NATIONAL INSTITUTES OF HEALTH • OFFICE OF THE DIRECTOR | VOLUME 29 ISSUE 2 • MARCH-APRIL 2021

Annals of NIH History: The 1918 Flu and COVID-19: A Tale of Two From Yellow Berets Pandemics to Nobel Laureates BY EIMEAR HOLTON, NIAID BY ETHAN SMITH, NINR

It may seem like a coincidence that Nobel laureates Michael Brown, Joseph Goldstein, Harold Varmus, and Robert Lefkowitz all started their training at NIH in the summer of 1968. But it wasn’t just happenstance, according to Raymond Greenberg, a professor at the University of Texas Health Center at Houston (Houston) and author of Medal Winners: How the Vietnam War Launched Nobel Careers. His book tells this overlooked story through the lives of those four men. As the United States’ involvement in Vietnam escalated in the late 1960s, a doctor draft ensured an adequate supply of freshly trained physicians for the armed forces. “If you were a male physician, you were subject to a special NIAID CREDIT: draft for physicians,” said Greenberg Colorized scanning electron micrograph of a cell (blue) heavily infected with SARS-CoV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. during a virtual lecture he gave at NIH in November 2020. “Pretty much everyone The COVID-19 pandemic is not our first rodeo with battling a deadly was going to serve for some period of time.” virus, and it likely won’t be our last. As we continue to process the past year, Not all of the drafted physicians served the juxtaposition of COVID-19 pandemic and the influenza pandemic of 1918 in the combat zone of Vietnam; some were puts today’s challenges into perspective. Two prominent NIH scientists shared posted to U.S. military hospitals around their perspectives (virtually) at the January 12, 2021, launch of the Demystifying the world. But with public opinion of the CONTINUED ON PAGE 12 war deteriorating, many physicians sought alternative types of public service to satisfy CONTENTS their draft obligation. FEATURES • |1| The 1918 Flu and COVID-19 |5| Fueling the Next Genomics Revolution |10| COVID-19 Timeline (January–February) |14| Introducing NIH’s Newest Lasker Scholars Yellow Berets. One such alternative |18| Stadtman Investigators Pursuing Their Passion for Science was NIH’s Associate Training Program DEPARTMENTS • |1, 7| NIH History: From Yellow Berets to Nobel Laureates; My Adventures as (ATP), a two-year research program under an NIH Yellow Beret |2| DDIR: How the IRP is Fighting COVID-19 |3| Abbreviations the Commissioned Corps of the United |4| Training: Becoming a Resilient Scientist |8, 13, 17| Research Briefs |24| Photographic CONTINUED ON PAGE 6 Moment: A Visit From the New President FROM THE DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH

How the NIH Intramural Program Is Fighting the COVID-19 Pandemic BY MICHAEL GOTTESMAN, DDIR

Given the constant presence of Currently, there are 23 institutes and Intramural Targeted Anti-COVID-19, NIH leaders such as NIH Director centers involved in COVID research a competition overseen by Ted Pierson Francis Collins and National with about 400 active projects— in NIAID. Of 159 applications, 40 were Institute of Allergy and Infectious ranging from basic science to preclinical funded. Diseases (NIAID) Director Anthony research to clinical trials—and 313 There have been so many important Fauci in the popular press, on distinct PIs. The research areas are intramural contributions to the TV and radio and in print, and in equally divided between immunology– COVID-19 effort that it is difficult commentaries in academic journals, host response and therapeutic to choose just a few to highlight in it is clear that the NIH has played (drugs and biologics) at 14%; 10% this essay, but I will do my best (and I a major role in strategic planning, in pathogenesis; 8% in genetics and hope that the architects of the equally communication of public-health genomics; and 7% in structural biology. important work that is not cited do not requirements, and development of Bioinformatics, virology, computational feel slighted). strategies to prevent, detect, and and systems biology, diagnostics, The most obvious is the contribution treat infection caused by severe acute epidemiology, and vaccines are all in of the dedicated team at NIAID’s respiratory syndrome virus Vaccine Research Center 2 (SARS-CoV-2), the virus There have been so many (VRC) to the development responsible for COVID-19. of a structure-based vaccine. What may not be as clear to important intramural contributions Since the SARS outbreak in many intramural staff are to the COVID-19 effort that it is 2002–2004, VRC Deputy the major contributions that Director Barney Graham and have been made over the difficult to choose just a few to his many talented associates past year by intramural— highlight in this essay. and colleagues, including and extramural—scientists, Kizzmekia Corbett, (NIAID), working in teams and as have been working on the independent contributors, general principles for creating to the science underlying our the 6% range. Natural history, clinical vaccines to counteract significant current understanding of the trial, and mental and behavioral health coronavirus epidemics. Targeting the diagnosis, prevention, therapy, and are in the 2–5% range. There are 63 coronavirus spike (S) protein, they pathophysiology of COVID-19. reagents available in the registry. discovered (with their collaborator Early in the COVID-19 Many of these research activities Jason McLellan, an alumnus of the pandemic, we sought to document were highlighted in the October VRC and now at the University of the contributions of our intramural 29–30, 2021, workshop organized Texas at Austin), that substitutions of scientists to the antipandemic effort by the NIH COVID-19 Scientific two prolines between two key areas by creating a dashboard in collaboration Interest Group (chaired by Pam would stabilize the S protein in its with Christine Cutillo (National Schwartzberg, NIAID) and colleagues native functional conformation. This Center for Advancing Translational at the FDA. In addition, the Office engineered structure has become the Sciences, NCATS) listing all of the of Intramural Research, with funding basis for many of the vaccines under projects being carried out in the by NIAID, provided grant support current development, all of which have intramural research program (IRP). for intramural scientists as part of the proven to be exceptionally effective in

2 THE NIH CATALYST MARCH–APRIL 2021 NIH ABBREVIATIONS FROM THE DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH 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 Health Research, NICHD FAES: Foundation for Advanced Education in the Sciences FARE: Fellows Award for Research Excellence FelCom: Fellows Committee FDA: Food and Drug Administration preventing SARS-CoV-2 symptomatic in SARS-CoV-2 is modulated by mucin FNIH: Foundation for the NIH Frederick National Laboratory infections. Specifically, this variant is type O glycosylation, which possibly FNL: IRP: Intramural Research Program encoded by the messenger RNA present explains why the UK B.1.1.7 variant HHS: U.S. Department of Health in the Pfizer and Moderna vaccines. It is more transmissible than the other and Human Services NCATS: National Center for Advancing is also encoded by the adenovirus type variants, because some of the mutations Translational Sciences 26 vaccine vector in the Johnson and in this variant are close to this site. At NCBI: National Center for Biotechnology Johnson–Janssen vaccine. the other end of the viral replication Information NCCIH: National Center for Complementary In the area of therapeutics, NCATS cycle, Nihal Altan-Bonnet (National and Integrative Health has done extensive work to screen Heart, Lung, and Blood Institute) NCI: National Cancer Institute existing drugs to be repurposed for demonstrated that SARS-CoV-2 uses NEI: National Eye Institute NHGRI: National Human Genome treatment of SARS-CoV-2 infection. a lysosomal pathway to leave cells, an Research Institute In addition, the team of Emmie unexpected finding that could have NHLBI: National Heart, Lung, and Blood Institute de Wit and Vincent Munster at important therapeutic implications. NIA: National Institute on Aging NIAID’s Rocky Mountain Laboratories Considerable progress has also NIAAA: National Institute on Alcohol (Hamilton, Montana) was one of the been made in understanding what Abuse and Alcoholism NIAID: National Institute of Allergy first to demonstrate the efficacy of the host factors predispose someone to and Infectious Diseases antiviral agent remdesivir in rodents severe disease. Helen Su and Luigi NIAMS: National Institute of Arthritis and Musculoskeletal and Skin Diseases and nonhuman primates. Their work Notarangelo, NIAID, in collaboration NIBIB: National Institute of Biomedical accelerated the development of this with the laboratory of Jean-Laurent Imaging and Bioengineering agent for treatment of hospitalized Casanova at Rockefeller University NICHD: Eunice Kennedy Shriver National Institute of Child Health and patients with moderate to severe (New York), showed that in up to 15% Human Development COVID-19; remdesivir remains a of persons severely ill with COVID- NIDA: National Institute on Drug Abuse NIDCD: National Institute on Deafness standard of care. 19, defects in the pathways involved and Other Communication Disorders There have been many contributions in the action of type 1 interferons NIDCR: National Institute of Dental to understanding the structure of the (interferons alpha and omega), caused and Craniofacial Research NIDDK: National Institute of Diabetes virus and how it enters and leaves either by mutations or neutralizing and Digestive and Kidney Diseases cells. In addition to the pioneering autoantibodies, played a significant NIEHS: National Institute of Environmental Health Sciences and elegant structural work from role. This work reinforces the role NIGMS: National Institute of the Graham group, NIH structural that even subtle defects in the immune General Medical Sciences biologists throughout the IRP have system play in susceptibility to severe NIMH: National Institute of Mental Health NIMHD: National Institute on Minority explored the structure of the S protein– viral infection and may lead to potential Health and Health Disparities angiotensin-converting enzyme 2 therapies for severely ill patients who NINDS: National Institute of receptor complex, providing a much have such defects. Neurological Disorders and Stroke NINR: National Institute of Nursing Research better understanding of the early steps Although these examples don’t NLM: National Library of Medicine in viral entry. begin to touch the tip of the coronavirus OD: Office of the Director Also relevant to viral entry, the iceberg at NIH, I think they are pretty OITE: Office of Intramural Training and Education team led by Kelly Ten Hagen (National “cool” science. We can expect much OIR: Office of Intramural Research Institute of Dental and Craniofacial more to come. ORS: Office of Research Services Research) showed that furin cleavage ORWH: Office of Research on Women’s Health OTT: Office of Technology Transfer

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

From the Fellows Committee Becoming a Resilient Scientist During My Trip to the Zoo BY ERICA WYNNE-JONES, NIAID

I first heard about resilience communicate. Jackal language is violent when I was in primary school in rural and focuses on blame. Conversely, giraffe Australia. It was part of a cognitive- language is empathetic and forgiving, behavioral program at the school called named after the giraffe’s large heart and “You can do it!” I volunteered to be on its tall stature, which gives it the ability to our “You can do it!” committee, where see the forest for the trees. These styles apply we would organize events based on one not only to communication with others but of the five keys to success: confidence, also within ourselves. persistence, organization, getting along, For me, this resilience training came and resilience. sharply into focus late last year. I was Organizing events for the other keys going through a tough time at work and was relatively easy, but resilience was much struggling in the aftermath of a difficult more difficult. As an 8-year-old, I had conversation with a colleague. So, I went NIAID WYNNE-JONES, ERICA only the rudimentary understanding that to the zoo. For me, the zoo is the perfect a tower of giraffes who stand tall and can resilience was the ability to “bounce back,” place to decompress. You get to walk around help me see the whole situation with more which sounded easy enough to me because outside, and, really, how can you be upset empathy. Practicing resilience seems to be a I played a lot of four square handball (a when you’re watching a sea lion fetch a lifelong journey, but in the moment, I was game in which four players—on a square Frisbee disk? I was halfway around the zoo glad to be riding the Metro with giraffes court divided into quadrants—bounce a when my phone died during a podcast I and not jackals. small rubber ball back and forth between was listening to. I had a battery charger, quadrants; players are eliminated when they but alas I had just witnessed my phone’s To register for or watch recordings of fail to touch the ball into another player’s last digital breath. My worst nightmare. OITE’s “Becoming a Resilient Scientist” quadrant.) In the zoo, I was able to distract myself series, go to https://www.training.nih.gov/ We ended up organizing a coloring with cute animals, but when I boarded the nih_becoming_a_resilient_scientist_series. competition to build resilience in our peers. Metro to go home, I was left with nothing To learn about OITE’s weekly resilience I’m not sure what we thought it had to do but my own thoughts. They were raging discussions that focus on specific topics, with resilience, but the ability to use crayons and twisting in my head as I replayed my go to https://www.training.nih.gov/events/ for coloring a black-and-white template bad conversation over and over and thought upcoming. seemed like an extremely valuable skill at about what had happened. “Is it all my fault? the time. Twenty years on, I rarely use my Am I a horrible person? Is the other person Erica Wynne-Jones is an Australian visiting coloring talents, and I’m learning a lot more a horrible person?” postdoctoral fellow in the Lab of Clinical about resilience through the monthly Office At that point, I was really grateful Immunology and Microbiology at the of Intramural Training and Education’s for the work and training I’d done with National Institute of Allergy and Infectious (OITE’s) series on “Becoming a Resilient OITE to build my resilience. I took a step Diseases, where she works on CD8+ T cells Scientist.” back and thought about how all sides in in viral skin infections. She is the Outreach One of the recurring themes in the this situation were understandable and Liaison on the Fellows Committee and “Becoming a Resilient Scientist” series is that communication and relationships is writing for and coordinating fellows’ empathetic, nonviolent communication. have become more difficult for everyone contributions to the NIH Catalyst Training American psychologist Marshall Rosenberg, during the COVID-19 pandemic. Even Page. Outside of work she enjoys cycling who developed nonviolent communication though those thoughts didn’t solve all of around Bethesda, cartooning, writing as a way to resolve conflict, coined the terms my problems, where there was once a pack science-themed satirical articles and sitcoms, “jackal language” and “giraffe language” of vicious jackals who would tell me horrible and performing stand-up comedy. to describe the ways in which we can things about myself and others, there is now

4 THE NIH CATALYST MARCH–APRIL 2021 FEATURE

Fueling the Next Genomics Revolution WALS Panel Discussion Highlights Achievements in Genomics BY NATALIE HAGEN, NCATS

NIH celebrated three special DNA fragments, then using a computer Future of genetics. Lander, who is now anniversaries at a Wednesday Afternoon to assemble them into chromosomes). serving as the White House Science Advisor Lecture Series (WALS) special event Her work paved the way for a myriad of to President Joseph Biden, explained that on January 13, 2021: the 25th-year other projects. From reverse vaccinology, the first “phase” of human genetics research, anniversary of the first complete bacterial which uses a genomic sequence to spanning from 1980 to 2015, involved genome; the 20th anniversary of the identify vaccine candidates, to a genomic mapping disease genes. However, it takes publication of the human genome; and catalog of the Earth’s microbiomes, too long to identify individual genes that the 15th anniversary of the first human almost no field has been left untouched. play a role in a disease. metagenome (of microbial communities). The future applications seem boundless. He also talked about a future in which NIH Director Francis Collins led a “We’re in the infancy of microbiome- integrating human genome data and lecture and panel discussion featuring based diagnostics and therapeutics,” microbiome data becomes commonplace. “I Claire Fraser, NIH alum and director pronounced Fraser. would love to see longitudinal microbiome of the Institute for Genome Sciences at The ubiquity of genomic sequencing data collected from all the participants in the University of Maryland (Baltimore); has led to a reexamination of the concept the ‘All of Us’ project,” NIH’s research Charles Rotimi, chief of the Metabolic, of a genome altogether, with the result program to collect genetic and health data Cardiovascular, and Inflammatory Disease being the development of the pan-genome from one million volunteers in an effort Genomics Branch at the National Human concept (all the genes in all the strains of to accelerate medical breakthroughs. By Genome Research Institute (NHGRI); a species.). There was found to be such integrating human genome and microbiome and Eric Lander, president and founding extensive diversity that the strain-specific data, “we can fully understand the genetic director of the Broad Institute (Cambridge, genes may even outnumber the size of the basis of common disease and go easily from Massachusetts) of MIT and Harvard. core genome. maps to mechanisms to medicine.” The WALS event also marked one year As we enter the new phase of since scientists at NIH’s Vaccine Research The history of humanity.Rotimi, who came human genetics research—fueled by the Center began working with Moderna to to NIH in 2008 to establish the trans-NIH establishment of large-scale human cohorts, create a COVID-19 vaccine, which has since Center for Research on Genomics and the falling cost of genetic sequencing, and received FDA Emergency Use Authorization Global Health, highlighted the necessity of the rise of cloud-based data platforms— and is being used to immunize millions of sequencing the genomes of African ancestry scientists aim to more efficiently determine people. The ability to achieve this feat so populations. Their genomes have more disease mechanisms from human samples. rapidly can be attributed to advancements variability and carry more diversity than Furthermore, the publication of datasets made in genomics over the past two decades. other genomes. He pointed out that Africa online allows for analysis by scientists all Collins himself is an important figure is the ancestral home of all humanity and the over the world. in the genome arena. He served as director place of 99% of human evolutionary history. of NHGRI (1993–2008), made landmark This greater genetic variation provides more To watch a videocast of the panel discussion, discoveries of disease genes, and led the power to detect the relationship of genes to which took place on January 13, 2021, go to international Human Genome Project, phenotypes. https://videocast.nih.gov/watch=40165. which mapped the human genome. Rotimi also emphasized the importance of studying African genomes as a social Natalie Hagen is a postbaccalaureate research Putting the past in perspective. Fraser, justice issue. “If we do not change course fellow in the National Center for Advancing who worked at NIH from 1985 to 1992, and include more African genomes, will Translational Sciences, where she is performing uncovered the first complete genome of a tomorrow’s medicine work for everybody?” pharmacokinetics studies of novel drug free-living organism, Haemophilus influenzae, By leaving out African genomes, health and candidates. After her fellowship is over in 2021, in 1995, using whole-genome shotgun economic inequities will only be exacerbated, she is planning to pursue a Ph.D. sequencing (a method for sequencing random he added.

https://irp.nih.gov/catalyst 5 FROM THE ANNALS OF NIH HISTORY

From Yellow Berets to Nobel Laureates CONTINUED FROM PAGE 1

States Public Health Service. The small The ATP proved to be an incredibly Learning to Think Like Scientists. In percentage of applicants admitted were successful program, ultimately producing the summer of 1968, Brown, Goldstein, known as clinical associates (CAs). The many of the top-notch physician–scientists of Varmus, and Lefkowitz became CAs and ATP had the pick of the best and brightest that generation. Compared with physicians joined NIH’s tight-knit, collaborative com- medical school graduates. After completing who weren’t in the program during the munity of innovative scientists. The four residency training, the successful applicants Vietnam War, NIH CAs were more likely attributed much of their later success to came to NIH where they performed to go on to hold academic positions as learning from their mentors, who taught clinical duties and conducted bench professors, department chairs, and deans. them how to think like scientists. research in the lab of a senior scientist. Six other physicians who were CAs during Goldstein was the only one who had The number of CAs in the ATP peaked the war went on to receive Nobel prizes, basic-research experience before coming around 200 per year at the height of the too—J. Michael Bishop (1989), Alfred to NIH. “If we think about our mythology war, then fell precipitously after a peace Gilman (1994), Stanley Prusiner (1997), about who goes on to be a great scientist treaty was signed in 1973. Ferid Murad (1998), Richard Axel (2004), and win Nobel Prizes, I think one of our Some people referred to the CAs as and Harvey Alter (2020). With such a cadre preconceptions is that these people know Yellow Berets. In contrast to the Green of distinguished alumni that also included from very early in life that this is the Berets, the Yellow Beret label implied National Institute of Allergy and Infectious pathway that they’re on,” said Greenberg. cowardice, possibly because supporters of Diseases Director Anthony Fauci, it’s not None of the four future Nobel laureates the war effort viewed the CAs as trying to surprising that the designation of Yellow had prior research experience or aspired stay out of harm’s way. Beret eventually became a badge of honor. to become serious scientists. The ATP CREDIT: OFFICE OF NIH HISTORY AND STETTEN MUSEUM

Clinical Investigators class photograph, National Institute of Arthritis and Metabolic Diseases: Michael Brown (row 2, third from right), Robert Lefkowitz (row 3, third from right), Harold Varmus (row 4, third from right), and Ira Pastan (row 2, fourth from left) are among the investigators present.

6 THE NIH CATALYST MARCH–APRIL 2021 FROM THE ANNALS OF NIH HISTORY

My Adventures as an NIH Yellow Beret proved to be a transformative experience, a cancerous state. Varmus later returned introducing them to bench science and to NIH, serving as director (1993–1999), BY ROBERT LEFKOWITZ WITH RANDY HALL launching their trailblazing research then president and CEO of Memorial Excerpted from A Funny Thing Happened on careers. Sloan-Kettering Cancer Center in New the Way to Stockholm: The Adrenaline-Fueled Brown worked in Earl Stadtman’s York (2000–2010), and later rejoining NIH Adventures of an Accidental Scientist, by lab, where he studied the activation of again as director of the National Cancer Robert Lefkowitz with Randy Hall (Pegasus glutamine synthetase, an enzyme involved Institute (2010–2015). Books, New York, 2021). in bacterial nitrogen metabolism. Goldstein Lefkowitz also worked with Pastan as worked in the lab of Marshall Nirenberg well as with Jesse Roth. At first, Lefkowitz The project that Jesse [Roth] and Ira [Pastan] (who shared the Nobel Prize in 1968 for the experienced repeated failures in the lab and, had given me was to identify the receptor “interpretation of the genetic code and its in frustration, planned to leave research for a hormone known as ACTH, which is a function in protein synthesis”) and studied altogether. But in the process of labeling key regulator of the stress response. For this how translation, the process of building the adrenocorticotropic hormone with project, the first thing I had to do was label protein chains, is terminated. Luckily, NIH radioactive isotope of iodine, and later ACTH with a radioactive tag, then separate had access to patients with rare diseases that demonstrating that the hormone attached the labeled hormone from the unlabeled. In most physicians outside of NIH had never to the membrane of adrenal-gland cells, theory, this sounds easy, but in practice, it was seen before. he found his passion for science. He later a titanic struggle…. In an event that sparked his curiosity joined Duke University (Durham, North I continued having technical troubles, but and foreshadowed his lifelong partnership Carolina), ultimately receiving the Nobel then suddenly, a year into my fellowship, a with Brown, Goldstein treated a girl with Prize in Chemistry with his former trainee miracle happened: my experiments started familial hypercholesterolemia, a condition Brian Kobilka, in 2012, for their work working. The essential insight that led to my that causes elevated concentrations of characterizing adrenaline receptors and the success was that I needed to ask others for cholesterol and can lead to heart attacks in structure of G-protein coupled receptors. help instead of just struggling by myself…. I childhood. Already close friends, Brown (See excerpt from his book on the right.) sought out several expert chemists on the NIH and Goldstein both went to the University The four Nobel laureates are still active campus to ask their counsel. With advice from of Texas Southwestern (Dallas) after in the scientific community: Brown and these sages … I finally got traction in achieving leaving NIH and discovered that people Goldstein hold endowed professorships chemical separation of the labeled ACTH from with familial hypercholesterolemia have at the University of Texas Southwestern the unlabeled. a defect in the receptor for low-density Medical Center; Varmus holds a named Once I finally had some pure labeled lipoprotein. They won the Nobel prize in professorship at Weill Cornell Medical ACTH, everything else moved with 1985 “for their discoveries concerning the College (New York); and Lefkowitz is a breathtaking speed. In short order, I showed regulation of cholesterol metabolism.” Their distinguished professor at Duke University that the labeled ACTH was biologically active, findings led to the subsequent development and an investigator with the Howard and then rapidly developed one of the very of cholesterol-lowering statin drugs. Hughes Medical Institute. first assays for studying the binding of a Varmus joined Ira Pastan’s lab and hormone to its receptor. Later in my career, I To watch a videocast of Greenberg’s virtual studied how lactose metabolites and cyclic realized that this is often how research works: lecture go to https://videocast.nih.gov/ adenosine monophosphate triggers the You experience nothing but failure for weeks watch=38976. transcription of genes involved in lactose or months, and then suddenly you overcome metabolism. Varmus left NIH for the a technical hurdle, like in this case finding the University of California at San Francisco Ethan Smith is a postbaccalaureate fellow in right chromatographic system to separate the (San Francisco), later receiving the Nobel the National Institute of Nursing Research. two forms of ACTH, and suddenly everything prize with fellow former CA J. Michael He is working on clinical studies involving starts moving like wildfire. These were heady Bishop in 1989 “for their discovery of the biomarkers for traumatic brain injury. months, as I felt intoxicated by the knowledge cellular origin of retroviral oncogenes” that I was exploring new realms of research that demonstrated how retroviruses can where none had previously trodden. trigger proto-oncogenes to push a cell into

https://irp.nih.gov/catalyst 7 CATALYTIC RESEARCH Intramural Research Briefs

NIEHS: FOXL2 LINKED TO ENDOMETRIOSIS, NIDA: NATIONWIDE INCREASE IN METHAM- FEMALE INFERTILITY, AND CANCER PHETAMINE OVERDOSE DEATHS Two teams of NIEHS authors published com- In a study published in JAMA Psychiatry, panion articles that underscored the impor- researchers at NIDA found a more than five- tance of the transcription factor forkhead box fold increase in methamphetamine-involved L2 (FOXL) in women’s ovarian physiology and age-adjusted overdose death rates over an fertility and clarified the role of excess FOXL2 eight-year period from 2011 to 2018, espe- in endometriosis. FOXL2 regulates sex differ- cially among American Indians and Alaska entiation and reproductive function. Natives. The analysis, based on data from

CREDIT: ERINA HE, NIH MEDICAL ARTS MEDICAL NIH HE, ERINA CREDIT: In humans, FOXL2 genes that mutate or the CDC’s National Vital Statistics System NHLBI: A new blood test measures donor DNA fragments and detects acute heart-transplant rejection earlier than lose function are associated with premature examined overdose death rates of individu- current methods. The illustration shows DNA fragments infertility and ovarian cancer. Expression of als aged 25–54 by gender and race/ethnic- (yellow) derived from a transplanted heart alongside the FOXL2 is increased in the uterine tissue of ity. The researchers found that overdose patient’s own DNA (blue). women with endometriosis, which can be death rates rose across all racial and ethnic NHLBI, NCI: NEW BLOOD TEST TO DETECT influenced by endocrine disruptors in the groups and among both men and women, HEART-TRANSPLANT REJECTION environment. In the first study, the research although men had significantly higher rates Researchers at NHLBI have developed a team generated mice with overexpression of than women within each racial/ethnic group. blood test for the early detection of acute FOXL2 and reported that too much altered American Indians and Alaska Natives had by heart-transplant rejection, a potentially fatal differentiation and function of uterine epi- far the highest death rates, which more than condition that can occur within a few months thelial cells. In addition, endometrial stromal quadrupled over the study period. “Identi- after receiving a heart transplant. In an article cells showed increased fibrosis, interfering fying populations that have a higher rate of published in Circulation, the authors including with development of the endometrial glands. methamphetamine overdose is a crucial step Sean Agbor-Enoh, chief of NHLBI’s Labora- The study identified mouse uterine pathways toward curbing the underlying methamphet- tory of Applied Precision Omics, estimated regulated by FOXL2 that are similar to path- amine crisis,” said Beth Han, lead author on that by using this new test, doctors can safely ways elevated in women with endometriosis, the study. “By focusing on the unique and avoid 81% of invasive heart-tissue biopsies, the suggesting the potential for better diagnostic culturally specific needs of individuals, we current method used to detect rejection. and therapeutic tools to treat endometriosis. can begin to move away from one-size-fits- The new blood test involves a quick blood In the second study, also based on a all approaches and toward more effective, draw and measures donor-derived cell-free mouse model, the researchers evaluated the tailored interventions.” (NIH authors: B. Han, DNA (ddcfDNA), short fragments of DNA effects of irregular FOXL2 activity on female J. Cotto, K. Etz, E.B. Einstein, W.M. Compton, released by donor heart tissue into the blood- reproductive physiology and disorders. In and N.D. Volkow, JAMA Psychiatry, 2021) stream if a recipient’s immune system attacks ovarian development and function from the [BY HENRY DIECKHAUS, NINDS] the heart. The researchers analyzed the blood fetal stage through adulthood, excessive concentrations of ddcfDNA in 165 heart-trans- FOXL2 production made it harder for certain NIAID (RML): SALMONELLA SWIMMING plant recipients finding higher concentrations cells to differentiate, and the follicles did not BEHAVIOR MAY PROVIDE CLUES TO of ddcfDNA in patients with acute rejection. form correctly. The female mice could not ovu- INFECTION The ddcfDNA is highly sensitive in detect- late and were infertile. This study reveals that Scientists know a lot about Salmonella enterica ing acute rejection and its performance was fine-tuned production of FOXL2 is absolutely serovar Typhimurium (S. Typhimurium), one better than that of heart biopsies. The new essential for proper ovarian physiology and of the most common causes of foodborne blood test may be able to detect rejection fertility. This potential cause of ovarian dis- infection, and how these flagella-propelled as early as 28 days (versus weeks or months) orders in women may point to treatment tar- bacteria swim in short, random spurts. Yet, after a heart transplant. (NIH authors: S. gets. (Study 1: NIH authors: R. Li, S.-P. Wu, L. until now, they didn’t understand how the Agbor-Enoh, C. Mutebi, K. Yu, P. Shag, I. Tunc, Zhou, B. Nicol, H.H.-C. Yao, and F.J. DeMayo, type of swimming can contribute to infection S. Hsu, H. Kong, A. Bikineyeva, A. Marishtam, Biol Reprod 103:951–965, 2020; Study 2: NIH of the epithelial cells lining the inside of the K. Bhatti, Y. Yang, M.K. Jang, and H.A. Valan- authors: B. Nicol, K. Rodriguez, and H.H.-C. intestine. Researchers at NIAID’s Rocky tine, Circulation 2021) Yao, Biol Reprod 103:966–977, 2020) Mountain Laboratories (Hamilton, Montana) [BY ETHAN SMITH, NINR] [BY KELLEY CHRISTENSEN, NIEHS]

8 THE NIH CATALYST MARCH–APRIL 2021 CATALYTICCATALYTIC RESEARCHRESEARCH

recently discovered that a certain protein can But the results were surprising: When turn S. Typhimurium bacteria in the gut into people were on the plant-based diet, they ate tiny missiles that swim straight. 550–700 fewer calories daily, but had higher The authors identified the protein McpC, insulin and blood glucose concentrations than short for methyl-accepting chemotaxis protein when they ate the animal-based diet. Despite C, that causes the bacteria to swim straight differences in calorie intake, there were no when they are ready to infect cells. “In the significant differences in terms of participant presence of McpC, the bacteria swim in longer, rating of hunger, enjoyment of meals, or feel-

straighter runs than McpC–defective mutants,” ing full. Both diets also resulted in weight loss, E.R. FISCHERR, A. ATHMAN, RML, NIAID said Olivia Steele-Mortimer, senior author although this loss was only significant for the NIAID: A scanning electron micrograph of Salmonella enterica on the study. “This [longer, straighter run] is plant-based diet during the first week. serovar Typhimurium (yellow), a common cause of food- borne infection, invading a human epithelial cell (blue). tightly coupled to invasion in the gut.” The findings suggest that the factors McpC could be a potential target for resulting in overeating and weight gain are microbiota of mice from the wild and the other developing new antibacterial treatments to more complex than the amount of carbs or fat experiencing a transient infection with an hinder the ability of S. Typhimurium to infect in one’s diet. In fact, there could be benefits to attenuated strain of the food-borne pathogen and colonize the gut, according to the authors. both diets if only in the short term. Yersinia pseudotuberculosis. They found that The researchers hypothesize that controlled “While the low-fat, plant-based diet helps both groups showed enhanced resistance to smooth swimming could be a widespread curb appetite, the animal-based, low-carb diet Kpn infections, demonstrating that the micro- bacterial infection strategy and that their resulted in lower and more steady insulin and biota that has already experienced an infec- findings could result in the development of glucose levels,” said NIDDK Senior Investi- tion helps resist a subsequent infection. novel antibiotics. (NIH authors: K.G. Cooper, gator Kevin Hall, the study’s lead author, in The researchers discovered that the A. Chong, L. Kari, B. Jeffrey, T. Starr, C. a news release. “We don’t yet know if these prior infection resulted in the proliferation Martens, and O. Steele-Mortimer, Nat Commun differences would be sustained over the long of a class of taurine-utilizing bacteria called 12:article number 348, 2021) term.” (NIH authors: K.D. Hall, J. Guo, A.B. Deltaproteobacteria in the gut. Taurine, an [BY JUNE GUHA, NIAID] Courville, J. Boring, R. Brychta, K.Y. Chen, V. amino acid, helps the body digest fats and Darcey, A.M. Gharib, I. Gallagher, R. Howard, oils and is naturally found in bile acids in the P.V. Joseph, L. Milley, R. Ouwerkerk, K. Rais- NIDDK, CC, NINR, NIAAA: COMPARING gut. Remarkably, taurine given to mice as a inger, I. Rozga, A. Schick, M. Stagliano, S. LOW-FAT AND LOW-CARB DIETS supplement in drinking water was sufficient to Torres, M. Walter, P. Walter, S. Yang, and S.T. NIDDK scientists led a small, highly controlled, train the microbiota to fight offKpn infections. Chung, Nat Med 2021) inpatient study to compare the effects of a Further experiments revealed that poisonous [BY LEANNE LOW, NIAID] low-fat, high-carbohydrate, plant-based diet hydrogen sulfide gas released as a byproduct with a high-fat, low-carbohydrate, animal- of taurine promoted enhanced resistance, based diet. They compared calorie (or energy) NIAID: HOW THE GUT MICROBIOTA IS possibly by inhibiting pathogen respiration. intake, hormone concentrations, body weight, TRAINED TO PREVENT INFECTIONS This study may aid in identifying microbiota- and satiety levels. Twenty adults (11 men In an NIAID-led study, NIH scientists have based alternatives to antibiotics for fighting and nine women), housed in the NIH Clinical made a quantum leap in our understanding off life-threatening bacterial infections. (NIH Center’s Metabolic Research Unit, were given of ways the gut microbiota wards off bacterial authors: A. Stacy, V. Andrade-Oliveira, J.A. one diet for two weeks, and then the other infections. They identified a nutrient— McCulloch, B. Hild, J.H. Oh, P.J. Perez-Chaparro, diet for two weeks. All were provided with taurine—that helps the gut recall prior C.K. Sim, A.I. Lim, V.M. Link, M. Enamorado, G. three meals a day plus snacks and allowed to infections and kill invading bacteria, such as Trinchieri, J.A. Segre, B. Rehermann, and Y. eat as much as they desired. Klebsiella pneumoniae (Kpn). Belkaid, Cell 184:615–627.e17, 2021) High-carbohydrate foods were expected The gut microbiota can shield us from [BY SUBHASH VERMA, NCI] to increase hunger and result in excess calorie Kpn and other bacterial infections via a mys- intake because they can cause large swings in terious process known as colonization resis- Read more at: https://irp.nih.gov/catalyst/ blood glucose and insulin. tance. The NIH researchers used two groups v29i2/research-briefs. of pathogen-free mice—one harboring the gut

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

COVID-19 Timeline at NIH (January–February 2021)

January 19: NIAID Director Anthony Fauci and with the more traditional use of low-dose others receive their second COVID-19 vaccine. heparin. This trial was mounted by NHLBI January 19: HHS Secretary Alex Azar gives the through the ACTIV partnership, motivated by HHS State of the Department address in which observations that COVID-19 induces a state of he highlights NIH’s accomplishments in fighting overactive blood clotting that can contribute to COVID-19 and developing the vaccine to fight bad outcomes. it. This is his final address before leaving office January 26: Vice President Kamala Harris and on January 20 when President-elect Joseph Second Gentleman Douglas Emhoff receive Biden and Vice-President-elect Kamala Harris their second doses of the Moderna COVID- will be inaugurated. 29 vaccine, at the NIH Clinical Center. Later January 20: Inauguration of President Joseph NIAID Director Anthony Fauci joins them in Biden and Vice-President Kamala Harris. filming a public service announcement to build CREDIT: NIAID CREDIT: January 21: NIAID Director Anthony Fauci is confidence in COVID-19 vaccines. Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color- immediately integrated into the White House January 26: NIH launches a database to enhanced at the NIAID Integrated Research Facility (IRF) COVID team. In December 2020, Biden had track neurological symptoms associated in Fort Detrick, Maryland. asked Fauci to serve as his chief medical with COVID-19. The new NINDS-supported advisor and on his COVID team. database—COVID-19 Neuro Databank/Biobank January 5: NIH announces that a large clinical January 21: Eli Lilly announces that the (NeuroCOVID), which was created and will be trial, sponsored by NIAID, will test combination phase 3 BLAZE-2 COVID-19 trial (conducted maintained by NYU Langone Health (New York) monoclonal antibody therapy for people with in partnership with NIAID) showed that —will collect information from clinicians about mild to moderate COVID-19. prophylactic use of its monoclonal antibody COVID-19-related neurological symptoms, January 8: NIH launches a website outlining bamlanivimab (LY-CoV555) reduced the risk complications, and outcomes as well as the COVID-19 Vaccination Plan for NIH Staff: of contracting symptomatic COVID-19 among COVID-19 effects on pre-existing neurological https://employees.nih.gov/pages/coronavirus/ residents and staff of long-term care facilities conditions. The database will be a resource of vaccination-plan-nih-staff.aspx. by as much as 80%. clinical information as well as biospecimens January 12: NIH Director’s blog post is about January 22: In his email message to staff, from people of all ages who have experienced the journal Science’s announcements of NIH Director Francis Collins shares all kinds neurological problems associated with SARS- breakthroughs of the year for 2020: https:// of COVID-related news and updates on the CoV-2 infection. directorsblog.nih.gov/2021/01/12/what-a- COVID-19 Vaccination Plan for NIH Staff. February 8: An international phase 3 clinical year-it-was-for-science-advances/. The biggest “Until we receive additional vaccine from trial, part of the NIAID-supported Accelerating breakthrough for 2020 was the development state health departments in the states where COVID-19 Therapeutic Interventions and of COVID-19 vaccines. Science also selected we have facilities, staff may see a slowdown Vaccines (ACTIV-3 inpatient master protocol), nine runner-up breakthroughs, three of which in vaccination scheduling for first doses. We will evaluate the safety and efficacy of “involved efforts supported by NIH: therapeutic ask for your patience as we await additional ADZ7442, a combination of two investigational applications of gene editing; basic research supplies,” he writes. He also advises that long-acting monoclonal antibodies developed understanding HIV, and scientists speaking up people who are 65 years of age check with their by AstraZeneca. Initial participants will be for diversity,” according to the blog post. county health departments to see if they are to hospitalized patients with mild-to-moderate January 15: Seventh Virtual Town Hall is held receive a vaccine there. The goal is to have staff COVID-19 and fewer than 13 days of symptoms. to discuss the NIH COVID-19 Vaccination Plan. vaccinated as soon as possible. Week of February 8: Other trials for Videocast link (NIH only): https://videocast.nih. January 22: NIH announces the results of an therapeutics for COVID-19 are underway. gov/watch=41396. arm of the Accelerating COVID-19 Therapeutic This week, NIAID announces the start of January 15: President-elect Joseph Biden Interventions and Vaccines (ACTIV)–4 inpatient five substudies under two master protocols announces key members of his White House trial, part of an international study, showing of the Accelerating COVID-19 Therapeutic Science Team and asks Francis Collins to that administration of full-dose heparin Interventions and Vaccines (ACTIV) remain as NIH director. provided significant benefit to moderately ill partnership. This brings the total ACTIV and hospitalized patients with COVID-19 compared ACTIV-associated trials to 27 studies testing

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20 therapeutic agents, with several already February 12: NIH Director Francis Collins showing promising results. NIAID also also announces, in his all-staff email, that the announces the addition of four substudies genetic sequencing of SARS-CoV-2—in NIHers under the ACTIV-2 outpatient protocol to who have tested positive for COVID-19 and test interventions for safety and efficacy in have given consent—initiative, led by NIAID participants who have tested positive for Senior Investigator Elodie Ghedin, identified SARS-CoV-2 but do not require hospitalization. one case of B.1.351 (the South African variant) Participants also must have a risk factor that and one case of B.1.1.7 (the U.K. variant) out of puts them at higher probability of progressing 108 samples tested. Collins also recommends to severe COVID-19. The investigational agents that nonclinical staff in high-exposure being tested are SNG001, an inhalable beta situations follow new guidance from the CDC interferon developed by Synairgen that is on how to improve mask fit and the use of a

delivered by nebulizer; AZD7442, a long-acting cloth mask over a medical-grade mask to NIAID CREDIT: monoclonal antibody combination developed improve protection from these fast-spreading Colorized scanning electron micrograph of an apoptotic cell by AstraZeneca that will be studied as both variants. (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image at the NIAID an infusion and an intramuscular injection; February 12: NIDDK researchers report that Integrated Research Facility (IRF) in Fort Detrick, Maryland. and camostat mesilate, an orally administered facemasks substantially increase the humidity serine protease inhibitor developed by Sagent in the air that the mask-wearer breathes in and February 24: NCI study finds that people with Pharmaceuticals that may block SARS-CoV-2 may lessen the severity of COVID-19. (Biophys SARS-CoV-2 antibodies may have a low risk from entering cells. J 2021; DOI:10.1016/j.bpj.2021.02.002) of future infection. (JAMA Intern Med 2021; February 9: Walter Reed Medical Center February 12: Enrollment has begun to test DOI:10.1001/jamainternmed.2021.0366) (Bethesda, Maryland) provides doses of both additional investigational drugs in the NIAID- February 26: In his all-staff email, NIH Director the Pfizer and the Moderna vaccines to NIH to sponsored Accelerating COVID-19 Therapeutic Francis Collins announces that this week help with the shortfall of vaccines. Interventions and Vaccines (ACTIV) program. NIH received 4,400 doses of the Moderna February 10: In a Journal of the American February 12: In an editorial published today in vaccine—3,400 doses from the federal supply Medical Association “Viewpoint” essay JAMA, NIAID Director Anthony Fauci, John R. chain plus 1,000 doses from the Maryland by NICHD Director Diana W. Bianchi and Mascola, director of NIAID’s Vaccine Research Health Department. colleagues, NIH calls for greater inclusion of Center (VRC) and Barney S. Graham, deputy February 27: The FDA issues an Emergency pregnant and lactating women in COVID-19 director of the VRC, outline how new COVID-19 Use Authorization (EUA) to the Janssen vaccine research. (JAMA 2021) variants have arisen, concerns about whether Pharmaceuticals Companies of Johnson & February 11: President Joseph Biden visits NIH’s current vaccines will continue to protect Johnson for its single-shot COVID-19 vaccine, Vaccine Research Center (NIAID) and later against new variants, and the need for a global called Ad.26.COV2S or JNJ-78436725. NIAID gives a virtual presentation (https://videocast. approach to fighting SARS-CoV-2 as it spreads and the Biomedical Advanced Research and nih.gov/watch=41581) to NIH employees and acquires additional mutations. (JAMA 2021; Development Authority, part of HHS, supported thanking everyone for their important work DOI:10.1001/jama.2021.2088) late-stage clinical testing of the vaccine. The on COVID-19: “On behalf of a grateful nation, February 12: A new study, supported by NIMH, Johnson & Johnson vaccine, which can be kept I want to thank you and your families for your has identified early risk factors that predict in regular refrigerators and does not require the work and sacrifice.” He also talks about his heightened anxiety in young adults during ultracold storage that the Moderna and Pfizer plans to expand the distribution of the COVID- the COVID-19 pandemic. (J Am Acad Child Psy vaccines do, is a recombinant vector vaccine 19 vaccine. 2021; DOI:10.1016/j.jaac.2021.01.021) that uses a human adenovirus to express the February 11: NIH receives 2,400 doses of the February 17: NICHD announces the launch of a spike protein found on the surface of the SARS- Pfizer vaccine through the federal supply chain. new study to evaluate the effects of remdesivir CoV-2 virus that causes COVID-19. It is the third February 12: In his email to NIH staff, NIH in pregnant women who have been prescribed COVID-19 vaccine in the United States to be Director Francis Collins announces that “We the drug to treat COVID-19. The study will be granted an EUA by the FDA. expect that the federal supply chain will be our conducted at 17 sites in the United States and primary source of vaccines moving forward.” Puerto Rico.

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

1918 Flu and COVID-19 CONTINUED FROM PAGE 1

or concentrate.” He briefly described the virology of coronaviruses, highlighting the importance of the spike proteins that sit crownlike (or corona-like) around the surface. He moved on to describing how COVID-19 is transmitted from person to person. “It’s respiratory, mainly through exposure to respiratory droplets that tend to drop within six feet,” Fauci said. Fauci cited therapeutics such as remdesivir as well as the many COVID- 19 vaccines as reasons for hope. In less

CREDIT: NIH CREDIT: than one year, we’ve gone from the

At the Demystifying Medicine lecture on January 12, 2021, NIAID Director Anthony Fauci gave a state-of-affairs address availability of the genomic sequence on what we know about the COVID-19 pandemic and what the future might hold. of SARS-CoV-2, the virus that causes COVID, to the development and administration of efficacious and safe Medicine lecture series for its 2021 “We in the United States have been vaccines—it really was warp speed! season: National Institute of Allergy hit harder than any other country in and Infectious Diseases (NIAID) the world,” said Fauci. At the end of A Tale of Two Epidemics Director Anthony Fauci and Jeffery February 2021, the United States had Taubenberger, whose laboratory was Taubenberger, chief of NIAID’s Viral more than 28 million cases and over the first to sequence the genome of the Pathogenesis and Evolution Section. 500,000 deaths, compared with 112 influenza virus that caused the 1918 Fauci gave a state-of-affairs address million cases and about 2.5 million pandemic, took us through the not-so- on what we know about the COVID- deaths worldwide. He painted a sobering distant history of that cataclysmic global 19 pandemic and what the future picture of the reality of the pandemic: event. might hold. Taubenberger highlighted about 40–50% of transmissions were “Pandemics have happened, are the similarities of the COVID-19 attributable to asymptomatic cases; happening, and will happen again,” but pandemic to the influenza pandemic of older people and those with underlying we’ve been caught flat-footed and found 1918—the pandemic that “never really medical conditions (representing 40% ourselves chasing this pandemic as a new went away.” of Americans) are most at risk of severe coronavirus emerged in 2019, he said. In disease; and racial and ethnic disparities fact, our response to the 1918 pandemic The State of Coronavirus Affairs in health-care access led to an increased was surprisingly similar, and it seems “We have been working with coronaviruses incidence of infection and severity that we’re still rather “mystified” by how for decades and decades,” said Fauci. He of disease among underrepresented pandemics form, with Taubenberger pointed out that many are zoonotic diseases minorities. In addition, “we are learning pointing to a book written by a German in which animals serve as intermediate hosts more and more about a very interesting doctor in 1820 that asked essentially the and viral reservoirs—such as severe acute phenomenon of post-acute COVID- same questions we are asking today: respiratory syndrome (SARS), which went 19 syndrome,” Fauci continued. Some “What is influenza? Where does it come from bats to civet cats to humans in 2002, “individuals, after they clear the virus, from? How did it behave in the past? and Middle East respiratory syndrome have persistence for up to six months How can we predict future occurrence (MERS), which went from bats to camels and maybe longer of lingering problems and halt spread?” to humans in 2012. SARS and MERS, dominated by fatigue that’s profound, He also likened the world’s embrace however, didn’t evolve into the pandemic muscle aches, temperature dysregulation, and resistance of today’s public-health that COVID-19, also a zoonotic disease, has. [and] brain fog, or the inability to focus measures to those introduced in

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New Insights into What 1918—from mask wearing to school to understand better why some viruses Fuels an Aggressive Form closures, as well as a moratorium on are more deadly than others, and to of Kidney Disease handshakes—and spitting! Despite ultimately feel the urgency to develop ADAPTED FROM AN NCI-CCR NEWS ARTICLE triumphs in technology and science, “universal” vaccines against all viruses, this past century’s deemphasis of public- not just influenza and coronaviruses. Scientists in the National Cancer health systems have left us in an even Looking to the past for insight for Institute have uncovered an important more delicate situation than in 1918. our future, both scientists pointed to mechanism that fuels an aggressive With 80,000 fatalities caused by important lessons from past eras. Merely form of kidney disease: Hereditary influenza in 2018, are we now in a twin 100 years ago the world was devasted leiomyomatosis and renal cell carcinoma pandemic? As the media is consumed by by the 1918 influenza, killing 675,000 (HLRCC). The results, published recently the latest global coronavirus outbreak, people in the United States alone, in Science Signaling, show how deficiency we have heard comparatively little about equivalent to 2.5 million in today’s terms. of an enzyme called fumarate hydratase this year’s flu season. One explanation We’ve had outbreaks before, and we’ll (FH) severely impairs cells’ ability to for this relative lull in attention could have them again. A universal vaccine is repair and maintain healthy mitochondrial be due to variations in influenza strains the way forward. DNA. The resulting mitochondrial DNA from year to year and subsequently mutations causes the cells to become more when it might peak—we might have a To view the videocast of the January 12, aggressive. later peak in 2021—and obviously our 2021, Demystifying Medicine lecture, W. Marston Linehan, chief of NCI’s infrastructure is overburdened right now, “COVID-19 and Influenza,” go to https:// Urologic Oncology Branch, has studied resulting in a lack of resources for the videocast.nih.gov/watch=41281. For Demys- HLRCC in the past and found that a FH surveillance of influenza. Taubenberger tifying Medicine’s full schedule and links to deficiency is associated with a shift in how poignantly reminded us that all influenza past lectures, go to https://demystifying- HLRCC cells process energy. Whereas A virus strains trace their origin to the medicine.od.nih.gov. healthy cells typically use mitochondria 1918 flu—”the founder virus”—and its to convert oxygen into energy, cancerous zoonotic jump to humans was similar Eimear Holton is a social media, web, and HLRCC cells tend to rely on a different to that of COVID-19. He emphasized outreach program specialist in NIAID. mechanism—called aerobic glycolysis— our need to be ahead of viruses through for energy production that doesn’t require surveillance of animal spillover events, oxygen. Linehan and his colleagues sought to better understand the mechanism behind this shift. They collected and analyzed 25 tumor samples from patients with HLRCC and found that, without sufficient FH, a harmful amount of fumarate, which is an oncometabolite, accumulates in the cells and can trigger cancer. Genetic analysis revealed that the accumulation caused damage to important mitochondrially encoded genes, including POLG, that are responsible for replicating and maintaining healthy DNA. “These findings provide the foundation for the development of targeted therapies for patients

CREDIT: NIH CREDIT: with [these] cancers,” said Linehan.

Jeffery Taubenberger highlighted the similarities of the COVID-19 pandemic to the influenza pandemic of 1918—the pandemic that “never really went away.” Read more at https://irp.nih.gov/catalyst/ v29i2/research-briefs-kidney-disease.

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

Introducing NIH’s Newest Lasker Scholars Program Gives Boost to Early–stage Investigators BY BRANDON LEVY, OD

If TV shows such as The Voice and the formation blood clots in some patients America’s Got Talent are any indication, with COVID-19. He subsequently launched there are many extremely talented an ongoing clinical trial through which his people out there who could become huge lab, along with colleagues at the University of successes if presented with the right Michigan, are testing a safe and inexpensive opportunity. A similar circumstance FDA-approved medication as a treatment for occurs in science, with thousands of excessive inflammation and blood clotting extremely bright individuals quietly in COVID-19 patients. toiling away in their mentors’ labs as they “The NIH has a unique environment await the chance to establish research that fosters curiosity-driven science to make programs of their own. big impacts on health and disease,” Kanthi Fortunately, initiatives like the NIH’s said. “There is incredible depth of expertise Lasker Clinical Research Scholars Program here across a breadth of disciplines. The exist to boost promising young researchers institutional and infrastructure support is onto the next stage of their careers. Every Yogen Kanthi unparalleled, and the NIH is able to launch year, the Lasker program allows a small projects that couldn’t be done anywhere else.” group of early-stage physician–scientists role in diseases that damage blood vessels to establish their own labs at the NIH and and lead to potentially deadly blood clots. Jacqueline Mays, D.D.S., M.H.Sc., carry out independent clinical research there Over the course of his career, he has Ph.D.: “Enabling Safer Transplants of for at least five years. also migrated from the clinic into the lab. A Blood-producing Cells” The six talented investigators selected as chance encounter with a physician–scientist Jacqueline Mays loves to bring smiles 2020 Lasker Scholars are pursuing a wide during his medical residency “changed my to people’s faces. As a teenager, she spent a range of research questions, from how the view of research,” Kanthi said. year in Germany entertaining audiences as immune system influences blood clotting “I spent a couple of months in his lab the sole American member of a traditional to the mechanisms driving a rare skeletal and realized that a research career would be folk choir. Now, as a trained dentist, she disorder. Read on to learn more about the creative and fulfilling,” he continued. “In the works hard to preserve the health of her latest crop of researchers ramping up labs research lab, I was able to ask and answer patients’ mouths and teeth. of their very own. questions that would often come up during patient encounters.” Yogen Kanthi, M.D.: “Inhibiting Immune Kanthi’s research focuses specifically Assault on Blood Vessels” on the relationship between blood clots Yogen Kanthi is used to long jour- and inflammation in blood vessels. While neys, having bused and backpacked his at the University of Michigan, his team way through more countries than there discovered that a common inflammation- are candles on his birthday cake, includ- inducing chemical in the body can cause ing a camping trip to the polar icecap in blood clots to form in veins; the team Greenland. More recently, his selection found a way to prevent the clotting using as a Lasker scholar in the National Heart, an FDA-approved drug. More recently, in Lung, and Blood Institute triggered a 500- work done at the NIH and in Michigan, his mile move from the University of Michigan lab has made important contributions to our (Ann Arbor, Michigan) to NIH’s campus in understanding of how overactive immune

Bethesda, Maryland, where he is continuing cells and other components of the immune Jacqueline Mays his investigation of the immune system’s system contribute to breathing failure and

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Diseases, which focused on skin infections “I grew up in a very rural community caused by the bacterium Staphylococcus aureus. without fluoridated water and saw my Now that he leads his own NIH lab, he is family dentist frequently while growing investigating how the bacteria that live on up,” she said. “Their gadgets and their our skin are involved in eczema, a common ability to quickly help patients made a deep skin ailment associated with an increased impression, and my initial career plan was to risk of staph infections. His research team become a dentist. Fortunately, as I learned is currently running a clinical trial to see more about both dentistry and science, I whether applying a different species of discovered there was a clear path to combine bacteria, Roseomonas mucosa, to the skin of them.” eczema patients relieves their symptoms. The Mays has been able to apply her skills study so far has shown promising results, in those domains at the National Institute with the patients who received the topical of Dental and Craniofacial Research for Ian Myles bacterial treatment seeing “significant more than a decade, most of which she improvement in their disease,” according has spent trying to combat the side effects Ian Myles, M.D., M.P.H.: “Managing to Myles. of hematopoietic stem-cell transplants, a Our Microbial Menagerie to Improve “I wanted the opportunity to work on procedure used to treat certain blood-borne Skin Health” a new approach to a common disease,” he diseases such as leukemia. The procedure People often claim to know things “like said. “The Lasker program affords me the attempts to reboot patients’ immune systems the backs of their hands,” but in recent years ability to take on challenges that I could not by wiping out the defective stem cells in their it has become increasingly clear that what tackle as a postdoc. I enjoy the ability to take bone marrow that produce blood cells and we see when we look at our hands and an idea directly from the bench and put it replacing them with properly functioning other parts of our bodies is not a complete into an intervention that might improve the stem cells from a healthy donor. However, picture. Teeming multitudes of organisms lives of patients and their families.” many patients who undergo this procedure too tiny for the human eye to detect live develop chronic graft-versus-host disease, on every inch of our skin, and scientists Stephanie Chung, M.B.B.S.: “Improving in which their new immune systems attack like Ian Myles are determined to learn as Care for Youth with Type 2 Diabetes” tissues throughout the body including in much as they can about how these organ- Most weekends during her childhood, the mouth. isms—collectively called the skin microbi- Stephanie Chung and her sister So far, Mays’s efforts have produced ome—influence our health. In particular, accompanied their cardiologist father on important insights into how graft-versus- Myles investigates how their interactions his rounds and then played on the hospital host disease affects the mouth, as well as with the environment affect their ability grounds while he saw to his patients. When how those effects might be more effectively to guide the immune system’s response to she followed her father into the medical assessed and alleviated. As the first dentist- skin disease and damage. field, she chose to specialize in both scientist to be selected as a Lasker Scholar, “I went to medical school thinking internal medicine and pediatrics, with a she hopes to leverage the opportunity not I would go into research in spinal-cord focus on helping young people with obesity only to bolster that important research but regeneration, but became fascinated by the and type 2 diabetes. also to pave the way for more dentists to way the immune system is able to tell the “Maybe it was the cartoons on the participate in the program. difference between the outside world and walls, or the fact that we had to learn “As a strong advocate of building an ourselves,” Myles said. “The narrow margin how to play with the kids and examine, excellent and diverse pipeline of oral-health for error afforded the immune system and cure, and treat them all at the same scientists, I hope that this selection serves as the need to balance inflammation with repair time,” Chung said, “or maybe it was their a sign of the rigor of the oral-health sciences grabbed my interest.” innocence and vulnerability to the social, and that more outstanding dental scholars Myles began his NIH career working in will follow,” she said. the Bacterial Pathogenesis Unit at the NIH’s CONTINUED ON PAGE 16 National Institute of Allergy and Infectious

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

Laskers CONTINUED FROM PAGE 15

up and attended medical school in Jamaica happens, it helps to home in on cases before continuing her medical studies of Parkinson disease that can be traced in the United States, she is particularly to an identifiable trigger, which is why dedicated to bringing people from diverse Narendra specifically works with patients backgrounds into her field. who have genetic mutations that cause “I believe that success is born out of early-onset Parkinson disease. hard work that comes from people from “In medical school, I was always all different backgrounds, experiences, fascinated by Parkinson disease,” abilities, and world views,” she said. “I Narendra explained. “I wondered why love teaching and mentoring and I am it is that this little subset of cells could committed to diversifying the scientific be selectively vulnerable and could workforce and inspiring the next generation lead to such a profound difference in of leaders.” the movement of someone who has lost them.” Stephanie Chung Derek Narendra. M.D., Ph.D.: “Pushing Narendra began studying Parkinson Forward Our Understanding of disease as a Ph.D. student in the lab genetic, and environmental factors that Movement Disorders” of Senior Investigator Richard Youle, mediate health disparities and childhood As an avid hiker, runner, and down- where he made important discoveries diseases.” hill skier, movement is an essential part about why mutations in two genes called Although she has been working with of life for Derek Narendra. It is not sur- PARKIN and PINK1 cause the disorder. this population at the NIH since 2013, prising, then, that his research at the Nowadays, his interests have shifted Chung’s selection as a Lasker Scholar National Institute of Neurological Dis- to other genes involved in the illness. in the National Institute of Diabetes orders and Stroke focuses on Parkinson For example, he has studied a patient and Digestive and Kidney Diseases will disease, a neurological condition that with a unique variety of Parkinson allow her to take her work to the next robs patients of their ability to move. disease caused by previously unreported level. Her new lab aims to understand how Parkinson disease occurs when a mutations in both copies of the DJ1 gene, genetic, environmental, and lifestyle factors specific set of neurons in the brain that and he has also investigated the cellular contribute to the increased susceptibility control movement begin to die off. effects of mutations in two other genes of young people from minority groups When it comes to figuring out why that linked to the illness, CHCHD2 and to diseases such as diabetes, obesity, and CHCHD10. As a newly minted Lasker heart disease. She is also attempting to Scholar, Narendra looks forward to figure out why the drug metformin, a collaborating with his NIH colleagues commonly prescribed treatment for type on more studies that will shed light on 2 diabetes, successfully lowers blood sugar the functions of these and other genes in adults but fails to help roughly half of linked to Parkinson disease. young people with diabetes. Already, her “I’m very excited about it,” he said. work has identified important differences “The Lasker program puts you in a in the way blood sugar behaves in young community of like-minded people within people and adults with type 2 diabetes and the NIH, and also kind of connects uncovered clues as to why metformin is less you to a larger network of physician– effective in children and teens. scientists to help inspire you and guide In addition to furthering her research, your work.” Chung hopes the boost provided by the Lasker Scholars program will enhance her ability to assist and influence future Derek Narendra scientists. As a Chinese Jamaican who grew

16 THE NIH CATALYST MARCH–APRIL 2021 FEATURE CATALYTIC RESEARCH

SPECIAL ISSUE: JOURNAL OF WOMEN’S HEALTH McCune-Albright syndrome, in which A special issue of the Journal of bone progressively transforms into Women’s Health (JWH) characterizes the fibrous tissue, leading to fractures, increasing problem of maternal mor- physical deformities, and problems bidity and mortality (MMM) in the with movement, vision, and hearing. United States. Articles in the issue sug- The condition also affects the delicate gest solutions and propose a research balance of hormones flowing through the agenda for understanding, treating, and body, potentially causing early puberty, preventing maternal health complica- thyroid issues, and other problems. In tions. U.S. women—particularly those addition to examining numerous patients from underrepresented racial and ethnic with the disease to learn more about their populations and those who reside in symptoms, Boyce’s team has identified rural areas—are more likely to die from promising therapeutic targets for the complications related to pregnancy or disease, leading to an ongoing clinical childbirth than women in peer nations. Alison Boyce trial investigating whether inhibiting a Office of Research on Women’s Health protein called RANKL improves some Alison Boyce, M.D.: “Making Associate Director Samia Noursi served of the disorder’s symptoms. Breakthroughs for a Rare Bone Disorder” as the guest editor for the JWH special Along with the opportunity to Alison Boyce has been a science issue and, along with NIH leadership work in the NIH Clinical Center and enthusiast all her life, fondly recalling colleagues, wrote the introduction. The collaborate with other NIH experts in the many hours she spent watching the authors state that the articles describe bone biology, Boyce believes her research science-themed television program Mr. “epidemiological patterns and trends, benefits from all of the time she spends Wizard’s World as a small child. Later, biological and physiological risk factors, outside of work with her face buried in the collaborative nature of medicine and external risk factors, social determinants a book. the opportunity to witness firsthand how of health, and proven and potential inter- “I’m a big reader and usually finish science affects people’s lives drew her to ventions that are poised to be delivered to one or two books a week,” she said. “I apply to medical school, after which she a broader audience.” Many NIH scientists especially like literary and speculative chose to specialize in the treatment of contributed articles to the issue: https:// fiction. I think engaging your brain with bone disorders. home.liebertpub.com/spcoll/preview- stories helps people think more creatively, “Bone is a really fascinating field maternal-morbidity-and-mortality/1121/. which is especially important in science.” because it requires you to think about Articles focus on how underrepresented biological systems on multiple levels,” To learn more about the Lasker Clinical racial and ethnic groups, transgender indi- Boyce explained. “Part of my research Research Scholars Program and read viduals, and women of advanced maternal focuses on cell signaling and how about other scholars, go to https:// age have higher rates of MMM as a result of different types of bone cells differentiate, www.nih.gov/research-training/ socioeconomic disadvantages, comorbidities, but I also need to consider bone on a lasker-clinical-research-scholars. and implicit bias; the risk of MMM increas- structural level—how it forms the es as the result of co-occurring conditions; scaffolding that moves our bodies other factors including homicide, suicide, through space and helps us interact drug overdose, and intimate partner violence; Brandon Levy is a Health Communications with the world. Even small changes in environmental factors; dietary supplements Specialist for the NIH Intramural Research bone biology can lead to huge impacts during pregnancy; and current and proposed Program and particularly enjoys writing on health and well-being.” efforts to mitigate the problem of MMM. about the cutting-edge research performed At the National Institute of Dental at NIH. He also produces videos, podcasts, and Craniofacial Research, Boyce’s Read more at https://irp.nih.gov/catalyst/ and content for social media. research is focused on a rare bone v29i2/research-briefs-maternal-morbidity- disorder called fibrous dysplasia/ and-mortality.

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

Stadtman Investigators Pursuing Their Passion for Science Trans-NIH Recruitment Attracts a Diversity of Researchers BY LAURA STEPHENSON CARTER

“Being a scientist at NIH is one Environmental Health Sciences as a postdoc perturbed in these diseases and why the of the greatest jobs you can dream of,” in 2015. “It provides the ideal opportunity resolution of inflammation can be followed said Eric Calvo, a Stadtman Investigator to conduct cutting-edge science.” either by tissue healing or irreversible in the National Institute of Allergy The 18 Stadtman investigators featured scarring that can lead to loss of kidney and Infectious Diseases, and one of 18 in this article have research interests function over time. We are looking at how investigators in the 2017-2018 class of ranging from cancer, kidney disease, transcriptional signals are integrated into Stadtman recruits. and vector-borne diseases (including immune cells to determine inflammatory That sentiment is shared by the more malaria) to minority health, aging, and versus regulatory immune responses; and than 100 Stadtman Investigators who gene regulation. Several of them have how mediators produced by immune cells have been recruited since 2009 when the also been named NIH Distinguished determine whether inflammation results Earl Stadtman Tenure Track Investigators Scholars (DSP), a program launched in in tissue healing or scarring. We hope program, named for the legendary 2018 to facilitate the hiring and career to develop strategies that manipulate biochemist who worked at NIH for 50 years, progression of tenure-track investigators the balance between inflammatory and began. Since then about 25% of them have who have demonstrated a commitment to regulatory immune responses to minimize become tenured investigators. promoting diversity and inclusion in the or prevent kidney scarring. “The program identifies the best biomedical-research workforce. For more What attracted you to the program? institute that fits my research goals, not the on the DSP, go to https://diversity.nih.gov/ It encourages high-risk, high-reward, other way around,” said fellow Stadtman programs-partnerships/dsp. imaginative research programs that cross Payel Sen, in the National Institute on “I applied to the Earl Stadtman traditional scientific disciplines. I found the Aging. program because it provides a way for young resource support and the time provided to Traditionally, institutes and centers investigators to develop research programs pursue key questions in my field, together (ICs) conducted their own individual, that cannot be developed elsewhere,” said with the extraordinarily rich and diverse programmatic searches to recruit new Jennifer Jones, a Stadtman Investigator in scientific environment of the NIH, investigators. But the Stadtman program, the National Cancer Institute. especially appealing. which began in 2009, complements this Read on to learn more about this process by conducting broad searches that group of Stadtman investigators. For ERIC CALVO, PH.D., NIAID cross all areas of biomedical research. more on the Stadtman program, how Chief, Molecular Entomology Unit, It’s designed to attract a diverse group of to apply, and links to stories about other National Institute of Allergy and Infectious talented early-career scientists who might Stadtmans, go to https://irp.nih.gov/ Diseases not apply to a more narrowly defined careers/trans-nih-scientific-recruitments/ Joined NIH: In 2004 as a postdoctoral position description at the NIH. Applicants stadtman-tenure-track-investigators. fellow in NIAID; became a Stadtman are asked to describe their research, and, Investigator and NIH Distinguished for those qualifying, NIH tries to create BEHDAD (BEN) AFZALI, M.D., PH.D., NIDDK Scholar in 2018. a tenure-track position in one of the ICs Chief, Immunoregulation Section, Kidney Research focus: Vector-borne diseases to match that talent. Once the Stadtmans Diseases Branch, National Institute of (West Nile virus, Lyme disease, malaria, are selected, they are offered competitive Diabetes and Digestive and Kidney Diseases and others) are infections transmitted salaries, research space, resources, supported Joined NIH: In 2014 as a clinical research by blood-feeding arthropods such as positions, and an operating budget. fellow in NIAMS; in 2018, became a mosquitoes, ticks, and fleas. My group is “The Intramural Research Program Stadtman Investigator in NIDDK. deciphering the mechanisms of the vector- has unparalleled resources and outstanding Research focus: Kidney diseases are often host and vector-pathogen interactions at the scientists,” said Class of 2017-2018 the result of autoimmune or inflammatory biochemical and molecular level; extending Stadtman Investigator Alexandra White, insults to the kidneys. My team is the functional characterization of salivary who came to the National Institute of investigating how immunoregulation is proteins from blood-feeding arthropods

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BEN AFZALI, NIDDK ERIC CALVO, NIAID CHONGYI CHEN, NCI-CCR SHERINE EL-TOUKHY, NIMHD JENNIFER JONES, NCI-CCR

and their role in pathogen transmission; so that I can focus on my scientific interest not be recruited under a traditional search. and furthering the understanding of disease without many distractions. The Stadtman position is a perfect avenue transmission and the host’s response to for investigators who are dedicated to the vector-borne diseases. We aim to develop SHERINE EL-TOUKHY, PH.D., NIMHD pursuit of lifelong passion for research that new transmission-blocking strategies for Digital Health and Health Disparities betters people’s health and lives. such diseases. Research Unit, Population and Community What attracted you to the program? Sciences, National Institute on Minority JENNIFER JONES, M.D., PH.D., NCI-CCR Being a scientist at NIH is one of the Health and Health Disparities Head, Translational Nanobiology Section, greatest jobs you can dream of (nerds in Joined NIH: In 2014 as a postdoctoral Laboratory of Pathology, Center for Cancer heaven?). The Stadtman program gives you fellow in NHLBI and NIMHD; became Research, National Cancer Institute the opportunity and freedom to pursue your a Stadtman Investigator and NIH Came to NIH: In 2012 as an assistant own scientific questions to understand the Distinguished Scholar in 2018. clinical investigator in NCI’s Vaccine mysteries of nature. Research focus: My research group Branch; became a Stadtman Investigator leverages digital technologies to improve and NIH Distinguished Scholar in NCI’s CHONGYI CHEN, PH.D., NCI-CCR minority health and reduce health Laboratory of Pathology in 2018. Laboratory of Biochemistry and Molecular disparities. We design, implement, and Research Focus: Decoding the biological Biology, Center for Cancer Research, evaluate individual-level just-in-time lexicon of circulating extracellular vesicles National Cancer Institute adaptive behavioral interventions such as and particles. My hypothesis is that this Joined NIH: In 2018. smoking-cessation interventions using decoded lexicon has the potential to Research focus: My lab is combining mobile phones (mHealth); examine provide critical knowledge on the status single-cell assays and genomic technologies disparities in system-level adoption, of patients’ tumors, the status of patients’ to examine chromatin structure and gene integration, and impact of digital responses to treatment, and the complex expression in human cells. We are also technologies within hospitals such as landscape of their other biological systems. developing new assays and techniques in electronic health records; and identify We are developing new ways to “read” the single-cell genomics, epigenomics, and connection points between individual- functional status of each patient’s many transcriptomics. We hope to apply the new and system-level digital technologies various interconnected systems, and we are knowledge in chromosome biology and the to maximize the reach of behavioral seeking to use that information to improve new methodologies in single-cell -omics to interventions and improve clinical patient care and quality of life. cancer biology and medicine. decision-making. What attracted you to the program? What attracted you to the program? What attracted you to the program? It provides a way for young investigators I was attracted to the NIH and the The Stadtman program shines a spotlight to develop research programs that cannot Stadtman Program by its stable funding on a pool of diverse investigators pursuing be developed elsewhere. The NIH Clinical and ample resources to support my research, pioneering research questions who might CONTINUED ON PAGE 20

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Stadtmans CONTINUED FROM PAGE 19

LAURA KEROSUO-PAHLBERG, EROS LAZZERINI DENCHI, NCI- ANDRES LEBENSOHN, NCI-CCR MARCOS MORGAN, NIEHS MEERA MURGAI, NCI-CCR NIDCR CCR

Center is the only hospital in the world that mechanisms of neural-crest stemness, the activation of the DNA damage-response is entirely dedicated to translational research provide a comprehensive picture of early pathway and suppression of end-to-end to advance patient care, and it is uniquely neural-crest development, and obtain a chromosomal fusions. We are also probing nested within a research community that better understanding of how neural-crest- the role of telomere shortening in aging has expertise across countless disciplines. derived diseases arise. and tumor onset, using mouse models that Those qualities alone would have been What attracted you to the program? recapitulate telomere dysfunction in stem sufficient motivation to apply for the NIH It caught my attention due to its reputation cells and other cellular compartments. Stadtman program, but what has been even for rigorous science and the generous What attracted you to the program? more valuable than those qualities is the infrastructure the NIH provides to its The chromosome biology community wisdom and support of my mentors and investigators. I saw the program as an at NIH is excellent, supportive, and colleagues within the NIH community opportunity to dive in and use all possible scientifically diverse. I enjoy access to who have generously provided input and creativity my team can come up with to advanced technologies and colleagues recommendations for how to make our work achieve exciting discoveries. With no from a wide range of disciplines. I can more robust and more impactful. teaching obligation and a generous budget, focus 100% on the science without the the program truly felt like an amazing pressures of teaching commitments and LAURA KEROSUO-PAHLBERG, PH.D., NIDCR chance to grasp even the riskiest of projects, securing funding. Neural Crest Development and Disease which one would hesitate to invest in as an Unit, National Institute of Dental and assistant professor outside the NIH. ANDRES LEBENSOHN, PH.D., NCI-CCR Craniofacial Research Laboratory of Cellular and Molecular Joined NIH: In 2018. EROS LAZZERINI DENCHI, PH.D., NCI-CCR Biology, Center for Cancer Research, Research Focus: I am studying the neural Laboratory of Genome Integrity, Center for National Cancer Institute crest, the stem cells that give rise to various Cancer Research, National Cancer Institute Came to NIH: In 2018. cell types ranging from melanocytes and Came to NIH: In 2018; tenured as a senior Research focus: My lab studies how cell peripheral ganglia to cells contributing to investigator in March 2021. -signaling pathways are used, reused, and the formation of the craniofacial skeleton Research Focus: Chromosome endcaps, repurposed to drive the many cellular and endocrine tissues. About 10% of birth called telomeres, shorten as one ages. I am processes that give rise to tissues and defects are derived from the neural crest interested in the mechanisms by which organs during embryonic development, including cleft palate and other craniofacial telomeres protect chromosome ends, thus and maintain them in adult life. Through malformations as well as cancers such ensuring chromosome and genome stability. powerful genetic screens we discovered as melanoma and neuroblastoma. My My lab is identifying telomere-associated several new regulatory mechanisms group aims to understand the molecular proteins to define their role in preventing in WNT signaling, a fundamental

20 THE NIH CATALYST MARCH–APRIL 2021 FEATURE

gene regulation at the cellular level and which DNA folding is established and the principles that define multicellular regulated and which proteins are involved. organization. We are exploring cell-lineage differentiation, What attracted you to the program? gene regulation, and how noncoding DNA The generous support allows me to focus elements and the 3D architecture of on my science. chromosomes contribute to these processes during development and disease. We are MEERA MURGAI, PH.D., NCI-CCR also fascinated with early mammalian Laboratory of Cancer Biology and Genetics, development as a system to decipher how

PEDRO PEREIRA DA ROCHA, MERU SADHU, NHGRI Center for Cancer Research, National cells make lineage decisions and how gene- NICHD Cancer Institute regulatory networks are established. Came to NIH: In 2013 as a postdoctoral What attracted you to the program? fellow; became a Stadtman Investigator and The emphasis on innovative and high-risk an NIH Distinguished Scholar in 2019. science together with a strong mentorship Research focus: Metastasis causes most program makes NIH an exceptional place pathway that orchestrates patterning and cancer deaths, and we need new therapies to start an independent research program. morphogenesis during development, and based on a deeper understanding of this promotes tissue renewal and regeneration process to improve patient survival. MERU SADHU, PH.D., NHGRI in adults. Dysregulation of WNT signaling My research centers on perivascular Head, Systems Biology and Genome can lead to many diseases, most notably cell plasticity and heterogeneity in the Engineering Section, Genetic Disease cancer. Based on our mechanistic insights, metastatic microenvironment. My group Research Branch, National Human Genome we aim to design more-effective and has been using single-cell sequencing, Research Institute -selective therapies to target WNT-driven immunofluorescent imaging, and Came to NIH: In 2018; became an NIH tumors. computational methods to elucidate the Distinguished Scholar in 2019. What attracted you to the program? stromal-cell populations that play pro- Research focus: I am striving to I was looking for a position where I could and anti-tumor roles in premetastatic and systematically identify the phenotypic dedicate myself entirely to doing cutting- metastatic microenvironments. We hope consequences of genetic differences. My edge research in a stimulating and collegial our findings will provide insight into future group is studying the functional effects of environment. I also wanted full intellectual therapeutic interventions to limit metastasis. genetic diversity, such as natural variation freedom and access to all the necessary What attracted you to the program? between individuals or between species, or resources to pursue bold research ideas. The NIH offers a strong and diverse community novel genetic changes that we create. We Stadtman program checked all the boxes. of highly engaged scientists, provides access apply genome-engineering methods and to leading technologies, and grants the use CRISPR gene-editing technologies, MARCOS MORGAN, PH.D., NIEHS ability to tackle exciting high-risk long-term large-scale oligonucleotide synthesis, yeast Head, Male Reproduction and RNA Biology questions. The collaborative environment models, and high-throughput phenotyping Group, National Institute of Environmental will enhance and accelerate our research. and genotyping to generate and study the Health Sciences effects of thousands of unique genetic Came to NIH: In 2019. PEDRO PEREIRA DA ROCHA, PH.D., NICHD variants. We also aim to develop new Research focus: Dysregulation of cellular Unit on Genome Structure and Regulation, approaches to study genetic diversity. RNA amounts leads to growth defects and National Institute of Child Health and What attracted you to the program? cancer. My team’s goal is to understand Human Development I was very excited that researchers in the the role of RNA metabolism during Came to NIH: In 2018. NIH’s intramural program can focus so development. We investigate animal models Research focus: DNA organization completely on their science. That, combined with deficiencies in RNA modification influences cell behavior and ultimately with the extraordinary breadth of research pathways. We hope to bridge the gap animal development and health. My group here, made the NIH my ideal destination. between the mechanistic knowledge of is investigating the mechanisms through CONTINUED ON PAGE 22

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Stadtmans CONTINUED FROM PAGE 21

PAYEL SEN, PH.D., NIA Head, Functional Epigenomics Unit, Laboratory of Genetics and Genomics, National Institute on Aging Came to NIH: In 2019 Research focus: My lab is trying to figure out what drives aging. We are investigating chromatin changes that occur during senescence, aging, and age-related diseases. To delineate the mechanisms that PAYEL SEN, NIA HUGO TEJEDA, NIMH JOEL VEGA-RODRIGUEZ, NIAID regulate aging, we rely on experimental, computational, and high-throughput technologies to discover novel epigenetic JOEL VEGA-RODRIGUEZ, PH.D., NIAID (Endogenous opioids, such as endorphins targets of aging. With the help of a naturally Chief, Molecular Parasitology and and dynorphins, are produced by the body aged mouse model, we hope to identify key Entomology Unit, National Institute of and act on opioid receptors throughout the enzymes and transcription factors. Our Allergy and Infectious Diseases central nervous system to relieve pain and long-term goal is to modulate these factors Came to NIH: In 2018 as a Stadtman regulate anxiety and mood.) My group using epigenetic drugs, CRISPR/Cas9 gene Investigator and NIH Distinguished focuses on the role of neuromodulation editing, and other cellular reprogramming Scholar. within motivational and emotional strategies to improve health and, ultimately, Research focus: My team is studying neural circuits in processing information extend life. the biology of malaria parasites (protozoa and orchestrating behavior. We are also What attracted you to the program? of the genus Plasmodium) during two identifying changes in neuromodulators There are two primary reasons I chose to vulnerable times in their lifecycle: when they (such as opioid receptors) and synaptic apply to the Stadtman Program: 1) The are sexually reproducing in the mosquito integration in limbic circuits of animal program identifies the best institute that midgut; and when the mosquito injects models of psychiatric disorder symptom fits my research goals, not the other way the parasitic sporozoites into the human clusters to identify novel therapeutic around; and 2) The program gives junior host. We are investigating the role of vector targets and increase our understanding of scientists the freedom to devote time at the and host factors for parasite infectivity conventional therapies. bench and mentor the next generation of and the molecular mechanisms required What attracted you to the program? scientists through hands-on training. for Plasmodium sexual reproduction The NIH provides a stimulating, supportive in the mosquito. Our long-term goal environment in which one can focus on their HUGO TEJEDA, PH.D., NIMH is to identify new targets that could be basic science. Simultaneously, the research- Chief, Unit on Neuromodulation and exploited for malaria interventions including focused clinical environment facilitates Synaptic Integration, National Institute chemotherapy, vaccine development, and reverse and forward translational research of Mental Health transgenic mosquitoes. influenced by basic science. Came to NIH: In 2008 to complete What attracted you to the program? graduate and postdoctoral fellowships It gave me the opportunity to establish at NIDA; in 2018, joined NIMH as a unique research program to study the a Stadtman Investigator and NIH transmission of malaria by mosquitoes Distinguished Scholar. as part of a diverse and vibrant scientific Research focus: T h e b r a i n ’s community at the NIH. The exceptional neuromodulatory systems, such as the resources available at the NIH foster endogenous opioid system, play a role in the advancement of my scientific and modifying synaptic integration, a process professional career as well as those of my by which neurons process incoming trainees. signals and convert them to output signals.

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FAUSTINE WILLIAMS, PH.D., NIMHD Health Disparities and Geospatial Transdisciplinary Research Lab, National Institute on Minority Health and Health Disparities Came to NIH: In 2018 as a Stadtman Investigator and NIH Distinguished Scholar. Research focus: Acculturation and social determinants influencing immigrant,

EMILY VOGTMANN, NCI-DCEG ALEXANDRA WHITE, NIEHS FAUSTINE WILLIAMS, NIMHD migrant, and minority populations’ health are particularly challenging. These factors, including sociocultural, environmental, EMILY VOGTMANN, PH.D., M.P.H., NCI-DCEG ALEXANDRA WHITE, PH.D., M.S.P.H., NIEHS economic, and biological factors and genetics are often interconnected, making Metabolic Epidemiology Branch, Division Environment and Cancer Epidemiology them difficult to address. Our research of Cancer Epidemiology and Genetics, Group, National Institute of Environmental program seeks to understand these complex National Cancer Institute Health Sciences dynamic factors. Subsequently, the lab Joined NIH: In 2013 as a Cancer Came to NIH: In 2015 as a postdoctoral has two interrelated research goals. The Prevention Fellow and later a research fellow; became a Stadtman Investigator in first is using transdisciplinary methods fellow; became Stadtman Investigator in 2019. including system science, geographic 2018 and an NIH Distinguished Scholar Research focus: My research focuses on information system, and mixture models in 2019. the role of air pollution and environmental to understand the complex interactions Research focus: I am investigating the chemicals, individually and in combination, of factors contributing to the health and association between the human microbiota in breast-cancer risk. My research aims to health disparities of immigrant, migrant, and cancer risk and how the microbiota may identify novel and modifiable environmental and minority populations. The second is mediate associations between exposures and exposures related to cancer risk and using our findings to develop and implement cancer risk. My team is looking at the effects explore underlying biologic mechanisms. culturally appropriate interventions to of cancer risk factors, such as tobacco use, Currently my group is investigating the improve diverse populations’ overall health betel quid use (chewing betel nuts), alcohol role of air-pollution components and other outcomes and reduce health disparities. intake, and diet, on microbial communities. environmental chemical mixtures in relation What attracted you to the program? We are also studying risk and lifestyle factors to epigenetics, breast-tissue characteristics, The NIH is the most robust research for head-and-neck and lower gastrointestinal and cancer incidence. This work will identify environment in the world! Working here cancers. We are characterizing the fungal environmental carcinogens for which will provide me resources to pursue my component of the microbiota and its exposure can be mitigated either with policy research ideas, which would be difficult to relationship to cancer risk. changes or individual-level interventions. conduct on the outside if I did not secure What attracted you to the program? What attracted you to the program? extramural funds. Another advantage is the As a postdoctoral fellow, I was closely NIH has unparalleled resources and opportunity to collaborate with NIH’s wide involved in the development of the outstanding scientists. It provides the range of researchers as well those outside microbiome research program, where we ideal opportunity to conduct cutting-edge the NIH. Additionally, the fulfillment evaluated sample-collection methods, science. of my long-term goal requires expanding laboratory handling, bioinformatics, and my research to understanding the impact statistical analysis methods. I applied for of interactions of social, behavioral, and the Stadtman program to continue this genetic underpinnings of health disparities. work and to start an independent research I believe there is no better environment for program using optimized methods to study these types of work than the NIH due to the impact of the human microbiome on its unique nexus of researchers. cancer risk.

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If you have a photo or A Visit From the New President other graphic that reflects an aspect of life at NIH (including laboratory life) or a quotation or confession that scientists might appreciate and that would be fit to print in the space to the right, why not send it via e-mail: catalyst@ nih.gov; fax: 301-402-1434; or mail: The NIH Catalyst, Building 60, Room 232. Also, we welcome “letters to the editor” for publication and your reactions to anything on OD CHANG, “CHARLIE” CHIA-CHI CREDIT: the Catalyst pages. President Joseph Biden met with scientists at NIH’s Vaccine Research Center (VRC) on February 11, 2021, and then gave a virtual pep talk to NIH staff thanking them for their hard work and outstanding contributions in fighting the COVID-19 pandemic. READ MORE ARTICLES, AND “On behalf of a grateful nation, I want to thank you and your families for your work and EXPANDED VERSIONS OF THE sacrifice,” he said. During his remarks, he also talked about his plans to expand the distribution ONES IN THIS ISSUE, ONLINE AT of COVID-19 vaccines. Here, Biden elbow bumps VRC researcher Kizzmekia Corbett, who https://irp.nih.gov/catalyst/v29i2. helped develop COVID vaccines, while NIAID Director Anthony Fauci (center) and NIH Director Francis Collins (right) look on.

PUBLISHER CONTRIBUTING WRITERS EDITORIAL ADVISORY BOARD The NIH Catalyst is published MICHAEL GOTTESMAN NATALIE HAGEN CHRISTINA ANNUNZIATA, NCI bimonthly for and by the Deputy Director for Intramural Research, OD EIMEAR HOLTON DAN APPELLA, NIDDK intramural scientists at NIH. ROBERT LEFKOWITZ & RANDY HALL TREVOR ARCHER, NIEHS EDITORS BRANDON LEVY MICHAEL ESPEY, NCI Address correspondence to: JOHN I. GALLIN ETHAN SMITH AUDRAY HARRIS, NIAID Building 60, Room 232, NIH Associate Director for Clnical Research ERICA WYNNE-JONES SUSAN LEITMAN, CC 1 Cloister Court Chief Scientific Officer, CC RESEARCH BRIEFS: KELLEY BERNARD MOSS, NIAID Bethesda, MD 20892 RICHARD S. CHADWICK CHRISTENSEN, HENRY DIECKHAUS, ROLAND OWENS Ph: 301-402-1449 Scientist Emeritus, NIDCD Fax: 301-402-1434 JUNE GUHA, LEANNE LOW, ETHAN HYUN PARK, NCI EDITOR-IN-CHIEF e-mail: [email protected] SMITH, SUBHASH VERMA EMILY PETRUS, NINDS (FELLOW) LAURA STEPHENSON CARTER JULIE SEGRE, NHGRI PHOTOGRAPHERS/ILLUSTRATORS The NIH Catalyst online: WRITER-EDITOR ANDY SINGLETON, NIA CHIA-CHI “CHARLIE” CHANG https://irp.nih.gov/catalyst CHRISTOPHER WANJEK GISELA STORZ, NICHD E.R. FISCHER AND A. ATHMAN, Director of Communications, OIR RONALD SUMMERS, CC ERINA HE, NIAID, OFFICE OF NIH WEI YANG, NIDDK COPY EDITOR HISTORY AND STETTEN MUSEUM

SHAUNA ROBERTS ERICA WYNNE-JONES