NATIONAL INSTITUTES OF HEALTH • OFFICE OF THE DIRECTOR | VOLUME 26 ISSUE 4 • JULY-AUGUST 2018

Barbra Streisand Talks Machine Learning Up Women’s Heart Teaching Computers to Think Health BY SUSAN CHACKO, CIT BY BRANDON LEVY, OIR

Barbra Streisand knows how to command an audience, whether she’s behind a microphone, a camera, or a podium. After a storied career beguiling theater-goers, Streisand’s new goal is not just to warm hearts but to save them from disease as well. The Broadway and Hollywood star, a lifelong advocate of health and gender equity, graced the stage of NIH’s Ruth THINKSTOCK.COM ALEXLMX, Kirschstein Auditorium (Building 45) on May 15 to give the annual J. Edward Rall Cultural Lecture named for former Deputy Director for Intramural Research Joseph “Ed” Rall. As this year’s invited speaker, Streisand is in good company; over its 30-year history, the event has featured a variety of celebrities from writer Maya Angelou, to musician Yo-Yo Ma, to doctor Enter Richard Leapman’s lab at the National Institute of Biomedical and news correspondent Sanjay Gupta. Imaging and Bioengineering (NIBIB) and you’ll find a serial block-face scanning Streisand took the opportunity to highlight electron microscope, the size of a lab freezer, busily slicing and scanning pancreatic an issue that is—literally—near and dear to tissue, blood platelets, or other biological matter. In 12 hours, there will be 20,000 her heart: women’s cardiovascular health. images of 25-nanometer-thick slices of each sample. Streisand’s quest to reduce gender Before the microscope arrived four years ago, Leapman had a team of postbacs manually disparities in cardiovascular medicine began delineating features of the objects in the images. Such work is labor-intensive, taking with her 1983 filmYentl . The movie—which a hardworking postbac a few hours to trace the outline of a single platelet in an image Streisand directed, co-produced, co-wrote, and starred in—tells the story of a young CONTINUED ON PAGE 10 woman living in Eastern Europe in the early 1900s who disguises herself as a man in CONTENTS order to pursue an education. Eight years FEATURES • |1| Barbra Streisand Talks Up Women’s Heart Health |1| Machine Learning after the movie’s 1983 debut, the New |5| Big Read Featured Ed Yong |6| Profile: Elisabeth Murray England Journal of Medicine published an DEPARTMENTS • |2| DDIR: Creating a More Diverse and Inclusive NIH |3, 15| SIG Beat: Metals editorial written by cardiologist and former in Biology; Sex and Gender in Health and Disease; Membrane Protein and Structural Biology

CONTINUED ON PAGE 14 |4| Training Page: Career Advice |8| Research Briefs |16| Colleagues: Recently Tenured |17| Announcements: Kudos |19| Abbreviations |20| Photographic Moment: Butterfly Effect FROM THE DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH

Creating a More Diverse and Inclusive NIH BY MICHAEL GOTTESMAN, DDIR, HANNAH VALANTINE, AND ROLAND OWENS

Evidence indicates that commitment to promoting diversity and In addition to these activities designed to heterogeneous groups of talented inclusion in the biomedical research strengthen relationships among cohort individuals, with experience in managing workforce and trainee pool. The DSP members, DSP scholars will participate in a diversity, are better equipped to tackle scholars will become the focal point of a curriculum of professional development and complex problems than are homogeneous new mentoring and networking initiative led skill-building activities. These professional- groups. It is also well documented that by the Office of Intramural Research (OIR) development activities will be open to all medical conditions are multidimensional and the Scientific Workforce Diversity office TTIs and ACIs. and influenced by many factors such (SWD). All NIH Institutes and Centers The next deadline for applications as race, genetics, gender, geography, (ICs) with IRPs have contributed funds to will be early in Spring 2019. To assist socioeconomic status, and community help fund the DSP scholars. with identification of DSP candidates in values. Tackling these complex the future, the IRP will have multivariable scientific and Tackling complex multivariable language in its PI-recruitment biomedical problems requires scientific and biomedical problems advertisements requesting a vibrant culture of inclusive applicants to include in their excellence that draws from a requires a program that draws from CVs a description of their diversity of perspectives and a diversity of perspectives and mentoring and outreach activities, experiences. As a testament to especially those involving women fostering such an environment, experiences and fosters those who and individuals from groups the NIH intramural research foster diversity. underrepresented in biomedical program (IRP) is recruiting research. talented scientists who also have The success of the DSP This spring, the first cohort of 10 tenure- experience in promoting and mentoring program will be measured not only by track investigators (TTIs) and three assistant individuals from groups underrepresented the scientific success of the DSP scholars, clinical investigators (ACIs) representing in biomedicine. but also by how they contribute to the seven ICs were selected as DSP scholars. There have always been individual NIH transformation of the NIH IRP into an All of them are expected to be on board principal investigators (PIs) who have gone environment in which inclusive excellence by the end of September. These individuals out of their way to make opportunities is the norm, rather than the exception. We were selected for the DSP because of their accessible to highly innovative biomedical welcome your ideas about how to make the scientific accomplishments and because researchers from underrepresented groups. DSP program the best it can be, and we hope they have demonstrated a desire to be To date, however, these PIs often worked you participate fully by helping to recruit change agents. Each DSP cohort will have in isolation and were therefore limited and make welcome scientific colleagues who a year-long program of monthly activities in their ability to promote an NIH-wide will help us create a diverse and inclusive designed to promote career development as environment of inclusive excellence. This community that maintains NIH’s status as well as interactions among DSP scholars, year, the IRP has begun a multi-year pilot, a top-tier biomedical research institution. between DSP scholars and other IRP called the Distinguished Scholars Program PIs, and between DSP scholars and NIH Hannah Valantine is the Chief Officer for (DSP), to create such an environment. The senior leaders. Embedded in the program Scientific Workforce Diversity, Office of the DSP is designed to create an annual cohort will be four to five highly accomplished Director; Roland Owens is the Director of of 10 to 15 recently hired PIs (primarily senior investigators, recruited to serve as Research Workforce Development, in the at the tenure-track level) who have a mentors and sponsors for the DSP scholars. Office of Intramural Research.

2 THE NIH CATALYST JULY-AUGUST 2018 THE SIG BEAT NEWS FROM AND ABOUT THE SCIENTIFIC INTEREST GROUPS

NEW SIG: Metals in SGHD SIG: Sex Biology Scientific Differences in Sleep Interest Group BY JOANNA CROSS, NIMH Fruit flies may hold the secret Metals are critical to a dizzying to helping scientists understand sleep. The array of biological functions. Up to one- little critters share many of the character- third of cellular proteins contain a bound istics relevant to sleep in humans—they metal cofactor, yet only a minority of these sleep mostly at night, stimulants can inter- SARAH NEEDLE, NHLBI cofactors have been identified. Metal ions fere with their sleep, and sleep depriva- also bind and modulate the structure and tion can wreak havoc on their memory. function of RNA in an equally intriguing In humans, sleep deprivation can lead to number of ways. By virtue of their variable impairments in learning and memory, coordination properties and redox behavior, neurological diseases, cardiovascular prob- metal ions often carry out unique functions lems, hypertension, and other disorders. NHLBI researcher Susan Harbison has found that male and female fruit flies have different sleeping habits. in biology. However, metal ions such as Scientists can use fruit flies (Drosophila copper and iron can be double-edged melanogaster) to study how genetic traits custom-mounted vortexer. The device was swords because, when unsequestered, they affect sleep, too. And some scientists like programmed to deliver a shaking stimu- can generate toxic radical species that can Susan Harbison are investigating some- lus once a minute for 12 hours during the damage proteins, nucleic acids, and lipids. thing rarely studied: how sex differences night. Harbison observed the flies’ rebound Consequently, cellular systems devote a may play a role in sleep. response (making up for lost sleep) the fol- considerable amount of resources to the Harbison, who joined NIH in 2012 lowing morning. “Flies don’t have a job, so trafficking, chaperoning, and homeostasis and is a Stadtman tenure-track investiga- they can sleep in!” Harbison said during of essential metal ions. tor in the National Heart, Lung, and Blood her talk. She found that short-sleepers Malfunctions of one or more elements Institute, gave a presentation on her research lost less sleep (up to 412 minutes) than (pun intended!) of this metal-ion machinery at the May 22, 2018, gathering of the Sex long-sleepers (up to 709 minutes) but the cause many devastating human diseases and Gender in Health and Disease (SGHD) rebound response was similar (up to 260 such as hemochromatosis, Friedreich ataxia, Scientific Interest Group (SIG). extra minutes of sleep). However, there Wilson disease and Menkes disease. In But how do you measure sleep in a crea- was a fair amount of variability among addition, metal ions have proved valuable ture as tiny as a fly? You use an infrared-based the lines, suggesting that the amount of in medicine including serving as magnetic- Drosophila activity-monitoring system: Each rebound sleep is more dependent on geno- resonance contrast-imaging reagents and fly is placed in a three-inch long glass tube; type than sex. Preliminary data also showed anti-cancer therapeutics. The Metals in when it is awake and active, its movements that intermittent disruptions also affected Biology SIG unites several active intramural disrupt an infrared beam; and the data can sleep; short-sleeping males had a decreased research groups whose interests span one be used to decipher sleep. arousal threshold (it takes less stimulus to or more aspects of the biology of metals. Some of us require more sleep than awaken them) compared to females. The new SIG facilitates interactions others. To investigate this trait in flies, As with humans, flies have a 24-hour among NIH researchers at the forefront Harbison genetically engineered 19 long- circadian rhythm pattern. Using a rhyth- of metallobiology and exposes trainees to sleeping and 20 short-sleeping lines. The micity index (the extent to which activity a wider spectrum of problems, approaches, long-sleeping flies slept for 17.8 hours in a patterns are similar from day to day), the and techniques. The SIG plans to host one 24-hour period, while the short-sleeping flies scientists determined that male flies have seminar every two months and continue slept for only 3.3 hours. That’s a staggering more rhythmicity within their circadian the biweekly journal clubs. For more 14.5 hours difference. patterns compared to females. information, contact Anirban Banerjee Harbison induced sleep deprivation ([email protected]). by disturbing the flies mechanically via a CONTINUED ON PAGE 15

https://irp.nih.gov/catalyst 3 THE TRAINING PAGE

Special from NIGMS Advice from an Early Career Investigator BY JENNIFER SIZEMORE, NIGMS

you’ll have more time to actually do your own research. • Before asking a professor or lab chief whether you can work in his or her lab, do some homework: Read one or more articles by the research group. Have an idea of relevant research questions. “If a student has read your work and has an idea, especially something they would be interested in pursuing, even if it needs to be further shaped, that means a lot in terms of my perception.” • Make an appointment to see the lab chief. Show up. On time. • Keep asking questions. “You tend to be more limited by your ability to address

CHIA-CHI CHARLIE CHANG CHARLIE CHIA-CHI questions than by the number of questions

University of Kentucky biologist Jeramiah Smith (left) offered career advice to undergraduate students from Morgan there are to address. It’s great, it’s job State University at the NIGMS Director’s Early Career Investigator Lecture hosted by NIGMS Director Jon Lorsch (right). security in a sense.”

The archived videocast includes the entire AMONG SMITH’S OTHER TIPS: “Embrace being wrong.” Rather lecture and the Q & A session afterwards: than feeling discouraged when an • If you’re interested in doing lab research, https://videocast.nih.gov/launch.asp?23827. experiment yields unexpected results, try don’t wait until your senior year in college. to understand what happened and why. It takes a while to learn the lab techniques, That’s how science advances. so if you start as a freshman or sophomore, Jeramiah Smith gave this and other career advice to the undergraduate students from Morgan State University (Baltimore, Maryland) who attended his lecture on April 17, 2018. Smith, a biologist from the University of Kentucky (Lexington, Kentucky), delivered the third annual National Institute of General Medical Sciences (NIGMS) Director’s Early Career Investigator Lecture. NIGMS established this lecture series three years CHIA-CHI CHARLIE CHANG ago to highlight the achievements of early-career grantees and to encourage undergraduates and other students to pursue biomedical research careers. After his lecture, Smith answered questions from the students about pursuing a career in laboratory research. Smith (left) offered more career advice to the Morgan State students as he chatted informally with them.

4 THE NIH CATALYST JULY-AUGUST 2018 FEATURE

Let’s Talk Microbes The Big Read at NIH Featured Author Ed Yong BY ALLISON CROSS, NCI

Let’s talk microbes! This is what members of the NIH community were doing this spring as they came together to discuss science journalist Ed Yong’s 2016 book I Contain Multitudes: The Microbes Within Us and a Grander View of Life as a part of the second annual Big Read at the NIH. Then, on June 5, the award-winning author visited NIH for CHIA-CHI CHARLIE CHANG an informal conversation about the book in Masur Auditorium (Building 10) with NIH Director Francis Collins. The Big Read, a nationwide event initiated by the National Endowment for the Arts, aims to foster collaboration and community across the NIH through The second annual Big Read at NIH featured Ed Yong and his book I Contain Multitudes: The Microbes Within Us and a the discussion about a single book over Grander View of Life. Yong visited NIH for an informal conversation about the book with NIH Director Francis Collins. several months. This is our second year participating in a local Big Read event. During his conversation with Collins, he book as a joy. It has become a New York To promote book conversations, the NIH explained that in deciding what to include Times best seller and earned him a spot in Library made an eBook version of I Contain in the book, he “gravitated toward things the best-of-2016 lists by the NYT, National Multitudes available through its collection, that would provide really good stories Public Radio, the Economist, the Guardian, held three discussion groups, and offered [and] would illuminate some of the and several others. training sessions to guide individuals in broader themes about how the microbiome “Do you have any advice for scientists organizing their own book groups. These works.” In structuring the book around the about their own responsibilities and Big Read activities brought together a wide particular relationships between microbes opportunities to communicate what they range of people from across the NIH. and their hosts, Yong wanted to create do?” Collins asked near the end of the Scientists have been studying the something that “would stand the test of program. microbiome for centuries, but research time even as new papers and discoveries “I think good science writing and good in this area has picked up dramatically were continuing to be published.” He science communication is not just about… in the last few decades. The idea that hopes that people who read his book will explaining it in lay language,” Yong said. bacteria cause disease, the well-known understand that “microbes are not just “It is also about explaining how that science germ theory, has misled many people to things to go ‘eww’ over or to fear [but] came to be, like the stories behind it and believe microbes need to be eradicated to are a dominant life from of the planet.” the stories of the people behind it. That’s cure disease. However, it is now understood Although this is his first book, Yong what I tried to get across in the book [and] that most microbes do not make us sick. is a prolific science writer and currently in all the pieces I write.” In his book, Yong explains the complex reports for The Atlantic; his work has relationships between bacteria and animals, been featured in National Geographic, The Big Read was sponsored by the the benefits of these partnerships, and what the New Yorker, Scientific American, and Foundation for Advanced Education in the happens when these partnerships go awry. other publications. It was with “an urge Sciences. To watch a videocast of Yong’s June Yong spent six months researching and to explain, to describe, to tell stories” that 5, 2018, presentation, go to https://videocast. reporting for his book and interviewed he first began science writing in 2006. He nih.gov/launch.asp?23932. more than 100 people in the process. described the experience of writing his first

https://irp.nih.gov/catalyst 5 FEATURE

Elisabeth Murray, Ph.D. Investigating the Role of Different Brain Regions in Memory and Decision-Making BY CLAIRE E. MCCARTHY, NCI

1990s, she showed that the amygdala and hippocampus were not the key for object-memory formation, but that two other regions within the medial temporal lobe—the entorhinal and perirhinal cortex—were. Her studies overturned long-standing theories about neurobiology at the time. Murray continues to challenge existing theories and explore new frontiers in neuroscience. During this year’s Anita B. Roberts Lecture held on May 17, 2018, she described her current research examining the role of the orbitofrontal cortex (OFC, the area of the brain directly above the eyes), which is important for learning and decision-making. In one set of studies with macaque monkeys (Macaca mulatta), she tested and rejected the established theory that the OFC itself plays a role in cognitive flexibility (the ability to adapt one’s thinking to

JULES ASHER, NIMH changing circumstances). Instead, she

NIMH Senior Investigator Elisabeth Murray, who studies the neural basis of learning, memory, emotion, and response, and her team were surprised to find that is holding a 3-D model of Patient H.M.’s brain. In 1953, the surgical removal of his medial temporal lobe helped stop his a fiber bundle connecting the temporal epileptic seizures but left him unable to form new memories. lobe to the frontal lobe—passing near the OFC—was involved. When you walk into Elisa beth carry on a normal conversation, In other studies, she is attempting Murray’s office, you can see a solve math problems, and write to gain a deeper understanding of how 3-D model of the brain belonging sentences. Based on this evidence, the OFC and the adjacent ventrolateral to Patient H.M. (Henry Gustav the prevailing dogma when Murray prefrontal cortex (VLPFC) work to Molaison), a man well known began her postdoctoral training in guide behavior. For example, she and by students in psychology and 1979 with Mortimer Mishkin at the her lab have investigated the OFC’s role neuroscience. In 1953, surgeons National Institute of Mental Health in the devaluation of rewards (when removed his medial temporal lobe (NIMH) was that specific areas the value of something is reduced in in an attempt to stop his epileptic within the medial temporal lobe—the a person’s mind and influences their seizures. Although the surgery hippocampus and amygdala—were actions). In her talk, Murray used the helped, there was an unfortunate the seeds of memory formation for example of the hardboiled-egg-eating side effect: He was unable to form previously encountered objects and contest in the 1967 movie Cool Hand new memories about individuals, people. Luke. Luke, played by Paul Newman, objects, or events. He did, however, But when Murray began sets out to win an impromptu bet retain most of his memories formed investigating the neural substrates that he could eat 50 eggs in an hour. prior to the procedure and could of this recognition memory in the Although he succeeds—the scene is

6 THE NIH CATALYST JULY-AUGUST 2018 FEATURE

MORE ABOUT ELISABETH MURRAY, PH.D. Senior Investigator and Chief, Section on Neurobiology of Learning and Memory, agonizing to watch—he goes from it. They determined that the loss of and Chief, Laboratory of Neuropsychology, valuing (liking) eggs to devaluing neural activity in the back of the OFC National Institute of Mental Health (hating) them. The eggs have become impaired the monkeys’ value-updating devalued because he doesn’t want to abilities; loss of activity in the front Born and grew up: In Syracuse, New York eat any ever again. interfered with goal selection (linking Research Interests: Understanding the Similar to Luke, monkeys will knowledge of outcome value to image neural basis of learning, memory, emotion, typically devalue a food if they eat choice). and decision making. Her laboratory has as much of it as they can during one Overall, Murray has improved pioneered the use of MRI-guided stereotaxic sitting. Normally in behavioral tests, the understanding of brain-behavior surgery, a method that has for the first time the monkeys would choose objects relationships by showing that the OFC allowed the examination of the selective that would reward them with a more contains distinct functional regions for mnemonic contributions of various medial desirable food, avoiding objects yielding determining the value of things and temporal lobe structures. the devalued food. But Murray found selecting goals. Her research may lead Education: Bucknell University, Lewisburg, that OFC-damaged monkeys continued to new insights about neuropsychiatric Pa. (B.S. in biology); University of Texas to choose objects that rewarded them and mood disorders that are associated Medical Branch, Galveston, Texas (Ph.D. in with the devalued food. This research with OFC dysfunction. physiology) showed that the OFC is involved in In addition to conducting research, Training: Postdoctoral training in NIMH’s decision-making based on desirability. Murray strives to be a good mentor—just Laboratory of Neuropsychology with Murray also explored the impact as Anita Roberts was—by helping junior Mortimer Mishkin of the OFC and the VLPFC on credit scientists. “I have been the beneficiary of Came to NIH: In 1979 for training in assignment, the ability to link an many efforts of the NIH Women Scientist neuropsychology and behavior; became a outcome with the choice or action that Advisors (WSA) and received good advice NIMH staff fellow in 1982, senior staff fellow produced it. In monkeys, this behavior from a handful of female role models in 1984, a research physiologist in 1989, can be tested by having them press who were able to mentor me in my own chief of the Section on the Neurobiology of images on a touch-sensitive screen to career development,” she said during the Learning and Memory in 1996, and chief of receive a piece of food. The monkeys lecture. Now, she passes on the lessons the Laboratory of Neuropsychology in 2015 learn to touch the images yielding she has learned by supporting trainees in What excites her about research: “There’s the most rewards, all while the “best” her lab, participating in the WSA, and something new every day and often it is image is changing over the test session. having discussions with young tenure-track something unexpected.” Murray and her team discovered that scientists at NIH to help them navigate Outside interests: Hiking and birding damage to the VLPFC—not damage the complexities of NIH while they work Little known fact: “When I was applying to to the OFC as expected—impaired toward achieving tenure. graduate school, I wanted to study dolphins. credit-assignment and the ability of I was fascinated with the work of John Lilly, monkeys to track the best image. The The “Anita B. Roberts Lecture Series: who was studying communication between VLPFC, therefore, is important for Distinguished Women Scientists at NIH” man and dolphins.” determining the value of an outcome honors the research contributions Roberts and Interesting fact about her family: “I recently based on the probability of reward and other female scientists have made. Roberts, learned that my great-aunt was one of the credit assignment. Thus, unlike OFC, who spent 30 years at NCI before her death early female graduates of the Columbia the VLPFC guides decision making in 2006, was known for her groundbreaking University College of Physicians (New York). based on the history of rewards, which work on transforming growth factor–beta. Childhood psychotherapy was her specialty relates to availability. To watch a videocast of her May 17 lecture, and she practiced in Ithaca, New York.” To further tease out how the OFC “Specializations for Decision Making in Website: https://irp.nih.gov/pi/ functions, Murray’s lab used a drug Primate Prefrontal Cortex,”, go to https:// elisabeth-murray that temporarily inactivated parts of videocast.nih.gov/launch.asp?23894.

https://irp.nih.gov/catalyst 7 CATALYTIC RESEARCH

Intramural Research Briefs

which is an estimate of how much blood passes through the glomeruli (the tiny filters within the kidneys that extract the waste) per minute. Researchers believe that a very high GFR rate can be a sign of early kidney damage. The work was conducted as part of the NICHD- funded Diabetes and Women’s Health Study. Researchers collected and analyzed blood and urine samples from Danish women who had pregnancies from 1996 through 2002. The data included results from tests for diabetes and kidney functioning an average of 13 years later. The group included 601 women who had gestational diabetes and 613 who did not. LARS NEUMANN,LARS THINKSTOCK.COM Results showed that women who had NIDDK: An NIDDK researcher was part of an international team that designed the first potentially therapeutic photoactive drug—MRS7145—to fight Parkinson disease. Shown: A 3D illustration showing neurons containing Lewy bodies (small gestational diabetes and later developed red spheres), which are deposits of alpha-synuclein proteins accumulated in the brain cells. diabetes were approximately nine times more likely to have an elevated GFR later in NIDDK: FIRST PHOTOACTIVE DRUG TO The MRS7145 is activated by violet light in a life compared to women who did not have FIGHT PARKINSON DISEASE wavelength that is non-toxic to neurons. In the gestational diabetes. In addition, women An NIDDK researcher was part of an current study, which involved rodent models who had gestational diabetes and later- international team that designed the first of PD, the researchers implanted optical fibers life diabetes were also more likely to have potentially therapeutic photoactive drug— in the striatum (area of the brain that controls elevated urinary albumin to creatine ratio MRS7145—to fight Parkinson disease (PD), a motor activity), then used a remote-control (UACR), an indicator of kidney disease. neurodegenerative disorder caused by a loss device to trigger the release of light. The Although the study could not prove that of dopamine, which in turn causes a gradual light activated the MRS7145, which blocked gestational diabetes is a direct cause of loss of motor control. Although there is no the A2A receptors, allowing dopamine to kidney damage, more research needs to be cure, there are drugs (such as levodopa) and be released and reducing the PD symptoms. conducted in order to confirm these findings. treatments (such as deep-brain stimulation) Although this photo-sensitive drug has only The authors noted, however, that women to treat symptoms, which include tremors, been tested in laboratory animals so far, who have had gestational diabetes may stiffness, slowed body movements, and poor the researchers hope their work will lead to benefit from periodic checkups to monitor balance. But the action of conventional drugs new therapeutic solutions for treating PD. for early-stage renal damage so clinicians can can be limited because they can’t precisely (NIDDK researcher: K. Jacobson, J Control initiate treatment to prevent or delay further target the areas of the brain involved in Release, 283:135-142, 2018, DOI: 10.1016/j. disease progression. (NIH Authors: S. Rawal, PD, their effects diminish over time and jconrel.2018.05.033) S.N. Hinkle, J. Wu, E. Yeung, J.L. Millis and the dosage may have to be increased, and C. Zhang, Diabetes Care 41:1378-1384; DOI newer drugs have unwanted side effects NICHD: POSSIBLE LINK BETWEEN 10.2337/dc17-2629) such as uncontrolled body movements. But GESTATIONAL DIABETES AND EARLY-STAGE [BY LESLIE REVOREDO, NIDCR] scientists have found that they can use certain KIDNEY DAMAGE wavelengths of light to control the precision Researchers may have uncovered a potential NCI: ENHANCING TUMOR RESPONSE TO of light-sensitive drugs and thereby avoid link between women who have had RADIOTHERAPY adverse effects. gestational diabetes and early stage kidney Radiotherapy plays a significant role in The researchers in the current study damage. According to the study led by NICHD the management of non–small cell lung developed MRS7145, a photo-sensitive investigators and other institutions, women cancer (NSCLC), but recurrence after adenosine receptor (A2AR) antagonist. A2A who had gestational diabetes were more likely treatment remains problematic. In a recent receptors play a role in controlling movement. to have a high glomerular filtration rate (GFR), study, investigators at NCI found a novel

8 THE NIH CATALYST JULY-AUGUST 2018 CATALYTIC RESEARCH

combination-therapy approach to treat NIEHS, NCI: OBESITY ASSOCIATED WITH also had fewer tumors and lived longer NSCLC. The researchers used a CDK4/6 LOWER BREAST CANCER RISK than mice that did not receive treatment. inhibitor, abemaciclib, and combined it Young women with high body fat have a Metarrestin breaks down an incompletely with ionizing radiation (IR) to enhance decreased chance of developing breast cancer understood component of cancer cells called radiosensitivity of NSCLC cells and tumor before menopause, according to NIH scientists the perinucleolar compartment (PNC). PNCs xenografts in mice. CDK4/6 inhibitors and an international team of researchers in the are found only in cancer cells, and in a higher are are a class of drugs designed to Premenopausal Breast Cancer Collaborative number of cells in advanced cancer when interrupt the growth of cancer cells. The Group. The international team pooled data it has spread to other sites in the body. The drug inhibited phosphorylation of the from 19 different sites comprising more Northwestern scientists had shown earlier retinoblastoma (RB) protein and effectively than 750,000 women (ranging in age that the more cancer cells with PNC in a blocked cell proliferation in cells as well from 18 to 54) from around the world. The tumor, the more likely it would spread. Those as in mouse tumors. This combination researchers evaluated questionnaires, filled findings suggested that reducing PNCs might therapy resulted in significant inhibition out by study volunteers, that included height, translate to less cancer progression and of IR-induced DNA-damage repair. Several weight, and other health-related factors. better outcomes in patients. To test these NSCLC cell lines with varied genetic It was determined that the relative risk of ideas, the Northwestern scientists relied on backgrounds were tested for the effect of premenopausal breast cancer was reduced NCATS’s expertise in screening, chemistry, this novel drug and IR combination. 12 to 23 percent for each five-unit increase in and compound development and testing to The study identified enhanced body mass index (BMI). The strongest effect evaluate more than 140,000 compounds for radiation-induced cell killing with this was seen in relation to BMI at ages 18-24, with their potential effectiveness in eliminating combination to be more effective in cells very obese women in this age group being 4.2 PNCs in cells in advanced cancer. The with functional RB protein. Interestingly, times less likely to develop premenopausal investigators identified one compound, the researchers found an unexpected role breast cancer compared to women with low metarrestin, that could effectively break of abemaciclib in inhibiting radiation- BMI at the same age. The NIH researchers are down PNCs in advanced prostate cancer cells. induced vasculogenesis (the process unsure why young, premenopausal women The NCI researchers evaluated the effects— of blood vessel formation). Tumor with a high BMI appear to be protected including toxicity—of metarrestin in pancreatic vasculogenesis is a backup pathway against breast cancer and caution that young cancer mouse models. The scientists found to restore tumor vasculature that may women should not intentionally gain weight to that the compound prevented the further contribute to recurrence of a tumor lower breast-cancer risk as there are so many spread of pancreatic cancer by disrupting the after radiotherapy. The study found that health risks associated with being overweight protein-making machinery of cancer cells, abemaciclib, when administered during and or obese. Understanding the biological and that mice treated with metarrestin lived after IR treatment, inhibited vasculogenesis mechanisms underlying the association of longer than mice without treatment. The NCI thus delaying tumor regrowth. Abemaciclib BMI and the risk of breast cancer could have and NCATS scientists are working together unexpectedly inhibited vasculogenesis by important implications for breast-cancer to collect the preclinical data on metarrestin reducing the activation of tumor hypoxia prevention. (NIH authors: D.P. Sandler , C.M. needed to further its development as a inducible factor-1 and the recruiting of Kitahara, M.S. Linet, K.M. O’Brien, JAMA candidate drug. The scientists plan to file an bone-marrow derived immune cells to Oncol; DOI: 10.1001/jamaoncol.2018.1771) Investigational New Drug (IND) application the tumor. The findings suggest that in the fall with the FDA. (NIH authors: Udo abemaciclib in combination with IR NCATS, NCI: STOPPING CANCER METASTASIS Rudloff (NCI), Juan Jose Marugan (NCATS), could provide a novel biomarker-driven NIH researchers and collaborators at and 15 others, Sci Trans Med 10:eaap8307, combination therapeutic strategy for Northwestern University (Evanston, Illinois) 2018; DOI: 10.1126/scitranslmed.aap8307) patients with NSCLC. (NCI authors: S. have identified a compound that blocks the Naz, A.L. Sowers, R. Choudhuri, M.F. spread of pancreatic and other cancers in Read more research briefs online at Wissler, J. Gamson, A. Mathias, J.A. Cook, various animal models. The team identified https://irp.nih.gov/catalyst/v26i4/ J.B. Mitchell, Clin Cancer Res, 2018; DOI: a compound, which they named metarrestin, research-briefs. 10.1158/1078-0432.CCR-17-3575) that stopped tumor metastasis in multiple [BY SARWAT NAZ, NCI] animal models. Mice treated with metarrestin

https://irp.nih.gov/catalyst 9 FEATURE

Machine Learning CONTINUED FROM PAGE 1 for common characteristics to organize the data. This process offers the additional possibility of finding subtle patterns in large multivariate datasets such as genetic, imaging, and neurological data and biomarkers from patients. Machine learning supports much of the technology around us. Smartphone cameras recognizing faces; online translating and captioning; credit-card NIBIB fraud detecting; personalized online A mouse blood platelet has been sliced into 80-some 25-nanometer-thick layers (left) by a serial block-face scanning electron marketing; and providing newsfeeds. In microscope. It takes a person a full day to manually trace the organelles through all the slices of one platelet (center). On the right is the resulting 3-D model of the platelet’s subcellular organelles. With machine learning, computers can be taught to do the the NIH intramural program, machine- job in minutes. The sample was provided by Brian Storrie, University of Arkansas for Medical Sciences (Little Rock, Arkansas); learning techniques are being used in data were analyzed by postbaccalaureate students Michael Tobin and Rohan Desai in Richard Leapman’s laboratory in NIBIB. several research areas: image processing; natural-language processing; genomics; set. Small wonder, given that a platelet at high speed. drug discovery; and studies of disease that measures two to three micrometers A more recent outgrowth of machine prediction, detection, and progression. across would be contained in about 80 learning is deep learning, which takes image slices. It soon became clear that even advantage of the availability of massive IMAGE PROCESSING the most zealous postbac would spend a amounts of data and powerful computers Analyzing X-rays and other images. lifetime working through the volume of data to train large and complicated artificial Ronald Summers’ group in the Clinical being produced by the microscope. When neural networks. For supervised deep Center has been using machine learning Matthew Guay joined Leapman’s lab as a learning, each element of the training data for two decades so that computers could postdoc data scientist, he suggested they use is labeled according to whether or not it examine and analyze X-rays, computed new developments in machine learning to contains an object of interest; however, the tomography scans, and magnetic resonance speed up the process. researcher doesn’t specify to the computer images (MRIs). The goal is to improve the Machine learning is by no means new. which features uniquely identify that object. accuracy and efficiency of the image analysis It’s been around for decades. But thanks to The computer learns to deduce the most- to enable earlier detection and treatment of big data and more-powerful computers, it predictive features of the object from the diseases. A few years ago, Summers and his has evolved into an amazing tool that has dataset and then develops computational group began using deep learning. “It has helped to advance—and often speed up— rules to identify labeled objects. This process been the most accurate technique, a signifi- scientific research. In machine learning, is akin to pointing out cats to a small child, cant performance jump,” he said. His group computer systems automatically learn who will eventually figure out the features recently released a curated set of 120,000 from experience without being explicitly that identify a cat without needing to be anonymized chest X-rays (CXRs) to the programmed. A computer program analyzes told about ears or whiskers or tails. scientific community. Researchers around data to look for patterns; determines the Reliability, reproducibility, the world can use this publicly available complex statistical structures that identify standardization, increased throughput, dataset to develop automated techniques specific features; and then finds those same and decreased cost of data processing are for disease detection and diagnosis. features in new data. For Leapman’s platelet among the benefits of machine learning. If Screening for diseases. At the Nation- images, a machine-learning program would larger datasets are available, deep learning al Library of Medicine’s (NLM’s) Lister start with the platelet structures that had can be used, and it is often more accurate Hill Center (LHC), Sameer Antani and been painstakingly outlined by the postbac than older machine-learning methods and George Thoma are developing deep- team, learn the features that identify less biased by human input. learning-based diagnostic methods that the structures, and then use computer Unsupervised machine or deep learning will improve disease testing, decrease its algorithms to demarcate platelets and goes a step further: Objects or features are cost, and produce more accurate, reliable, organelles in new sets of similar images not labeled at all and the program searches and standardized results. Antani is using

10 THE NIH CATALYST JULY-AUGUST 2018 FEATURE

CXRs to automatically screen for tubercu- hurdles to overcome in reducing mortality. of high-quality, point-of-care cervical losis (TB) and other pulmonary diseases, Jaeger developed a system on a smartphone screening, especially in developing countries with a special focus on sub-Saharan Africa attached to a microscope and is field testing where medical resources are scarce. regions where medical facilities are limited it in Bangladesh and Thailand. Thoma considers the results from and people have to travel long distances to Screening for HPV is important applying deep learning to this automated hospitals. Ideally, sick people there need to because, if not prevented or caught early, screening “nothing short of a revolution.” be tested and treated close to home. A truck it can develop into cervical cancer. Antani LHC Scientific Director Clement containing an X-ray generator and Antani’s and his colleagues Zhiyun Xue and Rodney McDonald concurs. McDonald was software has been travelling around rural Long are working with Mark Schiffman, initially chary of the claims for this Kenya since 2015, allowing more Kenyans Nicolas Wentzensen, and their team at technique but now says that the results of to get tested easily and treated early. the National Cancer Institute (NCI) deep learning have been truly impressive. Thoma’s group is applying deep-learning and collaborators at other organizations Analyzing complex brain activa - models to screen for other diseases such (including Global Good, which is supported tion patterns. The National Institute of as cardiovascular diseases, malaria, and by Bill Gates and the invention expertise Mental Health’s (NIMH’s) functional the human papillomavirus (HPV). Sema of Intellectual Ventures) to develop and MRI (fMRI) Core Facility, led by Peter Candemir is using deep learning—with validate an automated visual-evaluation Bandettini , supports structural MRI and CXR collections from international sources (AVE) algorithm that will identify fMRI for 70 clinical protocols including for as well as from Ron Summers—to detect precancerous lesions during visual inspection schizophrenia, autism, anxiety disorders, cardiomegaly (abnormal enlargement of the of the cervix. This AVE algorithm multiple sclerosis, epilepsy, and stroke. Tra- heart). Stefan Jaeger is applying a deep- outperforms human interpretation and ditionally, fMRI studies compared scans learning algorithm to classify and count provides sensitive screening with minimal from a patient group with those from a malaria parasites in blood-smear images clinical training or cost. Installing AVE on control group to identify specific differ- faster and more accurately than humans camera phones or similar devices, combined ences related to a disease. Now, machine- can. Malaria affects millions worldwide, with available low-cost treatments, could learning and deep-learning methods can and inadequate diagnosis is one of the permit unprecedented dissemination be used to analyze more complex and subtle brain-activation patterns as well as many other sources of information such as electroencephalograms. “Deep learning is more of an adaptive model that allows scientists to find subtle connections without imposing a structured model on the data,” said Bandettini. “There’s a push to get more information from the research, have it translate to patients, and there’s also this overwhelming increase in data because of newer imaging techniques.” Bandettini has recently started new collaborative teams within NIMH for data science and machine learning. The data- science team, headed by Adam Thomas, will share data across protocols so that intramural researchers can have access to well-curated image datasets and be able

SAMEER ANTANI SAMEER to mine data from public repositories. The A truck containing an X-ray generator and Sameer Antani’s software (developed via machine-learning) has been machine-learning team, led by traveling around rural Kenya, where medical resources are scarce and hospitals are often far away, since 2015, allowing Francisco more Kenyans to be screened for TB and other pulmonary diseases and treated early. CONTINUED ON PAGE 12

https://irp.nih.gov/catalyst 11 FEATURE

Machine Learning CONTINUED FROM PAGE 11

Pereira, will use various techniques—and train researchers to use them—including multivariate analyses to extract individual differences from fMRI data to predict which drugs may help treat particular conditions. Screening for eye diseases. Machine learning is proving useful in detecting eye diseases such as age-related macular degen- eration (AMD), the leading cause of incur- able blindness in people over 65. National Eye Institute (NEI) scientist Emily Chew, whose research focuses on AMD and other retinovascular diseases, is collaborating with A PubMed search for machine learning shows the explosive growth of published research in this field since 2000. Zhiyong Lu at NLM’s National Center for Biomedical Information (NCBI) to classify 60,000 retinal images and calcu- technology (developed by NCBI) behind advice and treatment options. An NLM late risk factors for AMD. In their most it. PubMed traditionally sorts search results team responds with suggestions pointing recent work, the automated deep-learning by date with the latest papers listed first. to accurate health information for patients technique was consistently more accurate Zhiyong Lu points out that this method and families at NLM’s MedlinePlus health- than human ophthalmologists. may not be ideal for satisfying various kinds information website, but this process is Chew is also working with Jongwoo of user information needs. In early 2017, his both slow and expensive. Dina Demner- Kim in Thoma’s group to develop deep- machine-learning work allowed PubMed Fushman in Thoma’s group has developed learning models that will improve screening users to search for relevance-based results by prototype systems using NLP and deep for glaucoma. Drawing from thousands of choosing the new sort option “Best Match.” learning to analyze incoming questions, images from NEI and international open- Lu’s training dataset was developed by extract question topics, and identify or access sources, the model has learned to mining tens of thousands of past PubMed generate precise answers. detect and classify features in specific searches in an aggregated fashion. Dozens Improving the grant-application regions of retinal images. of features are used to rank PubMed results, process. The NIH Center for Scientific the most important being past usage (access Review is the gateway for NIH grant NATURAL LANGUAGE PROCESSING statistics) of an article, publication date, applications and their review. To In natural-language processing (NLP), relevance score, and type of article. Some improve the grant-application process, researchers program computers to under- papers might not contain the precise words in Calvin Johnson’s group at the Center stand, interpret, and manipulate human a query or even synonyms of those words but for Information Technology (CIT) has language. Some of the ways that NLP is may still be relevant. Deep learning offers developed a tool that uses machine learning being used at NIH is for PubMed searches, great promise here: It can identify related to analyze the text in the application and dealing with medical questions that come articles by analyzing words in context. And recommend an appropriate study section. from the public, and helping to improve PubMed users, when responding to tests that the grant-application process. present both the date-sorted and relevance- DISEASE DETECTION, GENOMICS, AND Making PubMed searches better. Each sorted (“Best Match”) results, have indicated DRUG DISCOVERY day, some 2.5 million people use PubMed, that the relevance-based results are more Detecting diseases early. Parkinson disease NLM’s search engine that provides free useful to them. (PD) is characterized by a wide variation access to over 28 million biomedical Responding to medical questions. in age of onset, duration until death, and life-sciences publications. Few are Streams of medical questions come in to symptoms, and rate of progression. Until aware, however, of the machine-learning NLM every day from people looking for now, early detection and individualized

12 THE NIH CATALYST JULY-AUGUST 2018 FEATURE

predictions have been based on clinical applying machine-learning models across not work well on full-text papers because observations. Andrew Singleton’s group a broad spectrum of drug-discovery projects the nature of the data is different. at the National Institute on Aging is using including antiviral drugs, anti-infection In some cases, the algorithm can deep learning to examine multidimensional medications, epigenetic targets and produce the “right result for the wrong data—clinical reports, imaging data, deubiquitinating enzymes, and medications reasons,” said Antani. His program once blood tests, genetic data, and results of for rare diseases. correctly identified a patient as having TB neurological tests over time—from large NCATS researchers also use machine- due to an abnormality in the X-ray that was cohorts of patients with PD. learning to guide the optimization of new actually not TB-related. To find the cause Singleton points out that humans are drugs for adsorption and metabolism, select of such errors, Siva Rajaraman (NLM) is very good at identifying patterns in 2-D the best clinical candidate for efficient investigating the way in which the layers in or 3-D data, but only computers, using the and safe clinical trials, and develop better a multilayer deep-learning structure process latest techniques, can find subtle differences toxicity-assessment methods. The models the input images. and patterns in 130 dimensions. The are available to other NIH institutes and What are the prospects for using deep predictive models built by Singleton’s group centers and can be used, for example, to learning in clinical diagnosis? Lu believes allow for phenotypic clustering on a massive design RNA- and DNA-based nanoparticles that physicians may have more trust in a scale and indicates how patterns are related. with desired immunomodulatory activity as traditional computer program with rules The group recently used deep learning to well as to predict toxicity, measure estrogen- that can be understood and modified. An identify the natural subtypes of PD as well receptor activity, and determine whether the incorrect deep-learning prediction that is as identify and predict the progression rates stability of certain compounds depends on corrected by a physician might not change of each subtype. Singleton’s group is also specific human cytochromes. the next diagnosis: The algorithms learn collaborating with Sonja Scholz (National from thousands of examples, so modifying Institute of Neurological Disorders and CHALLENGES a single sample may not change the way an Stroke) on a deep-learning project that Although deep learning holds huge algorithm works. analyzes genomic data to predict and potential in several biomedical areas, its The heavy computational requirements differentiate among dementia syndromes. success depends on getting large training mean that the training phase of deep Detecting gene-gene interactions. datasets. Small training datasets can result learning takes longer than traditional Joan Bailey-Wilson at the National Human in the program’s defining functions that methods. Once training has been Genome Research Institute (NHGRI) has do not generalize well to real-life data. completed, however, deep learning can be been collaborating for decades with James Large annotated datasets can be difficult applied very rapidly. Malley (retired from CIT and now a spe- to obtain, however, so machine learning is Despite the challenges, machine cial volunteer at NHGRI) to develop open- a more practical approach for projects with learning is likely to produce impressive source software and methods for statistical small numbers (of patients, for example). results in the future. “Previous methods machine learning, with particular interest in In validating machine-learning methods, limited the questions that could be asked,” detecting gene-gene interactions. They have McDonald stresses how important it is to said Bandettini. “But machine learning is been applying machine-learning methods do a good statistical analysis of the datasets exciting because it’s taking all of the data to find genetic variants that increase the risk to avoid subtle biases. to the next level, [and] trying to make of complex traits such as childhood-onset Deep learning can be a black box. A it usable for individual patients, as well schizophrenia and several hereditary cancers. scientist cannot easily tell why the algorithm as pulling even more subtle information Accelerating drug discovery. Scientists comes up with a particular result. Singleton out of it.” at the National Center for Advancing is sanguine: At the start “much technology Translational Sciences (NCATS) are appears [to be] a black box,” he said. “But if For a list of resources and to read about collaborating with researchers at NIH the results are reliable, that’s good enough how other intramural researchers are using and beyond to accelerate the discovery to be getting on with [deep learning].” machine learning or deep learning in their of therapeutic medications. In an effort The sensitivity of deep learning work, go to led by NCATS Director Christopher also means that the algorithms may not https://irp.nih.gov/catalyst/v26i4/machine- P. Austin and Scientific Director Anton generalize well. A deep-learning program learning. Simeonov, NCATS is developing and trained on, say, PubMed abstracts might

https://irp.nih.gov/catalyst 13 FEATURE

Barbra Streisand CONTINUED FROM PAGE 1

Promisingly, the rise of organizations like the Women’s Heart Alliance and advocates like Streisand have led to considerable progress in closing the gender gap in cardiovascular care. Recent NIH policies encourage, and in some cases require, that NIH-funded research include members of both sexes. These directives pertain not just to human studies but also preclinical studies in which scientists have often limited their experiments to male animals and cells. Streisand specifically highlighted an NIH-funded endeavor called the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), launched in 2015, citing its goal to recruit a diverse AARON CLAMAGEAARON cohort in order to examine differences in As the featured guest at the annual J. Edward Rall Cultural Lecture, Barbra Streisand took the opportunity to highlight an outcomes between men and women. issue that is near and dear to her heart: women’s cardiovascular health. Her lecture was followed by an on-stage conversation with NIH Director Francis Collins and, later a tour of an NIAID lab at the Clinical Center. From left: NIAID Director Anthony Despite these developments, Streisand Fauci, Streisand’s husband, the actor James Brolin, Streisand, and Collins. said, more work remains to be done. She called for increased research funding for the study of sex differences in heart health. NIH Director Bernadine Healy titled attitudes toward heart disease. The Women’s Heart Alliance is also taking “The Yentl Syndrome.” The piece detailed “I think women are embarrassed to talk steps to eliminate gender disparities in the a woefully under-recognized disparity in about heart disease because there is a stigma quality of cardiovascular care and to educate how physicians treated men and women attached to it,” Streisand said. “It is known women about lifestyle changes that reduce with cardiovascular disease (CVD). Women as an old man’s disease in a sense, so many the risk for CVD. admitted to the hospital with signs of a heart people think it just affects older men, but “We start from the recognition that, attack or other severe cardiovascular ailment that is not true.” In fact, heart disease is biologically, women and men are not the were significantly less likely than men to the leading cause of death for both men same,” Streisand said. “We have different receive the standard tests and treatments. and women. Moreover, even after adjusting equipment, we have different plumbing. “The problem is to convince both the lay for age, women are 25 percent more likely And we advocate for funding and research and the medical sectors that coronary heart than men to die, develop heart failure, or so we can understand even more and apply disease is also a woman’s disease, not a man’s experience a stroke within five years of their those breakthroughs to provide prevention, disease in disguise,” Healy wrote. first heart attack. care, treatment, and outcomes for everyone. Given its relationship to her film, the In 2008, Streisand helped raise As we like to say, we want to make sure editorial unsurprisingly piqued Streisand’s $22 million dollars—including a $10 women’s hearts are on everyone’s minds.” interest, prompting her to learn more about million donation of her own—for the the issue of women’s heart health. She was Women’s Heart Center at Cedar Sinai This article is adapted from a May 29, 2018, “I “astonished and upset” to discover the stark Medical Center in Los Angeles, which Am Intramural Blog” post gaps in the awareness and diagnosis of CVD was subsequently renamed after her. Six (https://irp.nih.gov/blog/post/2018/05/ in women, as well as the dramatically lower years later, she co-founded the Women’s barbra-streisand-talks-up-women-s-heart- levels of treatment and needlessly inflated Heart Alliance, a non-profit group that health). To watch a video of Barbra Streisand’s death toll that result from them. Much like advocates for increased research into gender presentation at the May 15, 2018, J. Edward Healy, Streisand attributed the problem differences in cardiovascular health and Rall Cultural Lecture, go to https://videocast. partly to mistaken cultural beliefs and medical treatment. nih.gov/launch.asp?23875.

14 THE NIH CATALYST JULY-AUGUST 2018 THE SIG BEAT

The SIG Beat CONTINUED FROM PAGE 3 MPIG and SBIG: Sex differences were also detected when social interaction was a factor. Previous Determining studies had shown that a fly had increased Molecular Structures daytime sleep if it was exposed to 30 same- BY MANJU BHASKAR, NINDS sex flies for five days compared to being JIANSEN JIANG, NHLBI JIANG, JIANSEN kept in isolation. Harbison discovered that The Membrane Protein Interest males were more sensitive to this paradigm Group (MPIG) and the Structural Biol- than females; almost all the males in social ogy Interest Group (SBIG) are science groups had increased daytime sleep whereas hubs for brainstorming interactions the female response was more varied. among scientists who strive to determine Harbison’s studies established that there molecular structures by applying the In his keynote talk, Jiansen Jiang (NHLBI) described how are indeed differences in sleep between male cryo-EM revealed structures of telomerase and provided new principles of computational biology and and female fruit flies. Genome-wide associ- insights into telomeric DNA synthesis. Shown: A map of the biophysics and using experimental tools ribbon structure of a telomerase complex. ation studies (GWAS) have investigated 1.9 such as X-ray crystallography, electron million variants for association with sleep microscopy (EM), mass spectrometry, and assembly machinery complex; and a in flies; three studies have found thousands nuclear magnetic resonance (NMR), membrane enzyme that serves as a basis of genes. But if only one sex was focused cryo-electron microscopy (cryo-EM), and for designing in silico inhibitors. on, 17-35 percent of genes would have been computational approaches. The symposium’s keynote speaker, Jian- missed! She did note that she would like to The SBIG/MPIG Student and Postdoc sen Jiang (National Heart, Lung, and Blood investigate gene expression in the fly brain Symposium, held at the NIH Cloisters Institute, NHLBI) spoke about how cryo- to determine if the same differences occur (Building 60) on May 24, showcased EM structures of telomerase, a critical deter- there as at the whole-body level. the novel discoveries and significant minant of human health—affecting aging, Fruit flies are invertebrates and therefore contributions made by the research groups cancer, and stem-cell renewal—can reveal not covered by the NIH policy that requires from several institutes. new insights into telomeric DNA synthesis. sex as a biological variable to be factored Many of the researchers in the SBIG/ Structural biology has also paved way for into research using vertebrate animals and MPIG use cryo-EM, an EM technique phenomenal contributions in the discovery in human studies. But Harbison urged that in which a sample is cooled to extremely of novel therapeutics. One such noteworthy unless there is a compelling reason to not low temperatures. Cryo-EM helps scien- discovery is how proton pump inhibitors— look at both sexes, it should be done…even tists decipher and visualize the structural traditionally used to treat gastrointestinal in fruit flies! properties of a variety of protein molecules tract bleeding, stomach ulcers, and acid The SGHD SIG promotes information including the human anion exchanger 1, reflux—could be also used as inhibitors of exchange and interaction among NIH and the major membrane protein in red blood HIV-1. NHLBI postdoc Madeleine Strick- other scientists who work on or are interested cells that plays a key role in carbon diox- land explained how her group used NMR in aspects of sex-based research in any ide exchange in the blood; tubulin isoform to determine the high-resolution structure segment of the research continuum or in sex composition and microtubule dynamics; of one of the inhibitors that plays a role in differences research relevant to health and Ton, a multi-subunit membrane protein the pathogenesis of HIV. disease as approached via a wide variety of complex and molecular engine found in Read more online at https://irp.nih.gov/ scientific disciplines. For more information, the inner membrane of gram negative catalyst/v26i4/the-sig-beat/. visit https://oir.nih.gov/sigs/sex-gender- bacteria; voltage-activated potassium For more information on the MPIG, health-disease or contact the co-chairs: Elena channels in lipid nanodiscs (synthetic contact Reinhard Grisshammer (reinhard. Gorodetsky ([email protected]) or Katrina model membrane systems); particles of [email protected]). For more on Serrano ([email protected]). virus-associated RNA-I/protein kinase RNA-activated PKR inhibiting; transpo- the SBIG, contact Antonina Roll-Mecak sons widely used for genomic engineering; ([email protected]) or Anirban the outer mitochondrial membrane sorting Banerjee ([email protected]).

https://irp.nih.gov/catalyst 15 COLLEAGUES

Recently Tenured

BIBIANA BIELEKOVA, NIAID STEPHEN GILMAN, NICHD RAPHAELA GOLDBACH- NASSER RUSAN, NHLBI HUMPHREY HUNG-CHANG MANSKY, NIAID YAO, NIEHS

BIBIANA BIELEKOVA, M.D., NIAID Research interests: My laboratory is study- (CSF) biomarkers and statistical learning Senior Investigator and Chief, Neuroim- ing the mechanisms of immunoregulation we have defined (and validated in an inde- munological Diseases Section, National and immune-mediated central nervous pendent cohort) molecular signatures that Institute of Allergy and Infectious Diseases system (CNS) tissue injury in multiple differentiate MS from other CNS diseases Education: Comenius University School of sclerosis (MS) and other neuroimmu- and predict rates of MS progression. Our Medicine, Bratislava, Slovakia (M.D.) nological diseases. Our long-term goal goal is to formulate (and validate) a frame- Training: Medical internship, SUNY is to develop effective therapies for these work in which CSF biomarker-based models Downstate Medical Center (Brooklyn, diseases. Because observational studies provide reliable diagnostic, prognostic, and New York); neurology residency, Boston cannot determine causal relationships, we therapeutically-predictive information that University School of Medicine (Boston); use proof-of-principle interventional trials will empower neurologists to practice preci- neuroimmunology fellowship in NINDS’s supported by biomarker/mechanistic stud- sion medicine. Neuroimmunology Branch ies and mathematical/statistical modeling Among my lab’s scientific achievements Came to NIH: In 1997 for training; staff clini- to investigate major hypotheses about the is the development of a CSF-based test that cian in NINDS (2000-2005); left NIH to be a pathophysiology of MS. identifies and quantifies compartmentalized tenured associate professor of neurology and Because immunomodulatory treatments CNS inflammation specific for T cells, B director, Waddell Center for MS, University of do not work well for progressive MS, it cells, and monocytes/macrophages without Cincinnati (Cincinnati, Ohio); returned to NIH was believed that progressive MS is mainly the need for a brain biopsy. In addition, in 2008 as an investigator in NINDS a neurodegenerative disease. We demon- we used statistical learning to develop a Selected professional activities: Elected strated that the levels of CNS inflammation CSF-based molecular diagnostic test that fellow of the American Academy of Neurol- are the same for patients with progressive can differentiate MS from other CNS dis- ogy; elected fellow of the American Neuro- MS and those with relapsing-remitting MS. eases (including inflammatory). We also logical Association; reviewer for several jour- The multiplicity of potential pathogenic pro- developed much more sensitive measures of nals; co-organizer of a multiple sclerosis (MS) cesses in progressive MS makes it unlikely clinical outcomes and a MS disease severity biomarker workshop, a Center for Human that a single therapeutic agent will have scale (MS-DSS) that can be used to predict Immunology workshop, and the Spinal Fluid major clinical efficacy. Effective therapy will the progression of the disease. Consortium for MS require combinations of therapeutics that Outside interests: Taking photographs; target patient-specific drivers of disability. If you have been recently tenured, the NIH hiking; volunteering on medical missions in To produce such combination treat- Catalyst will be contacting you soon about developing nations ments, we must reliably measure the diverse including you on these pages. It’s a great Website: https://irp.nih.gov/pi/ CNS pathophysiological processes in living way for your colleagues to get to know bibiana-bielekova people and thereby define process-specific about you and your work. biomarkers to use as outcomes in Phase 2 trials. Indeed, using cerebrospinal fluid

16 THE NIH CATALYST JULY-AUGUST 2018 COLLEAGUES KUDOS

STEPHEN GILMAN, SC.D., NICHD childhood and adulthood. Discovering the Senior Investigator, Social and Behavioral mechanisms that produce social inequalities Sciences Branch, Division of Intramural in psychopathology is integral to advancing Population Health Research, National our understanding of the developmental Institute of Child Health and Human origins of psychiatric disorders. Development This research has directed our focus Education: Tufts University, Medford, MA on neurodevelopment as a key underlying (B.A., social psychology); Harvard School pathway. For example, in a recent study, of Public Health, Boston (Sc.M. and Sc.D. in we found that neurologic abnormalities in Two Elected to NAS health and social behavior) infancy were more likely to occur in the Training: Postdoctoral fellowship in context of socioeconomic disadvantage; in Mich ael Got tesm an and Clare behavioral medicine, Brown Medical School part the abnormalities were associated with Waterman have been elected to the (Providence, Rhode Island) lower concentrations of the proinflammatory National Academy of Sciences (NAS) for Before coming to NIH: Associate profes- cytokine interleukin-8 in prenatal serum 2018. Together they join more than 40 sor, Department of Social and Behavioral during mid to late gestation. This work active NIH scientists in the NAS. Sciences and Department of Epidemiology, suggests that stress-immune mechanisms In addition to being the Deputy Direc- Harvard School of Public Health are one potential pathophysiologic pathway tor for Intramural Research, Gottesman Came to NIH: In 2015 involved in the early origins of population- leads the National Cancer Institute’s (NCI’s) Selected professional activities: Adjunct health inequalities. Other work involves Laboratory of Cell Biology. His interests professor, Department of Mental Health, examining neurodevelopmental and other have ranged from how DNA is replicated Johns Hopkins Bloomberg School of early childhood risk factors for suicide, a in bacteria to how cancer cells elude che- Public Health; elected fellow and councilor, leading cause of death among young people. motherapy. Collaborating with Ira Pastan, American Psychopathological Association; chief of NCI’s Laboratory of Molecular member, Education Committee, Society for Biology, and others, Gottesman identi- Epidemiologic Research; associate editor, RAPHAELA GOLDBACH-MANSKY, M.D., fied the multi-drug resistant gene (MDR1) Nicotine & Tobacco Research M.H.S., NIAID responsible for resistance of cancer cells to Website: https://irp.nih.gov/pi/ Senior Investigator and Chief, Translational many of the most common anticancer drugs stephen-gilman Autoinflammatory Disease Studies Section, and showed that this gene encodes a protein National Institute of Allergy and Infectious that acts to pump anticancer drugs out of Research interests: Common mental dis- Diseases drug-resistant human cancers. orders—depression, anxiety, and substance- Education: Universität Witten/Herdecke Waterman is a Distinguished Investiga- use disorders—account for a substantial Medical School, Witten, Germany (M.D.); tor in the National Heart, Lung, and Blood portion of the global burden of disease. Duke, Durham, North Carolina (M.H.S.) Institute’s Laboratory of Cell and Tissue My group investigates the life-course epi- Training: Postdoctoral research fellow, Morphodynamics. She has made pioneering demiology of common mental disorders Memorial Sloan-Kettering Cancer Center discoveries into the complex and dynamic with an emphasis on understanding their (New York); combined residency in inter- mechanical interactions among organelle developmental origins. Given that there are nal medicine and pediatrics, Case Western systems within cells that are required for substantial social inequalities in common Reserve University, MetroHealth Medical directed movement. She has made key con- mental disorders, we also seek answers to Center (Cleveland, Ohio); and rheumatology tributions to our understanding of the cel- the question “Why do social inequalities in fellowship at NIAMS lular cytoskeleton, including how integrin, common mental disorders emerge early in Came to NIH: In 1997 for training; became microtubules, and filamentous actin work the life course, persist into adulthood, and staff clinician in 2001 and tenure-track inves- together to produce movement. She has also become transmitted to the next generation?” tigator in 2008; in 2016 became tenure-track created cutting-edge technologies such as We are investigating the mechanisms investigator in NIAID quantitative fluorescent speckle microscopy for the link between disadvantaged child- that have enabled new studies and insights hood environments and the onset and recur- into these systems. rence of mood and substance disorders in CONTINUED ON PAGE 18

https://irp.nih.gov/catalyst 17 COLLEAGUES

Recently Tenured CONTINUED FROM PAGE 17

Selected professional activities: Founder and DIRA. Our work led to the FDA’s Research interests: My lab studies of the trans-NIH Translational Autoinflam- 2012 approval of the IL-1-blocking agent the role of centrosomes during animal matory Research Initiative; editorial board anakinra for the treatment of NOMID. development. The centrosome is a non- member of Rheumatology, JCI Insight, and More recently we identified diseases pre- membrane bound organelle that serves as Frontiers in Immunology senting with chronically elevated blood the main microtubule organizing center Outside interests: Reading about and study- IFN signatures suggesting excessive IFN of most animal cells. Centrosomes help ing world and art history; hiking; gardening; signaling (in CANDLE and SAVI). build mitotic spindles, which are the and listening to classical music Treatment in a compassionate program molecular machines required for chro- Website: https://www.irp.nih.gov/pi/ using a JAK inhibitor that blocks IFN mosome separation during cell division. raphaela-goldbach-mansky signaling confirmed a key role for IFN Given the importance of cell division for in causing the disease. proper development and tissue mainte- Research interests: My translational Many genetically defined autoinflam- nance, it is not surprising that defects in autoinflammatory research focuses on matory diseases have become models for centrosome function lead to a wide range children who have early-onset autoinflam- understanding the pathogenesis of more of failures at the cellular level, which matory diseases (immune dysregulatory common inflammatory diseases and are in turn, lead to tissue defects and many diseases with excessive sterile inflamma- providing models for treatment. human diseases. tion that cause organ dysfunction and Our work benefits from the NIH Clini- My lab is trying to determine how damage). My research team conducts cal Center’s help in phenotyping patient; centrosomes are properly constructed pathogenesis and treatment studies in conducting interventional studies; and from their individual parts and how they patients who have interleukin-1 (IL- providing inpatient- and outpatient-care function in a wide range of cell types to 1)-mediated autoinflammatory diseases— facilities, laboratory services, and first-class avoid human diseases such as polycys- including neonatal-onset multisystem imaging modalities. My active collaborations tic kidney disease, microcephaly, cancer inflammatory disease (NOMID) and with specialists in many NIH institutes and and many others. We have streamlined deficiency of the IL-1 receptor antagonist the NIH Clinical Center’s radiology and a system to investigate multifunctional (DIRA)—and in patients with the type I physical therapy department are crucial in centrosome proteins and figure out how interferon (IFN)-mediated autoinflamma- our studies and in supporting our patients. they play unique roles in different devel- tory diseases, CANDLE and SAVI. Fur- opmental stages, cell types, and cell-cycle thermore, we evaluate and study patients stages. Using Drosophila genetics, cell with undifferentiated autoinflammatory NASSER RUSAN, PH.D., NHLBI biology, super-resolution microscopy, bio- diseases that respond poorly to treatment. Senior Investigator, Laboratory of Molecular chemistry, and modern molecular biol- We apply a diagnostic approach that Machines and Tissue Architecture, National ogy, we have uncovered unexpected new includes careful clinical, genetic, and Heart, Lung, and Blood Institute roles for centrosome proteins including immune evaluations. We are part of the Education: University of Massachusetts, in interphase neural stem cells during NIAID Clinical Genomics Program and Amherst, Massachusetts (B.A. in biology and embryogenesis and spermatogenesis. aim to identify novel genetic variants that Ph.D. in molecular and cellular biology) We have found that diversity in cause or modify inflammatory disease Training: Postdoctoral training, University protein-protein interactions networks phenotypes. of North Carolina (Chapel Hill) is responsible for the diversity of cen- With the goal of translating clues Came to NIH: In 2011 as an Earl Stadtman trosome functions across cell types and from early pathogenic and genetic stud- Investigator in NHLBI cell-cycle stages. In other words, not all ies into novel treatments, we develop Selected professional activities: Editorial centrosomes are made equally. Under- treatment studies for our patients. Past board member of Molecular Biology of standing this centrosome diversity is a studies using treatments that block IL-1 the Cell and of Frontiers in Developmental priority because it could help explain signaling confirmed a key role for the and Cell Biology; chair of the Drosophila why different mutations in centrosome proinflammatory cytokine IL-1 in causing Image Award proteins affect specific cell types and the disease manifestations of NOMID Website: https://irp.nih.gov/pi/nasser-rusan manifest different diseases.

18 THE NIH CATALYST JULY-AUGUST 2018 NIH ABBREVIATIONS COLLEAGUES CBER: Center for Biologics Evaluation and Research, FDA CC: NIH Clinical Center CCR: Center for Cancer Research, NCI CIT: Center for Information Technology DCEG: Division of Cancer Epidemiology and Genetics, NCI DIPHR: Division of Intramural Population My laboratory is also venturing Compelling animal evidence and Health Research, NICHD FAES: Foundation for Advanced Education into developmental neurobiology. This human epidemiological data have in the Sciences direction started as a project aimed at revealed that impairments in the devel- FARE: Fellows Award for Research Excellence investigating centrosomes as micro- opment of fetal organs have profound FelCom: Fellows Committee FDA: Food and Drug Administration cephaly-suppressor organelles. We have consequences on adult health. The FNL: Frederick National Laboratory now expanded our research well beyond concept of “fetal origins of adult dis- IRP: Intramural Research Program the centrosome, taking a hardcore cell- eases” also applies to the reproductive HHS: U.S. Department of Health and Human Services biology approach to understanding systems—defects in the formation of NCATS: National Center for Advancing brain development using all the latest reproductive organs manifest as dis- Translational Sciences imaging technologies. orders of sex development. However, NCBI: National Center for Biotechnology Information minor abnormalities often go unde- NCCIH: National Center for Complementary tected and become a potential cause and Integrative Health National Cancer Institute HUMPHREY HUNG-CHANG YAO, PH.D., NIEHS of fertility problems and neoplasia NCI: NEI: National Eye Institute Senior Investigator, Reproductive Develop- when the affected individual reaches NHGRI: National Human Genome mental Biology Group, National Institute adulthood. Research Institute NHLBI: National Heart, Lung, of Environmental Health Sciences My group uses organogenesis of and Blood Institute Education: Fu-Jen University, Taipei, Taiwan the gonads and reproductive tracts as NIA: National Institute on Aging (B.S. in biology); University of Illinois at a model for understanding the basic NIAAA: National Institute on Alcohol Urbana, Urbana, Illinois (M.S. in animal sci- Abuse and Alcoholism process of organ formation. We are NIAID: National Institute of Allergy ence; Ph.D. in reproductive biology) trying to determine how exposure to and Infectious Diseases Training: Postdoctoral fellow in developmen- NIAMS: National Institute of Arthritis endocrine disruptors affects the forma- and Musculoskeletal and Skin Diseases tal biology, Duke University (Durham, North tion of reproductive organs in fetuses NIBIB: National Institute of Biomedical Carolina) and fertility in adults. Reproductive Imaging and Bioengineering Before coming to NIH: Associate professor, NICHD: Eunice Kennedy Shriver organs exhibit a dramatic sex-specific National Institute of Child Health and Department of Comparative Biosciences, pattern of dimorphic development. This Human Development National Institute on Drug Abuse University of Illinois at Urbana unique pattern of development provides NIDA: Came to NIH: In 2010 NIDCD: National Institute on Deafness us with opportunities to understand and Other Communication Disorders Selected professional activities: Chair for not only the basic mechanism of sex NIDCR: National Institute of Dental the 2018 Gordon Research Conference and Craniofacial Research determination, but also how progenitor NIDDK: National Institute of Diabetes on Mammalian Reproduction; associate cells make the decision to differenti- and Digestive and Kidney Diseases editor, Biology of Reproduction; editorial NIEHS: National Institute of ate into tissue-specific cell types, the Environmental Health Sciences board member, Sexual Development and fundamental concept of embryology. NIGMS: National Institute of Endocrinology Disorders of sex development, which General Medical Sciences Outside interests: Playing tennis and golf; NIMH: National Institute of Mental Health affect one in 4,500-5,500 newborns, NIMHD: National Institute on Minority cooking; being a public-speaking coach; and are major birth defects with significant Health and Health Disparities translating English literature to Chinese health and psychological impacts on NINDS: National Institute of Website: https://irp.nih.gov/pi/ Neurological Disorders and Stroke patients and their families. By using NINR: National Institute of Nursing Research humphrey-yao genetically modified mice to model NLM: National Library of Medicine human disorders of sex development, OD: Office of the Director OITE: Office of Intramural Training Research interests: My lab is defining we hope to identify the potential causes and Education the normal process of how gonads of these disorders. We hope that our OIR: Office of Intramural Research and reproductive tracts form during research will, one day, enable doctors ORS: Office of Research Services ORWH: Office of Research on Women’s Health embryogenesis. We are investigating to make appropriate diagnoses and OTT: Office of Technology Transfer whether this process is susceptible to in treatments. utero exposure to endocrine disruptors.

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If you have a photo or Butterfly Effect other graphic that reflects an aspect of life at NIH This male Eastern Tiger (including laboratory life) or Swallowtail butterfly Papilo( glaucus) a quotation or confession that is feeding on a Liatris spicata, a scientists might appreciate and plant commonly known as blazing that would be fit to print in star or dense blazing star, on the the space to the right, why not NIH Bethesda campus. The photo send it via e-mail: catalyst@ was taken by Joanna Cross, a nih.gov; fax: 301-402-4303; visiting fellow studying the genetics or mail: The NIH Catalyst, of neuropsychiatric disorders in Building 1, Room 333. the National Institute of Mental Health. In addition to working in Also, we welcome “letters to the lab, she’s an accomplished nature the editor” for publication and

photographer and is especially good JOANNA CROSS, NIMH your reactions to anything on at macrophotography. “I love to the Catalyst pages. take walks through the countryside or woods whenever possible, often taking my camera with me,” said READ MORE ARTICLES, AND Cross. “Macro shots are fascinating EXPANDED VERSIONS OF THE as they show the level of detail ONES IN THIS ISSUE, ONLINE AT contained within the multitude of tiny things that make up the world in which we live.” She used https://irp.nih.gov/catalyst/v26i4 a Panasonic Lumix TZ60 camera to take a photo of this butterfly right on the Bethesda campus.

PUBLISHER CONTRIBUTING WRITERS EDITORIAL ADVISORY BOARD The NIH Catalyst is published MICHAEL GOTTESMAN MANJU BHASKAR CHRISTINA ANNUNZIATA, NCI bimonthly for and by the Deputy Director for Intramural Research, OD SUSAN CHACKO DAN APPELLA, NIDDK intramural scientists at NIH. ALLISON CROSS, JOANNA CROSS TREVOR ARCHER, NIEHS EDITORS BRANDON LEVY, ROLAND OWENS MICHAEL ESPEY, NCI Address correspondence to: JOHN I. GALLIN CLAIRE E. MCCARTHY AUDRAY HARRIS, NIAID Building 1, Room 333, NIH Associate Director for Clnical Research SARWAT NAZ, LESLIE REVOREDO SUSAN LEITMAN, CC Bethesda, MD 20892 Chief Scientific Officer, CC JENNIFER SIZEMORE BERNARD MOSS, NIAID Ph: 301-402-1449 PAUL H. PLOTZ HANNAH VALANTINE HYUN PARK, NCI Fax: 301-402-4303 Scientist Emeritus, NIAMS e-mail: [email protected] EMILY PETRUS, NINDS (FELLOW) EDITOR-IN-CHIEF PHOTOGRAPHERS/ILLUSTRATORS JULIE SEGRE, NHGRI The NIH Catalyst online: LAURA STEPHENSON CARTER ALEXLMX, SAMEER ANTANI, ANDY SINGLETON, NIA JULES ASHER, SUSAN CHACKO, https://irp.nih.gov/catalyst WRITER-EDITOR GISELA STORZ, NICHD AARON CLAMAGE CHRISTOPHER WANJEK RONALD SUMMERS, CC CHIA-CHI CHARLIE CHANG Director of Communications, OIR RICHARD WYATT, OIR JOANNA CROSS, JIANSEN JIANG WEI YANG, NIDDK COPY EDITOR SARAH NEEDLE, LARS NEUMAN

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