infectious The researchers also plan to distribute medication disease instructor at the School of Medicine. “Children in schools to counter the tapeworms and administer who are affected during formative school years risk cog- vaccines and anti-parasitic medications to pigs in the nitive deficits which could enforce a cycle of poverty.” region. One such drug is particularly promising, ac- The study, published online May 8 in PLoS Neglected cording to co-author Stephen Felt, DVM, MPH, as- Tropical Diseases, focuses on Taenia solium, a tapeworm sociate professor of comparative medicine. The drug, that infects millions of impoverished people worldwide oxfendazole, not only kills muscle-encysted larvae in and can cause a disorder of the central nervous system pigs, but protects them from reinfection for up to three called neurocysticercosis. The World Health Organiza- months. Felt cautioned that oxfendazole may lead to tion estimates that the infection is one of the leading unsightly scarring of the meat, which might turn off causes of epilepsy in the developing world and results consumers. A vaccine called Cysvax also appears to be in 29 percent of epilepsy cases in endemic areas. It highly effective, but it requires booster doses — a sig- is thought to affect about 7 million people in China nificant drawback. Combining Cysvax and oxfendazole alone. might be the most effective approach, according to Felt. “While historically researchers have studied adults In schools, Openshaw and his colleagues are work- with this disease, the burden on kids and what that bur- ing to install working hand-washing stations near bath- den means for affected countries in terms of lost pro- rooms, develop cost-effective ways of supplying soap, ductivity and lost income is unknown,” Openshaw said. provide curriculum materials about the disease and “We hope our work will fuel interest in figuring that hand-washing, and integrate good hand hygiene into out.” school-based reward systems. The study’s senior author is Stephen Luby, MD, Researchers are working to improve hygiene practices at schools The researchers have forthcoming work that mea- professor of medicine and senior fellow at the Stanford in China’s Sichuan province to help prevent tapeworm infection in sures cognitive deficiencies in the children, and better Woods Institute for the Environment and the Freeman children. defines social links — likely transmission pathways — Spogli Institute for International Studies. among them. A global scourge remote Himalayan region of western Sichuan province. “The tools to eradicate this disease are available,” The majority of the children boarded at their schools Openshaw said. “We hope that as the true burden of Found commonly in the muscle of pigs allowed to during the week. The researchers found antibodies for this disease on children becomes clearer, governments roam and consume human feces in regions without in- neurocysticercosis in as many as and nongovernmental actors will door toilets, the tapeworm can infest the intestines of 22 percent of the children they commit more resources.” people who consume under-cooked pork. Thousands tested in some schools — a rate “The tools to eradicate Openshaw is also a faculty fel- of tapeworm eggs are then shed in the infected person’s that’s higher than what the group this disease are low at Stanford’s Center for Inno- feces, contaminating the environment, including drink- saw in adults in surrounding vation in Global Health. ing water sources and food crops fertilized with human villages. available.” Other Stanford co-authors are feces. Openshaw said that the brain Alexis Medina, project manager The disease can take a tragic turn when people di- form of this disease spreads human to human, with for health and nutrition at Stanford’s Rural Education rectly consume the tapeworm eggs, either through con- no pigs required. “All you need is a couple people with Action Program; and Scott Rozelle, PhD, the Helen tact with a person who has the eggs on their hands and gastrointestinal tapeworms and poor hygiene,” he said, C. Farnsworth Professor in International Agricultural clothing or by eating food contaminated with the eggs. conditions that exist in rural schools. Policy and a senior fellow at the Stanford Institute for In those cases, the tapeworm migrates out of the human Unlocking a solution Economic Policy Research. digestive tract and can invade the brain. Symptoms of Researchers from Sichuan Centers for Disease Con- this infection can range from chronic headaches to sei- Many of the children have only one or two pairs of trol and Prevention and Sichuan University also con- zures to psychiatric disturbances, such as hallucinations. clothes at school, so they wear and sleep — sometimes tributed to the study, which was funded by Stanford’s Schools as infection points in shared beds — in the same set of clothes for days at a Global Development and Poverty Initiative, the Bur- time. Attempts to have the children wash their clothes roughs Wellcome Fund and the American Society of To explore whether children are particularly at risk are infrequent and of mixed success, according to Tropical Medicine and Hygiene. of tapeworm infection, the researchers tested fifth- and Openshaw. School bathrooms are generally unhygienic Stanford’s Department of Medicine also supported sixth-grade students, mostly 11- to 13-year-olds, in a pit latrines, soap is rarely available and taps for hand- the research. ISM

At colloquium, a range of views on value of predictive algorithms

STEVE CASTILLO By Kris Newby called the “green button,” which enables Stanford physicians to submit a clinical Is prediction enough? question to a bioinformaticist, then re- This was the question animating a ceive a quick-and-dirty answer in a few lively, debate-style colloquium — as well seconds, culled from 150 million patient as the title of the event — April 25 on records. He asserted that only a hand- the promises and perils of machine learn- ful of these clinical questions could be ing. Organized by the Department of answered with a medical guideline or Health Research and Policy’s Division a randomized clinical trial, so health- of Epidemiology, some 200 data wran- care providers shouldn’t let perfection glers and scientists attended the event be the enemy of the good; rather, phy- to hear an interdisciplinary lineup of sicians should be allowed to apply their speakers present their best arguments expert knowledge to this kind of data- for and against various machine-learning driven evidence to make the best clinical strategies. decisions. A video of this half-day event can The colloquium featured tales of in- be viewed at http://med.stanford.edu/ vestigators led astray by biased data, woe- epidemiology/causal_inference_collo- fully misguided causal inferences and quium.html. “black box” algorithms, so called because Value of expert knowledge their decision-making processes are in- scrutable to outside observers. Presenta- Miguel Hernan, MD, DrPH, profes- tions included “Data science is science’s sor of epidemiology and biostatistics at second chance to get causal inference the Harvard T.H. Chan School of Public right: A taxonomy of data science tasks During a colloquium on machine learning on April 25 at the Clark Center, Miguel Hernan (far right), said, Health, advocated for pairing algorithms and its implications,” “Avoiding dis- “For causal questions, we need data and a good algorithm, but we also need expert knowledge.” with expert knowledge with. “For causal crimination through causal reasoning” questions, we need data and a good al- and “Learning objectives for causal infer- and assistant professor of medicine at the entific method. We are the ones, through gorithm, but we also need expert knowl- ence,” “An informatics consult service for School of Medicine, issued a cri de coeur several generations, who have codified it, edge,” Hernan said. using aggregate patient data at the bed- to attendees to not let algorithmic learn- mathematized it and quantified it. We Nigam Shah, MBBS, PhD, associ- side” and “Offline policy evaluation for ing obliterate what we know about how guide the content experts beyond the ate professor of biomedical data science, algorithmic decisions.” to practice good science: “Being a statis- gate to help them find new knowledge described a project at the medical school Michael Baiocchi, PhD, a statistician tician means we are defenders of the sci- and bring it back.” ISM INSIDE STANFORD MEDICINE MAY 21, 2018 3 New center sets out to detect, stop disease before it starts By Hanae Armitage is looking for “spikers”: people whose glucose level sky- parameters from the first part of the study, but also rockets after eating carbohydrates. The sharp uptick in buttress the data with new measures of inflamma- It’s not often that world-class scientists band to- glucose indicates that something is askew with either tory markers, high levels of which are often seen in gether to investigate disease with no intention of curing their insulin — a hormone that helps the body turn depression. it. Yet upward of 55 scientists at Stanford’s Precision carbohydrates into usable energy — or how the body “We tend to neglect healthy people, but people Health and Integrated Diagnostics Center are doing takes up glucose, and it’s a telltale sign of diabetes. aren’t born with the disease state we’re looking at,” Got- just that in a push to get researchers and physicians But as it turns out, insulin and carbohydrates are not lib said. “These things — depression, anxiety, suicidal off their heels and onto their toes in the battle against the sole culprits of blood glucose booms. “The micro- behavior — develop through adolescence, and the only disease. biome plays a big role in people’s glucose levels spik- way to understand that development is to start with a At the center, the goal is not to find a fix for the ing,” said Snyder, who is the Stanford W. Ascherman, sample of healthy people and study what the risk fac- world’s most pressing ailments; it’s to detect them at MD, FACS, Professor in Genetics. tors and biological signs are. This early detection and their earliest stage, if not prevent them entirely. “So what we plan to do with this trial is monitor understanding the basics of the disease is central to “We want to be proactive, not reactive,” said center each person’s glucose levels, the composition of their PHIND’s mission.” director Sanjiv “Sam” Gambhir, MD, PhD, professor microbiome and their metabolome, and use this infor- Blood-based cancer clues and chair of radiology. “My thinking here was, ‘What mation to ideally piece together a diet plan that keeps can we do so that the whole diagnostic field better their glucose levels under control.” The need for quicker cancer diagnostics has re- aligns with precision health?’ I think the way to get the The key here, Snyder said, is precision. searchers combing the genome for molecular hiccups biggest gain — although it will take several decades to “It’s not just ‘Don’t eat carbs.’ Different people spike indicative of the disease — whether it’s how tumors play out — is to lead the charge on proactive research to different things,” Snyder said. “I spike to bananas; start, spread or, ideally, how they can be stopped. In a across multiple diseases in a broad-picture kind of way.” you might be fine with bananas, but you might spike PHIND-funded project, Christina Curtis, PhD, assis- STEVE FISCH PAUL SAKUMA tant professor of medicine and of genetics, and Anshul Kundaje, PhD, assistant professor of computer science and of genetics, have turned to a simple blood draw, or liquid biopsy, to reveal cancer’s most complex secrets. Curtis’ goal: use blood analysis as a tell-all source that not only flags the presence of cancer, but reveals where it came from in the body and if it’s poised to infiltrate other organ systems. And she wants to do it all on an earlier timeline, with heightened precision. It’s a lot to ask of a run-of-the-mill blood draw, but Curtis and her group are devising a search tactic that goes beyond identifying rare mutations in DNA. She’s looking at epigenomic footprints, types of markers typically embedded in DNA. While these markers are often found enclosed in the cell, Curtis takes advantage of cell-free DNA, which floats openly in the blood- stream after shedding from a tumor or from healthy tissues. “We’re taking a really different approach. We lever- Sam Gambhir is director of the Precision Health and Integrated Diagnostics Center. (Right) Christina Curtis, an associate member of the age epigenomic profiles, which contain information center, aims to create a blood test that can detect early on whether cancer is present and determine other complex information about it. about which tissue the cell-free DNA is derived from and if it’s cancerous,” Curtis said. “And while certain Officially established last year, the Precision Health to rice. We need to pinpoint the dietary needs for each mutations are important hallmarks of cancer, there’s a and Integrated Diagnostics Center, abbreviated person.” unique profile that the epigenome provides, including PHIND (and pronounced “find”) now backs dozens of Eventually, Snyder’s goal is to compile all of this in- clues about the cell’s activity or state.” scientists eager to test out some pretty nontraditional formation — glucose readings, microbiome and me- Research from Curtis’ lab shows that some cancers health-research ideas, such as nanosensor-equipped toi- tabolome profiles — and use machine-learning to not are simply born to be bad. That is, from day one, mu- lets that extract data from daily, um, deposits; bras that only predict who’s at high risk for diabetes, but also to tations and epigenomic factors render the cancerous image breast tissue in search of abnormal changes; and prescribe diets that harmonize with the needs of their cells aggressive, malignant and more lethal overall. One a menstrual pad that can detect biomarkers of disease. metabolic tendencies to prevent the onset of diabetes. day, Curtis hopes, a blood-based analysis could detect But the central concept at play here is one that grounds “About 70 percent of prediabetic people become dia- that kind of aggressive cancer and its point of origina- the very philosophy of PHIND: using repetitive, pre- betic, and that’s why it’s so crucial to catch and manage tion, all before the patient even shows symptoms. In cise measurements of individuals’ health to make diag- these conditions before people even show symptoms,” that sense, it would work as a screen, she posits, that noses earlier and ultimately stop disease before it causes Snyder said. “We think the PHIND center will be very everyone could incorporate into their routine annual real damage. powerful for understanding basic metabolic control. checkup. “PHIND is the only center to use precision health in It’s one of the biggest problems out there, and we hope That’s still a long time away, Curtis said. But in her such an enormous scope and scale,” said Ryan Spitler, this project will help us better understand and control research, she’s beginning to apply the blood-based tech- PhD, deputy director of the center. “We’re looking at people’s metabolic function, especially in glucose con- nique to consenting cancer patients, working backward healthy and at-risk individuals to understand cardio- trol and diabetes.” to test her technology’s ability to pinpoint cancer types vascular disease, cancer, neurological and mental health Preventing depression, suicide in teens and aberrant signaling from cell-free DNA. So far, their and diabetes. In conjunction with those disease areas preliminary research has yielded robust results. are the different ways in which you can measure transi- The beauty of precision health is that it can apply to “A big part of the challenge is that cell-free DNA in tions from health to disease: wearables, implantables, nearly any field of biology, even the “squishier,” harder- and of itself hasn’t been deeply studied yet. What we’re data analytics and molecular mechanisms.” to-pin-down ones, like mental health. In partnership looking for here are really needles in haystacks — rare It’s an effort that exemplifies Stanford Medicine’s fo- with PHIND, Ian Gotlib, PhD, professor of psychol- molecules that have been shed from somewhere in the cus on precision health under the leadership of Lloyd ogy, is applying a rigorous approach to understand the body,” Curtis said. “There’s still a question surround- Minor, MD, dean of the School of Medicine. many spokes that support psychological well-being, ing what the makeup of a healthy individual looks like, The reality upon which all the PHIND projects particularly as it relates to depression and suicidal be- so we’re working on understanding that too, because hinge is often overlooked: Almost every person to ever havior in teens. Gotlib’s goal is to compile neurobio- without that, we have no meaningful reference.” fall ill was, at one point, healthy. So while other big logical, molecular and experience-based information The future of PHIND research entities gun for the next breakthrough therapy, and use machine-learning to predict which mixes of PHIND scientists put the transition to disease, rather factors could predispose someone to dangerous, even Technology, however, can advance only as far as than disease itself, under the microscope in an effort to life-threatening, behaviors. researchers’ understanding of biology enables it. “The prevent healthy people from becoming patients. “We know that adolescence is a peak period for the smart toilet, which is being developed in my lab, can’t Stopping the ‘spikes’ rise of depression, but we cannot predict these increases work miracles if it doesn’t know what to look for in in depressive or suicidal behavior,” said Gotlib, who is the urine. It’s not a crystal ball; it has to know what One such scientist is Michael Snyder, PhD, profes- the David Starr Jordan Professor. “We don’t yet have a biomarker(s) to detect,” said Gambhir, the Virginia and sor and chair of genetics. More casually, he’s known sense of how to do that, which makes prevention dif- D.K. Ludwig Professor for Clinical Investigation in as “the omics guy.” At PHIND, Snyder and a team ficult. So for the past five years my group has been con- Cancer Research. “That’s why we need more people on of collaborators are putting various omics profiles to ducting a comprehensive assessment of mental health the basic biology side to understand the early changes work in a clinical trial that aims to prevent Type 2 dia- in children and adolescents, and now with PHIND as cells transition from normal to ill cells.” betes. (“Omics” more or less means “the study of” — we’re empowered to go even deeper and consider new To this end, PHIND has so far doled out $2.75 so genomics would equate to “the study of genes,” for mental health factors for longer periods of time.” million to help catalyze basic, prevention-focused re- instance.) Gotlib’s study follows 220 boys and girls from late search at Stanford based on a competitive formal pro- They’re studying 100 people, all considered healthy childhood (8-11 years old) into their early teenage years cess. There were some 20 projects funded in the initial but potentially prediabetic. All participants receive a (13-16 years old). In the first leg of the study, scientists round. Earlier this month, the center officially an- device to track levels of glucose (sugar) in their blood interviewed children and their parents about the chil- nounced the availability of an additional $1.5 million in real time, around the clock. But there’s more: Snyder dren’s stressful early life events — moving hometowns, in seed funding. The goal is to launch up to 12 new and his group also take samples of every participant’s parents’ divorces, witnessing violence, things of that na- research projects by the end of this year. microbiome (the mass of bacteria that mobs our gut) ture. They also measured other aspects of stress, includ- “Science isn’t often discovery out of nowhere. and metabolome (the collection of molecules produced ing cortisol levels, and assessed pubertal hormone levels It comes out of fortuitous collisions, in which different during metabolism). They store these samples for later and functional and structural brain connectivity. fields that don’t typically communicate come together,” examination. Now, Gotlib and his team are continuing to fol- Gambhir said. “And that’s what we want to facilitate The participants’ glucose-tracking devices report low these adolescents into their teen years and, with with PHIND to empower the science behind precision levels of blood glucose throughout the day. Snyder is PHIND, they’re not only able to keep measuring health and earlier diagnostics of multiple types.” ISM 4 MAY 21, 2018 INSIDE STANFORD MEDICINE Spring issue of Stanford Medicine magazine explores the art, science of listening and hearing

By Patricia Hannon ten with compassion, empathy and un- effect of hearing loss. derstanding is as important as technical • Researchers are examining how Are you listening? skills and that it’s time to address the birds regenerate crucial hearing cells so It’s such a simple question, but your challenges of modern medicine that are they can try to replicate the process in answer could be complicated, depend- harming their ability to connect with humans. ing on who you are and why you’re patients. • In two examples of sound research, listening. From singers to bioengineers a bioengineer has developed an app to Someone with trouble hearing gather recordings of the hums of dis- might be straining to hear family con- Throughout the issue, you’ll find sto- ease-carrying mosquitos to help eradi- versations. A scientist could be track- ries about the healing power of sound, cate them, and researchers are using ing distinct hums of various species of as well as potential breakthroughs in sound waves to manipulate heart cells mosquito to help eliminate those that treating hearing loss. Opera singer into patterns that resemble natural car- spread disease. A doctor might be lis- Renée Fleming explains why she is diac tissue to help heal heart disease. tening to a patient’s story for clues that working with scientists to explore how • And given that machines are al- can guide treatment. music can improve overall health and ready listening to us, a Stanford group The new issue of Stanford Medicine well-being. Amy Yotopoulos, director is among a coalition of people around witness but that can still cause brain focuses on the importance of listening of the Mind Division of the Stanford the world who are unpacking the host damage. and hearing, and how new discoveries Center on Longevity, recalls her father’s of ethical, legal and social challenges The issue also includes an essay from could improve both. growing frustration and isolation as he of artificial intelligence in medicine. a doctor who uses a wheelchair and In his letter to readers, Lloyd Minor, started losing his hearing. Finding the Yet the possibilities for how the infor- says it’s time for the medical field to MD, dean of the School of Medicine, right hearing aids helped him engage mation machines are capturing can be be more inclusive of people with dis- explores why listening and hearing with his family again. The article de- used for better diagnostics and treat- abilities, and a story and video about matter so much, and how new research scribes why better and less costly de- ment are intriguing: An AI researcher an infectious disease expert who builds could go a long way toward solving vices are on the horizon. found that people speak more openly kinetic sculptures to explain compli- the mysteries of how we process sound Several stories explore breakthroughs about problems to nonhuman listen- cated science. and how it affects us physically and in medicine and technology related to ers; two scientists are mining social The magazine is available at emotionally. hearing, listening and sound: media to learn more about the side stanmed.stanford.edu. Print copies are Minor and other physicians also dis- • A professor of biophysics and of effects of prescription drugs; and a being sent to subscribers. Others can cuss the unique relationship physicians otolaryngology is working with a phy- composer and a neurologist are tap- request a copy at (650) 723-6911 or by have with people who are suffering. sician-scientist to redesign a popular ping into sound waves in the brain to sending an email to medmag@stanford. They say a care provider’s ability to lis- class of antibiotics to prevent their side detect seizures that are too minute to edu. ISM

Bereavement during pregnancy, child’s mental health linked

By Beth Duff-Brown Their analysis compared the outcomes plementary evidence linking early-life death of a relative up to three generations Losing a loved one during pregnancy of children whose mothers experienced a circumstance to adult mental health, but apart during pregnancy has far-reaching may affect the mental health of the child relative’s death while they were pregnant breaks new ground by focusing on stress, consequences for mental health during as he or she grows into adulthood, ac- with those of children whose maternal which may be more pertinent than mal- childhood and adulthood,” the research- cording to a study by two Stanford relatives died in the year after birth. They nutrition in modern developed countries ers write. researchers. were thus able to isolate the impacts of such as the United States and Sweden, Their findings that preventing fetal “We find that prenatal exposure to fetal exposure to maternal stress from be- and by tracing health out- exposure to severe stress could the death of a maternal relative increases reavement from all other consequences comes throughout the time result in large welfare gains: take-up of ADHD medications during associated with a family member’s death, period between the fetal For example, based on the childhood and anti-anxiety and depres- such as changes to family resources or shock and adulthood.” 2008 figure for the U.S. mar- sion medications in adulthood,” wrote household composition, which affect all Mental illness results in ket, the 8 percent decrease in the researchers — Maya Rossin-Slater, children in their sample. great financial and social the consumption of prescrip- PhD, assistant professor of health re- Additionally, by considering the costs. In 2008, the market tion drugs for depression can search and policy, and Petra Persson, deaths of different relatives, the research- for prescription drugs for de- be valued at around $800 PhD, assistant professor of economics — ers’ approach presents a new measure of pression totaled $9.6 billion million annually. in the study, published in the April issue intensity of stress exposure: the closeness in the United States alone, They conducted a back- of the American Economic Review. between the mother and the relative who a sales volume exceeded of-the-envelope calculation to “Of course, you cannot prevent family passed in the family tree. only by cholesterol and pain Petra Persson understand how exposure to members from dying, and we certainly Studying birth, medical records medications. economically induced stress do not want our findings to constitute In 2013, 1 in 7 school-age boys in during pregnancy might affect the men- yet another source of stress for expecting Using birth and medical records, the the United States were treated with pre- tal well-being of the next generation by mothers, who already face rather intense researchers examined information about scription drugs for attention deficit hy- relying on past research estimating cor- pressure to eat the right foods, avoid ac- the children’s health throughout child- peractivity disorder, fueling a $9 billion tisol responses to grief and to economic tivities deemed harmful, and experience hood and into adulthood. They were market — five times larger than the $1.7 shocks like unemployment and poverty. an avalanche of health advice,” Persson aided by Sweden’s novel prescription billion market “Our calculation said. “But our findings potentially point drug registry, which contains all pre- just a decade suggests that in utero to the importance of generally reduc- scription drug purchases and the exact earlier. The au- “Our findings potentially exposure to stress ing stress during pregnancy, for example substances and doses prescribed in the thors note that point to the importance of from unemployment through prenatal paid maternity leave country. estimates also may lead to a 17.3 and programs that provide resources and “Our research suggests that policies suggest mental generally reducing stress percent increase in social support to poor, preg- that can reduce stress dur- illness accounts during pregnancy” the likelihood of ever nant women.” ing pregnancy can have sub- for more than purchasing a drug to Their research focused stantial benefits for the next half of the rise in disability costs among treat ADHD in middle childhood,” they specifically on singleton chil- generation,” Rossin-Slater men in the last two decades. wrote, “and a 9 percent and 5.5 percent dren in Sweden born between said. “Moreover, since poor Moreover, in Sweden — the setting increases in the likelihoods of ever pur- 1973 and 2011 whose moth- families are more likely to for their study — mental illness accounts chasing drugs to treat anxiety and de- ers lost close relatives during experience stress than more for a larger share of health expenditures pression in adulthood, respectively.” their pregnancies. They used advantaged ones, our results on prescription drugs than any other The newly published findings can population registers to con- imply that stress-reducing therapeutic class of medicines. inform one way by which policymakers struct family trees that span policies that target low-in- The scholars said that their study con- and the medical community can tackle four generations, from the Maya Rossin-Slater come pregnant women could tributes to the research in this area by the prevalence and rising costs of men- children to their maternal play a role in mitigating the documenting a causal link between fetal tal health issues: by considering ways to great-grandparents. Their sample in- persistence of socio-economic inequality stress exposure and mental health later make pregnancy — an inherently stress- cluded all children whose mother lost a across generations.” in life. Moreover, by following the same ful time — a little easier to manage. close relative — a sibling, parent, mater- Persson and Rossin-Slater said they children from birth to adulthood, they Rossin-Slater and Persson are both fel- nal grandparent, the child’s father or her were initially inspired by two recent eco- were able to observe the onset of adverse lows at the at the Stanford Institute for own older child — in the nine months nomic studies using data from Uganda effects of exposure to maternal bereave- Economic Policy and Research. after the child’s date of conception or and Iraq, which found that fetal expo- ment in utero. The research was supported by the the year after the child’s birth. The study sure to malnutrition had adverse conse- ‘Far-reaching consequences’ Royal Swedish Academy of Sciences and did not account for the quality of those quences for adult mental illness. by the Jan Wallander and Tom Hedelius relationships. They wrote: “Our study offers com- “In sum, our results show that the Foundation. ISM INSIDE STANFORD MEDICINE MAY 21, 2018 5 o b it ua ry Renowned microbe hunter Stanley Falkow dies at 84 By Krista Conger for the beauty of it, for the intrigue, for the fun.” teaching and mentoring, a skill he cultivated through- In 2008, Falkow, who was the Robert W. and Vivian out his life. Many generations of students would benefit Stanley Falkow, PhD, often proclaimed, “I never met K. Cahill Professor in Cancer Research, was honored from Falkow’s careful attention to this role. a microbe I didn’t like.” with the Lasker-Koshland Award for Special Achieve- Denise Monack, PhD, is one such example. For 14 A professor emeritus of microbiology and immunol- ment in Medical Science — a prize often referred to years, she worked as Falkow’s lab manager at Stanford, ogy at the School of Medicine, Falkow spent most of as “America’s Nobel.” The special achievement award is working and publishing alongside his students. But his lifetime championing the cause of the tiny creatures given once every two years to commemorate a life of sci- Falkow was concerned about her future, and he encour- that have coevolved to live peaceably with humans. He entific contribution and service. More recently, Falkow aged her to go to graduate school. As a result, Monack is considered by many to be the father of the field of was awarded the 2015 National Medal of Science for is now a professor of microbiology and immunology at bacterial pathogenicity — the study of how bacteria his studies of how bacteria can cause human disease and Stanford, with an office next to Falkow’s. cause human disease. how antibiotic resistance spreads. But his proudest ac- Public speaking never became easy, however. “Stanley He spoke out nationally against the routine use of complishment was his election in 2007 to the United was more comfortable in many ways around microbes antibiotics in animal feed and devoted himself to men- Kingdom’s Royal Society as a foreign member. than he was around people,” Relman said. “We all saw toring more than 100 students and postdoctoral schol- “It meant the world to him,” said Tompkins, the him give talks many times. He would sweat bullets. It ars, many of whom went on to establish their own Lucy Becker Professor in Medicine and a professor of was really hard for him, and in some ways this anxiety highly successful laboratories around the world. microbiology and immunology. “He was crying when brought out this kind of self-deprecating humor that His colleagues at Stanford and around the world are he called me to tell me the news. He was such an an- made him immensely likable and effective.” now mourning his loss. glophile, and this was such an incredible honor. When “One of my greatest joys at Stanford has been teach- Falkow died May 5 at his home in Portola Valley, he was asked to sign the book of members — the same ing a course with Stan,” said Justin Sonnenburg, PhD, California, due to complications of myelodysplastic book signed by Charles Darwin and Christopher Wren associate professor of microbiology and immunology. syndrome and multiple subsequent strokes. He was 84. — he was so nervous he dropped the quill pen on the “Although he was teaching with three junior faculty At his side were his wife and fellow Stanford professor floor. When he did sign, his signature was exceedingly (and all of us idolized him), he always just acted like Lucy Tompkins, MD, PhD; his friend, colleague and tiny. He was so overwhelmed.” one of the crowd, and was always joking around. The

L.A. CICERO / STANFORD NEWS SERVICE Falkow first made his mark in only really bad part was having to lecture after him — science by identifying the existence his lectures were always a lively journey filled with wit in bacteria of extrachromosomal and storytelling, and always saturated with brilliant in- circles of DNA known as episomes, sight that he made really accessible. There was no way or plasmids. He subsequently to follow that act.” showed in a series of elegant experi- The mechanism of antibiotic resistance ments that these bits of DNA could be transferred even between dis- At the Ciba symposium in 1968, Falkow was intro- tantly related bacteria to confer new duced to the idea that plasmids could transmit not just traits on them, such as resistance to antibiotic resistance, but also the ability to make toxins antibiotics or the ability to produce that could harm the host cell and cause deadly diar- disease-causing toxins. rheal disease in animals and humans. He subsequently “I would call Stanley a scientist’s showed during his days as a faculty member at the Uni- scientist,” said David Schneider, versity of Washington in Seattle that the genes that con- PhD, professor and chair of mi- ferred these abilities could be swapped like trading cards crobiology and immunology. “His between bacterial species to allow the rapid handoff of experiments were beautiful. But resistance or virulence in ways that vastly affect human more than that, his personality was health. exceedingly generous and his sense After the advent of DNA cloning, Falkow partici- of humor helped to bring people pated in the Asilomar conference of 1975, which was together.” convened to provide guidelines for recombinant DNA “Stanley lived and acted as if experiments in bacteria and plasmids. He was also a Stanley Falkow is considered the father of the field of bacterial pathogenicity. He died May 5. he was never going to run out of member of a Food and Drug Administration commit- ideas,” said Manuel Amieva, MD, tee investigating the routine use of antibiotics in animal former student David Relman, PhD; and his longtime PhD, associate professor of pediatrics and of microbiol- feed — a practice which Falkow, knowing the ease with assistant Sara Fisher. ogy and immunology and a former Falkow postdoctoral which antibiotic resistance can be transmitted between “Without question, Stanley Falkow was a giant in scholar. “He was incredibly generous, insisting that his species, advocated against strongly. the field of microbiology. But rather than his scientific students leave his lab not just with ideas for future re- “Stanley was often a mediator bringing together accomplishments, he was most proud of the many stu- search, but with whole projects and model animal sys- people with disparate opinions,” said Stanley Co- dents he happily mentored during his long career,” said tems with which to launch their own careers.” hen, MD, the Kwoh-Ting Li Professor in the School Lloyd Minor, MD, dean of the School of Medicine. Finding inspiration in the library of Medicine at Stanford, who met Falkow in 1966 at “He invariably deflected any mention of his own suc- Georgetown. “We worked closely together as members cesses and awards with a discussion of the many other Falkow was born in 1934 in Albany, New York. His on many of these committees, and his scientific insight individuals with whom he wished he could share the father had immigrated from Kiev before World War I, and creativity were always apparent. He had the unique honor. He will be sorely missed, not just within the and his mother was born in the United States after her ability to get to the heart of an issue with a humorous Stanford community, but around the world.” family immigrated from Poland. His first language in statement.” The joy of science the home was Yiddish. In 1943, his family moved to Arriving at Stanford Newport, Rhode Island, and Falkow caught the bug Colleagues and family members remember him for bug. Partly at Cohen’s urging, Falkow came to Stanford his devotion and selfless generosity to his students, his “Somehow I discovered the public library and hap- in 1981 to serve as the chair of microbiology and im- wry and self-deprecating wit and his uncanny ability to pened on a book called Microbe Hunters by Paul de munology. In 1983, he and Tompkins were married ask the creative, unexpected and insightful questions Kruif,” he recalled in a 2008 autobiographical career at Stanford’s Memorial Church, and he began a new necessary to drive science forward to new discoveries. retrospective published in the Annual Review of Micro- chapter of his life filled with travel and visits to the Outside the lab, he enjoyed fly-fishing in the Bitterroot biology. “These microbe hunters became, and remain, symphony and opera. In 2004, Falkow was diagnosed River near his second home in Hamilton, Montana, ty- my heroes. Their search to understand microbes was to with myelodysplastic syndrome and given about two ing flies and, later in life, piloting small aircraft. me the most extraordinary adventure that I could imag- years to live. He devoted what he felt was his remaining During his career, Falkow identified the mechanisms ine. It still is.” time to turning over his research program to his former by which antibiotic resistance spreads. He played a key Dealing with anxiety students Amieva and Monack. But every trainee held a role in the development of DNA cloning and served on special place in his heart. a committee organized to assess the safety of recombi- In 1955, Falkow started graduate school at the Uni- “When he talked about one of his students, he would nant DNA technology. Later in his career, he observed versity of Michigan, but recurrent panic attacks soon nearly cry,” Tompkins said. “He was so proud of them the dawn of large-scale DNA sequencing and immedi- caused him to drop out and return to his hospital job. all.” ately realized its potential to help him accomplish one Although he successfully completed graduate school Falkow outlived his original prognosis by many years. of his fondest wishes: to identify the genetic changes and then postdoctoral studies — first at Brown Univer- And he never stopped asking questions and wondering that rendered usually harmless bacteria potentially sity and subsequently at the Walter Reed Army Institute what was around the next bend, whether in the river in deadly to their human hosts. of Research — his ongoing anxiety and developing ago- which he loved to fish, in the experiments unfolding on Falkow’s research helped uncover the molecular raphobia, about which he spoke freely, colored his early the benches of his students or behind the next cloud causes of human diseases as varied as diarrheal disease, professional life. on the horizon. At 72, he snuck out of his Montana plague, food poisoning, whooping cough, ulcers and cat A colleague at the hospital taught him how to fly home for flying lessons against Tompkins’ wishes (she scratch fever. But, although his findings are directly ap- fish in an attempt to alleviate his anxiety, sparking a later relented and learned to fly herself as a precaution plicable to human health, he arrived at his discoveries lifelong love. In graduate school, Falkow discovered a for when they flew together), and they loved soaring by approaching scientific problems from the viewpoint new way that bacteria could transmit certain traits to into the big Montana sky. At Stanford, he brought his of the bacteria he found so endlessly fascinating. one another through the transfer of plasmids, which golden retriever, Honey, to the lab every day. “Stanley was one of these rare people who truly did are separate from bacterial chromosomes. One of these Falkow’s honors include the 2000 Robert Koch Prize, live for and embody the joy of science,” said Relman, plasmid-transferrable traits was, crucially, the ability to considered one of the most prestigious awards in the professor of microbiology and immunology at Stanford break down compounds that would normally kill the field of microbiology; election to the National Academy and a former postdoctoral scholar in Falkow’s labora- bacterial cell. of Medicine; membership in the National Academy of tory. “For him, science was never a struggle. It was fun Now at Georgetown, he and his students investi- Sciences and the Royal Society; and a former presidency every moment along the way. And he showed that in his gated the molecular basis of how plasmids encoding of the American Society of Microbiology. smile, in the lilt in his speech and even in the way he these antibiotic resistance factors, or R-factors, were Falkow is survived by two daughters, Jill Brooks and constructed his sentences. ‘What a great question,’ he’d transmitted between individual bacterium. Lynn Short; a stepson, Christopher Tompkins; his sister say. Or ‘I wonder why this might be?’ He loved science It was there that Falkow also discovered his love of Jeanette Andriesse; and four grandchildren. ISM 6 MAY 21, 2018 INSIDE STANFORD MEDICINE Seaweed Multigene 20 percent of women receiving BRCA-only testing continued from page 1 — perhaps due to a recognition by clinicians that in- continued from page 1 terpreting the results of a multigene panel can be com- presumably healthful bacterial cultures naturally found 26 percent of those tested in early 2013 to about 66 plex and requires the expertise of genetic counselors, in food such as yogurt or included in over-the-counter percent in mid-2015. Conversely, the proportion of who are not always rapidly available. oral supplements — is an example of a growing public women who received BRCA-only testing during the “Furthermore, patients and their clinicians may awareness of the importance of gut bacteria. Even if you same time period decreased from about 74 percent to view genetic testing as a lower priority than tumor don’t take probiotics or eat yogurt, however, each of us about 34 percent. biology and pathology testing unknowingly consumes low levels of gut-adapted mi- Multigene panel testing was which most directly inform crobes throughout our life. But, regardless of the source, about twice as likely as BRCA- the treatment options.” said it’s not known what causes one strain to be successful only testing to identify disease- “More genetic counselors Katz. over another. Many pass quickly through our digestive associated mutations. But it are needed.” “As genetic testing has be- tract without gaining a foothold in our teeming intestinal was also more likely to reveal come more comprehensive carpet. mutations of uncertain clini- and less expensive, we have be- Sonnenburg and his colleagues wondered whether a cal significance, particularly gun to see a significant prob- dietary boost would give specific bacterial strains a leg in racial or ethnic minorities. This disparity is likely lem in terms of the genetic-counselor workforce,” up in the wild west of the gut microbiome. To investi- due to the fact that most genes were sequenced first in Kurian said. “More genetic counselors are needed, and gate, they trekked to the San Jose Wastewater Treatment white patients, and the causative effect of variations in they should be integrated into routine cancer care. Facility to find members of the Bacteroides — the most other minorities is not clear. This finding emphasizes There is also a need for new care-delivery models that prominent genus in the human gut microbiota — spe- the need for research in diverse populations to clarify effectively triage appropriate patients to timely genetic cifically looking for strains that are able to digest an in- genetic uncertainty and reduce racial disparities in the counseling.” gredient relatively rare in American diets: the seaweed clarity of genetic test results, the researchers say. Researchers from the University of Southern Cali- called nori used in sushi rolls and other Japanese foods. Timing of tests varied fornia, Emory University and the Memorial Sloan- They screened the bacteria collected in the primary ef- Kettering Cancer Center also contributed to the study. fluent for an ability to use a carbohydrate found in nori The timing of the tests also varied, the study found. The research was supported by the National Insti- called porphyran. Although the majority of the women tested got their tutes of Health, the National Cancer Institute and the “The genes that allow a bacterium to digest porphyran results prior to surgery to remove the tumor, many did University of Michigan Cancer Center. are exceedingly rare among humans that don’t have sea- not. About 33 percent of women receiving multigene Stanford’s departments of Medicine and of Health weed as a common part of their diet,” Sonnenburg said. panel testing were tested after surgery, versus about Research and Policy also supported the work. ISM “This allowed us to test whether we could circumvent the rules of complex ecosystems by creating a privileged niche that could favor a single microbe by allowing it to exist in the absence of competition from the 30 trillion other microbes in the gut.” Once they’d found a nori-gobbling strain of Bacteroi- des, the researchers attempted to introduce it into each of Tracer Gambhir acknowledges that one could simply wait three groups of laboratory mice. Two groups of the mice continued from page 1 to see physical changes in the tumor volume to deter- had their own gut bacteria eliminated and replaced with mine whether the therapy is working. But that poses the naturally occurring gut bacteria from two healthy study. Gambhir, the Virginia and D.K. Ludwig Pro- a problem. It may take weeks, or even months, to de- human donors, each of whom donated exclusively to fessor for Clinical Investigation in Cancer Research, is finitively see whether the cancer is responding to the one group or the other. The third group of mice har- the senior author. treatment. Say the vaccine doesn’t work. In the time bored a conventional mouse-specific community of gut Two for one it took to find out, the cancer would have continued microbiota. to spread, becoming more molecularly heterogeneous A direct effect The tracer was born out of a collaboration with and even more difficult to treat the next time around. Ronald Levy, MD, professor of oncology, who was Knowing sooner gives the patient more time to try The researchers found that when the mice were fed in the process of devising what’s now considered a other options, hopefully leading to better outcomes. a typical diet of mouse chow, the porphyran-digesting promising cancer “vaccine.” The goal of the vaccine — Clinical trial strain was able to engraft in two groups of mice to vary- which is different from a traditional preventive shot ing and limited degrees; one of the groups of mice with because it works more as an injected immunotherapy Levy has moved his vaccine into a phase-1 clini- human gut bacteria rejected the new strain completely. — is to prompt the T cells into an activated state and cal trial. In the next few months, Gambhir plans to However, when the mice were fed a porphyran-rich diet, get them to attack tumors in the body. But cancer move this new OX40 tracer into that same clinical the results were dramatically different: The bacteria en- therapies are not often one-dose-fits-all. So the ques- trial, so that the tracer and therapy can be tested in grafted robustly at similar levels in all the mice. Further- tion became: Is there a way to know, right away, if the conjunction. more, Shepherd found that she could precisely calibrate vaccine is working? “We were able to predict what was going to happen the population size of the engrafted bacteria by increasing “Our challenge was to find a molecule that’s almost in mice several weeks out by looking only 48 hours or decreasing the amount of nori the animals ingested. exclusively present on activated T cells — not just any from the start of the immunotherapy. We could figure “The results of this dilution experiment blew us away,” T cell — because there are many T cells that just sit out which mouse was going to respond to the immu- Sonnenburg said. “The direct effect of diet on the bacte- around resting,” Gambhir said. notherapy and which wasn’t be- rial population was very clear.” By coincidence, the molecule fore they actually did or did not In addition to showing that they could favor the en- he found was the same one that respond,” Gambhir said. “And graftment and growth of the nori-gobbling bacterial Levy harnessed in his vaccine, The tracer scours the that’s exactly what we’re trying strain, the researchers went one step further by showing a protein on the surface of acti- to do. We’re trying to show that that the genes necessary to enable the digestion of por- vated T cells called OX40. entire body in search of this approach can, in humans, phyran exist as a unit that can be engineered into other Boiled down, Levy’s can- cancer-killing T cells. allow us to image early and Bacteroides strains, giving them the same engraftment cer vaccine is a package of two thereby let us evolve the therapy advantage. Now they’re working to identify other genes stimulating agents. One coaxes quickly.” that confer similar dietary abilities. T cells into producing OX40 on Gambhir also is pursuing “We can use these gene modules to develop a vast their surface; the other binds to OX40 and enables the work to establish the OX40 tracer as a diagnostic for toolkit to make therapeutic microbial treatments a real- cell to engage with tumor cells. Together the tag-team other applications, such as the autoimmune disease ity,” Sonnenburg said. “Porphyran-digesting genes and agents essentially prod loafing immune cells into high multiple sclerosis. “It’s important to remember that a diet rich in seaweed is the first pair, but there could gear. this is a really general approach to visualizing activated potentially be hundreds more. We’d like to expand this Once the tracer is injected, it scours the entire body, T cells — this shouldn’t be thought of as specifically simple paradigm into an array of dietary components and including the immune system, in search of cancer-kill- for cancer immunotherapy alone,” he said. “That’s just microbes.” ing T cells — but only those laden with OX40. Upon one important application.” The researchers also envision developing bacteria that meeting, the tracer binds to OX40 and, when hitched The work is an example of Stanford Medicine’s fo- harbor kill switches and logic gates that will permit cli- together, the radioactive complex glows under a PET cus on precision health, the goal of which is to antici- nicians to toggle bacterial activity on and off at will, or scan, revealing only those T cells that have been suc- pate and prevent disease in the healthy and precisely when a specific set of circumstances occur. cessfully activated, ready to ravage the tumor. If the diagnose and treat disease in the ill. “It’s become very clear over the last 10 years that gut scan comes back with low to no signal in the tumor Other Stanford co-authors of the study are Idit microbes are not only wired to many aspects of our biol- or tumors, it’s an indication that doctors (in theory, as Sagiv-Barfi, PhD, instructor of oncology; Kezheng ogy, but that they are also very malleable,” Sonnenburg the vaccine and tracer have only been tested in mice) Wang, MD, PhD, a visiting faculty member in the said. “Our growing ability to manipulate them is going ought to reevaluate the immunotherapy dosage or Gambhir lab; postdoctoral scholar Ophir Vermesh, to change how precision health is practiced. A physi- change the treatment course altogether. PhD; Debra Czerwinski, life science research assistant; cian whose patient is about to begin immunotherapy for The power of PET Emily Johnson, life science research professional; and cancer may choose to also administer a bacterial strain Michelle James, PhD, assistant professor of radiology known to activate the immune system, for example. Gambhir’s lab tested the tracer first in cell cultures. and of neurology and neurological sciences. Conversely, a patient with an autoimmune disease may They found that the compound was able to suss out Gambhir and Levy are members of Stanford Bio-X benefit from a different set of microbiota that can dial activated T cells about 95 percent of the time. Later in and the Stanford Cancer Institute. Gambhir is also a down an overactive immune response. They are just a mouse models, they still saw success overall, but it was member of the Stanford Cardiovascular Institute and very powerful lever to modulate our biology in health a bit more subdued. In a group of about 50 mice, the the Stanford Neurosciences Institute. and disease.” PET tracer performed accurately upward of 90 percent A researcher at Harbin Medical University also con- Stanford graduate student Kali Pruss is a co-author of the time. tributed to this work. of the study. Researchers from Novome Biotechnologies “It’s really only now that this tactic is coming into The study was funded by the Ben & Catherine Ivy also co-authored the study. play; the PET scan is usually focused on assessing Foundation, the Canary Foundation, the National The research was supported by the National Institutes only the tumor cells,” said Gambhir. “But now, with Cancer Institute and the Leukemia and Lymphoma of Health and the National Science Foundation. new imaging agents like this, we’re able to image the Society. Stanford’s Department of Microbiology and Immu- immune cells, and that’s really the second half of the Stanford’s Department of Radiology also supported nology also supported the work. ISM equation.” the work. ISM INSIDE STANFORD MEDICINE MAY 21, 2018 7 p eo p le Sheila Dolezal, ‘team player extraordinaire,’ wins Amy J. Blue Award By Kathleen J. Sullivan and technical skills, Sheila is a team player extraordi- Dolezal worked in the hospital’s admitting office for naire,” one group of professors wrote. “She embraces about four years, then joined the finance and adminis- When Sheila Dolezal arrives at her office on the third everyone and anyone even remotely affiliated with our tration staff in the Department of Radiology. Some five floor of Stanford Hospital, there is one thing she knows department as an essential part of our overall success, years later, she joined the Department of Obstetrics & for certain — that there will be nothing “typical” about and they certainly don’t need an MD title following Gynecology. her workday. their name to be part of the family. She has a remark- Commended for dedication, grace, humor “One day I can come in and spend the entire day able way of letting you know that you are a valued part in one-on-one meetings with staff members, and the of our overall mission.” Colleagues who nominated Dolezal for the Amy J. next day, I can be working on a business plan to expand Dolezal is one of three Stanford employees who were Blue Award said her door is always open: clinical care in underserved areas or to introduce a new recently named 2018 Amy J. Blue Award winners. The “As busy as she is, Sheila somehow finds the time to service in a clinic,” said Dolezal, the director of finance award honors staff members who are exceptionally ded- genuinely listen to and care for the myriad of people and administration in the Department of Obstetrics & icated, supportive of colleagues and passionate about who seek her out. From faculty member to adminis- Gynecology at the School of Medicine. their work. trative staff, from fellow-in-training to resident, she is L.A. CICERO / STANFORD NEWS SERVICE The other winners are Chris- there to listen to concerns, provide meaningful feed- tina Ablaza, the program manager back and help chart a path forward. She is a mentor to of the Creative Writing Program, so many, including young administrative and research and Rafael Velazquez, a food service managers trying to develop a skill set in how to cre- worker in Stanford Dining, a division ate productive, nurturing teams. She is a caring, special, of Residential & Dining Enterprises. can-do person. It is hard for us to imagine this depart- Stanford President Marc Tessier- ment without her.” Lavigne presented the awards at a Colleagues also praised Dolezal’s “inclusive and per- May 15 ceremony for the winners and vasive” sense of humor: their families, friends and colleagues. . “I have heard laughs ring out during the most serious The award, which was established in of finance meetings, easing tensions and bringing ev- 1991 to honor the life and work of eryone into the fold. She wins over others quickly with Amy J. Blue, an associate vice presi- joy and warmth, and sees well-timed opportunities for dent for administrative services and levity in the midst of the sometimes ‘heavy’ hospital facilities, includes a $4,000 prize. setting. Her authenticity in this joy is so engaging and A career change led to Stanford endearing, that, when taken together with her strategic mind, it is clear why she has had such an impact on the Dolezal, who was born and grew people in this department.” up in Santa Clara, California, earned Professors said Dolezal was instrumental in the es- a bachelor’s degree in organizational tablishment of gynecologic oncology services at the behavior at the University of San new Stanford Cancer Center South Bay in San Jose, Sheila Dolezal (center), who won an Amy J. Blue Award, meets with members of her team. Francisco. California, and at Stanford Health Care’s ValleyCare After graduating, she served as a Medical Center in Pleasanton, California, and played a branch manager of a savings-and-loan key role in launching and expanding the department’s “I could be working on issues related to human re- in nearby Sunnyvale, California, but realized after a few faculty midwifery program. sources, operations, financial or strategic planning. My years that the job wasn’t a good fit. “In addition to her in-depth knowledge of finances job includes many responsibilities, and that makes it re- She decided to follow her late mother’s advice: “If and business aspects that are important to the viability ally exciting.” your heart’s not in it, find where of our entire department, Sheila While there is no such thing as a typical workday, your heart is.” “She wins over others has a profound understanding of Dolezal said every day has one thing in common. Dolezal found her heart and the systems and workflows within “I am surrounded by people who are very passionate her passion at Stanford. quickly with joy and the School of Medicine and the about women’s issues and women’s health and women’s “I witnessed firsthand the warmth.” two hospitals — Stanford Health empowerment,” said Dolezal, who joined the depart- many health and other strug- Care and Lucile Packard Chil- ment in 2000 and handles financial and administrative gles my mother experienced in life, and I have always dren’s Hospital,” one professor wrote. affairs for about 120 people, including 50 professors, 50 wanted to be part of a mission and vision to advance “It is difficult to imagine a more accomplished and researchers and 20 staff members. “It makes me feel so a woman’s place in society, and health care is a foun- knowledgeable director of finance and administration good to be part of that. I love the idea that I am contrib- dational element of this vision,” she said. “I was so for any department. On top of this, Sheila has extraor- uting in some way to advancing the position of women.” impressed by how Stanford had cared for my younger dinary people skills and an always positively reinforcing The colleagues who nominated Dolezal for a 2018 sister, who had several orthopedic surgeries here, and attitude that percolates not only through the adminis- Amy J. Blue Award said she helps hold the large the care they gave to my mother, who had diabetes. trative staff, but the entire department, including fac- and complex department — and its seven divisions So I had a deep respect for this institution as a whole. ulty, fellows, resident and students. By all measures, — together. When I had the opportunity to join Stanford in 1990, Sheila is a more-than-worthy recipient of the Amy J. “In addition to her superb leadership, organizational I grabbed it.” Blue Award.” ISM

of note reports on significant honors and awards for faculty, staff and students

Resident KATHERINE BLEVINS, MD, and postdoctoral scholars VIVIAN DE RUIJTER, MD, and ERIC KRAMER, PhD, received a 2018 Translational Research Award from the Wallace H. Coulter Katherine Blevins Vivian de Ruijter Eric Kramer Michael Eisenberg Melanie Hayden Gephart Foundation. The $100,000 award in- cludes mentoring and oversight to help Alexandra Jane Noble advance their large-bore arterial closure Science Courage Award technology toward patient care. from Novim. The award MICHAEL EISENBERG, MD, was pro- “recognizes those who moted to associate professor of urol- speak out professionally ogy, effective March 1. He specializes in as well as scientifically male infertility and sexual health, with to correct a misimpres- a research focus on surgical innovation, sion or right a wrong in epidemiologic studies and basic science the name of science and discoveries to improve the treatments, public understanding,” John Ioannidis Sun Kim Michael Khodadoust Gordon Lee outcomes and reproductive health of according to the non- men. profit institute, based in Santa Barbara, His research focuses on examining how and improving outcomes and developing MELANIE HAYDEN GEPHART, MD, was California. the body’s immune system fights can- new techniques in microsurgery and re- promoted to associate professor of neu- SUN KIM, MD, was promoted to as- cer cells and developing immune-based constructive surgery. rosurgery, effective March 1. Her re- sociate professor of medicine, effective therapies for the treatment of T-cell CLEMENT MARSHALL, MD, resident in search focuses on understanding the March 1. She specializes in treating Type lymphomas. surgery, was a co-recipient of the 2018 genetic and epigenetic mechanisms driv- 2 diabetes, polycystic ovarian syndrome GORDON LEE, MD, was promoted to Thomas R. Russell, MD, FACS, Re- ing tumor formation and disease pro- and obesity, with a research focus on the professor of surgery, effective April 1. search Paper Competition Award from gression in malignant brain tumors. pathophysiology and treatment of Type He is the residency program director for the Northern California Chapter Ameri- JOHN IOANNIDIS, MD, DSc, professor 2 diabetes. plastic surgery and director of microsur- can College of Surgeons. He was hon- of medicine and of health research and MICHAEL KHODADOUST, MD, PhD, was gery. He specializes in surgical education ored for the paper, “Gene expression policy and the C.F. Rehnborg Professor appointed assistant professor of medicine and training in plastic surgery, and his analysis in abdominal adhesion forma- in Disease Prevention, received the 2018 and of dermatology, effective March 1. research interests include understanding tion.” ISM 8 MAY 21, 2018 INSIDE STANFORD MEDICINE