June 30, 2017, NIH Record, Vol. LXIX, No. 13

June 30, 2017 Vol. LXIX, No. 13

epidemic; and an argument for an accelerated pathway toward a universal influenza vaccine. Not Ready for Prime Time ACD Supports Early Collins traced the half-year Investigators, Applauds history of the effort to reallo- Collins’ Reappointment cate NIH funding for early and BY RICH MCMANUS mid-career scientists in a more optimum way, starting with what Two days before the 114th meeting of the was known last fall as the Research advisory committee to the NIH director on Commitment Index. That effort, June 8, the President invited NIH director known temporarily as RCI, later Dr. Francis Collins to remain in that post morphed into the Grant Support permanently. NIH director Dr. Francis Collins (l), flanked by ACD Index, or GSI. “I am grateful and honored to have member Dr. Jose Florez of the Broad Institute of MIT and “[GSI] created quite a lot of received that invitation,” said Collins, who Harvard, told the group that he thought last December’s interest—not all of it positive—about ACD meeting might have been his last. had been serving as a holdover appointment as much as I’ve seen in a grants since Jan. 18, “and I am happy, along with my funding policy in 8 years,” said wife Diane, to accept it.” of the Next Generation of Researchers Collins. “We did hear significant concerns The news was met with a round of Initiative (NGRI) to support early and about the validity of the index, and how it applause before the ACD got down to a mid-career investigators; presentation of might discourage collaboration.” It became 2-day agenda that included announcement NIH’s efforts to reduce the nation’s opioid SEE ACD, PAGE 4

JUNGLE TRAVEL NOT REQUIRED Genetics, Evolutionary Daly Lecturer Describes 21st Biology Help Identify Rare Century Drug Discovery Mendelian Disorders BY CARLA GARNETT BY DANA TALESNIK

Just recently back from a trip to South If Charles Darwin had read the findings of Africa, where she had a “pretty scary” Gregor Mendel, he might have saved himself face-to-face with a lot of grief. While a deadly black Mendel was holed mamba snake, Dr. up in a monas- Fiona Marshall had tery discovering Bill Gates (l) talks global health at NIH, p. 12. the perfect intro- hereditary traits by ALSO THIS ISSUE duction to NIH’s experimenting on 2017 Daly lecture. pea plants, Darwin Briefs...... 2 Renowned jungle was struggling to Global Myositis Conference Joins Researchers, explorer Dr. John prove his theories of Patients...... 3 W. Daly, the late natural selection and ‘Kidney Sundays’ Increase Lupus Awareness. .5 NIDDK biochemist descent-with-modi- and pharmacologist fication. Asian, Pacific Islander Heritage Celebrated. . 9 for whom Marshall’s Dr. Fiona Marshall Dr. David Valle “Darwin’s big Digest...... 10 talk was named, problem was that, Milestones...... 11 pioneered in natural product research. with descent-with-modification, there In much of the last half of last century, he was no theory of genetics, no knowledge of Seen...... 12 SEE MARSHALL, PAGE 6 SEE VALLE, PAGE 8 BRIEFS

Workshops on Work/Life and Well-Being OHR and ORS are offering a free supervisory workshop titled “Work/Life @ NIH: A Supervisor’s Guide to Enhancing Workforce Well-Being.” It provides an overview of workforce well-being and how it can benefit your organization; highlights the policies and programs NIH offers to promote workforce well-being; and provides supervisors with strategies to manage the use of various workplace flexibilities. The workshop is led by NIH’s own subject matter experts and has been approved for 2 Continuous Learning Points for supervisory refresher purposes. Registration is available in the Learning Management System. You may register by search- ing for course ID #NIHWRD1003. There are two remaining sessions for 2017: July 13 and Nov. 8. The July offering is currently full, but seats may become available via the waitlist. Can’t attend these sessions? Stay tuned for announce- ments about 2018 offerings. Questions? Email Courtney Bell, ORS (bellcd@mail. nih.gov) or Kelly Peralta, OHR ([email protected]) All Along the Water Towers for more information. The two new water towers on campus are moving toward completion and will 10th Graduate & Professional School Fair soon be familiar features of the local Set, July 18 skyline. In the photo above, the top of the Industrial Water Storage System The 2017 NIH Graduate & Professional School Fair can be seen at left, already dressed in will be held on Tuesday, July 18 from 8:45 a.m. to its masonry façade. Awaiting similar 3:30 p.m. at the Natcher Conference Center. treatment in the foreground of that photo is the Thermal Energy Storage The event provides an opportunity for NIH summer System (also shown at right), which interns (especially those in college) and postbacs, has a bright yellow metal skin at the as well as other college students in the D.C. area, moment but will resemble its smaller to prepare for the next step in their careers by cousin once complete. exploring educational programs leading to the PHOTOS: RICH MCMANUS Ph.D., M.D., D.D.S., M.D./Ph.D., and other graduate and professional degrees. More than 195 outstanding colleges and uni- versities from across the U.S. will be sending representatives of their graduate schools, medical and dental schools, schools of public health and other biomedically relevant programs to the fair to recruit NIH trainees. The day will also include workshops on getting to graduate and professional school, M.D./Ph.D. programs, interviewing, careers in public health, computational biology/bioinformatics, psychology and dentistry. Exhibits will be open from 9:45 a.m. to 2:15 p.m. Find a list of institutions planning to attend and registration information at https://www.training. nih.gov/gp_fair.

Glass Mouse Cage Sought Do you have a glass mouse cage like the ones in the photo above? If so, the DeWitt Stetten Jr. Museum of Medical Research would like to borrow it for an exhibit going into the Clinical Center on Michael Potter, NCI. The photo shows the mouse room of Dr. Lloyd Law’s NCI laboratory in the 1950s. If you have a glass mouse jar like these, contact Michele Lyons, curator, at (301) 496-7695 or [email protected].

2 • NIH RECORD • JUNE 30, 2017 “The conference focused on trainees addressing what patients want and what we Myositis Conference Joins and young investigators,” said Dr. Lisa are doing to support them,” he said. Researchers, Patients Rider, deputy chief of the EAG and a leading NIAMS director Dr. Stephen Katz and researcher of juvenile myositis. Six trainees Dr. Andrew Mammen, a researcher in the The second Global Conference on Myositis received abstract awards and made oral pre- NIAMS muscle disease unit, were also (GCOM 2017) brought together myositis sentations, she noted. The event also offered involved. researchers, patients and a special mentoring session With 310 participants, the meeting was support group represen- on how to become success- twice the size of the 2015 inaugural confer- tatives from around the ful myositis researchers. ence in Stockholm. Building on the success world. Dr. Fred Miller Dr. Hanna Kim, an of this year’s conference, the next of the chaired the steering and NIAMS clinical fellow, biennial series, GCOM 2019, will take place scientific committees for received an outstanding in Berlin. the recent event, which abstract award for her Ongoing clinical studies led by NIEHS, took place at the Bolger research on juvenile NIAMS and others are recruiting volunteers. Center in Potomac. Miller is dermatomyositis. In addition to support from NIEHS, the con- head of the environmental “This gave me the ference received funding from NIAMS and autoimmunity group (EAG) chance to give a plenary NINDS, as well as 20 patient support group at the National Institute presentation,” she said. and corporate sponsors.—John Yewell of Environmental Health “I got a lot of thoughtful Sciences. feedback from interna- Myositis is a rare, tional experts.” multi-symptom disease that GCOM 2017 highlighted can affect people of all ages the involvement of patients “The field has expanded greatly and involves dermatology, in terms of its research scope,” and their advocates. Two rheumatology, neurology said NIEHS’s Dr. Lisa Rider. “This major support groups, the and pulmonary disease, conference took it to a new level.” Myositis Association and among others. Also known PHOTO: RITA VOLOCHAYEV the CureJM Foundation, as idiopathic inflammatory participated. myopathies, myositis consists of a diverse “As a rare, neglected disease, myositis group of complex diseases that result from doesn’t get much official attention or ON THE COVER: Zebrafish group used in studies chronic muscle inflammation. funding,” Miller said. “Patient support of behavioral genetics. One such program aims to identify brain cells that control the startle reflex, “Our main goal was to share state-of-the- groups serve an important function which may help us understand post-traumatic stress art research covering all forms of myositis in raising awareness and funding for and other anxiety disorders in people. and to include basic researchers and all research.” IMAGE: J. SWAN, NICHD specialties caring for myositis patients,” Dr. Adam Schiffenbauer, an EAG staff said Miller. “It was a great success and clinician, heard satisfaction expressed by The NIH Record laid the groundwork for important future many of the patients at the conference. Since 1949, the NIH Record has been published biweekly by the Editorial Operations Branch, collaborations.” “A lot of the program was directed at Office of Communications and Public Liaison, National Institutes of Health, Department of Health Grantee Deisseroth Awarded and Human Services. For editorial policies, email Fresenius Prize editor or phone (301) 496-2125. Germany’s Else Kroner-Fresenius Editor: Rich McManus Foundation awarded the 2017 Fresenius [email protected] Research Prize to Stanford University Associate Editor: Carla Garnett professor and Howard Hughes [email protected] Medical Institute investigator Dr. Karl Deisseroth (l). He accepted the award Staff Writers: at a ceremony on May 31 in Berlin. Eric Bock • [email protected] It recognized his achievements in Dana Talesnik • [email protected] optogenetics, hydrogel-tissue chemistry Subscribe via email: Follow: and research in depression. The [email protected] http://nihrecord.nih.gov/ Fresenius Research Prize is awarded Facebook “f” Logo CMYK / .eps Facebook “f” Logo CMYK / .eps every 4 years and is the world’s largest The NIH Record monetary award—4 million euros— is recyclable as to a single researcher for scientific mixed paper. achievement. Deisseroth has been an NIH grantee since 2005, when he was selected for an NIH Director’s Pioneer Award. He is shown here with NIBIB director Dr. Roderic Pettigrew following the 2016 Hector Lopez Memorial Lecture.

PHOTO: KATE EGAN

NIH RECORD • JUNE 30, 2017 • 3 ★ ★ ★ “We tried to create a simple framework [GSI], but it would not capture the incredible complexity of modern team science.”

~DR. LAWRENCE TABAK

★ ★ ★

“We tried to create a simple framework and the sheer NIH principal deputy director Dr. Lawrence Tabak (l) explains the GSI brouhaha. [GSI],” Tabak explained, “but it would not width of the capture the incredible complexity of modern problem—“This ACD team science.” crisis affects CONTINUED FROM PAGE 1 Ironically, the $1.1 billion in reallo- everybody, cated funds matches almost exactly the including those apparent, he said, that “the GSI approach is recommendations of an independent never exposed to not ready for prime time.” analysis of the same subject published in drugs before.” Of the brouhaha that accompanied the Proceedings of the National Academy of Volkow said proposal of the GSI and its subsequent Sciences just days before the ACD meeting, that, even though removal from the table, NIH principal noted Dr. Michael Lauer, NIH deputy opioid prescrip- deputy director Dr. Lawrence Tabak, who director for extramural research. tions have been Dr. Nora Volkow explains had outlined the plan before some 19 science of addressing decreasing since advisory councils in recent months, said, opioid addiction. 2010, fatalities “This is the way this is supposed to work. are still increas- Maybe there was some tension involved, but ing. Opioid overdose is the leading cause of as the saying goes, without tension, there is death in those age 50 and younger, she said. no music.” NIH’s approach, outlined in three Both the NIH-Wide Strategic Plan, which summer workshops held on campus, will Tabak was involved in drafting, and the 21st focus on “acceleration points” in the science Century Cures Act, call for creation of NGRI, of addressing opioid use disorders, said which will extend the payline for early-stage Volkow. Three areas are targeted: pain investigators. management, through safer, more effective NGRI will also “prioritize support for strategies; opioid addiction treatment those about to lose all NIH support and using new medications and technology; and who are maybe likely to leave the work- Dr. Richard Lifton said GSI might not help overdose reversal, including Narcan nasal force,” said Tabak. It will also give a boost early-stage investigators at all. spray, which Volkow dubbed “naloxone for to those going for their second RPG, but dummies,” since it doesn’t require injection. who just missed the payline, the so-called Among concerns about limitations of “rising stars,” he added. the GSI approach—including that “a formu- NGRI is estimated to require about la-driven approach to evaluating individuals $210 million per year for 4-5 years, or a flew in the face of…long-standing principles total of about $1.1 billion, Tabak continued. of making decisions based on individual Inasmuch as NIH is not in the business of merit,” said Collins—is that GSI “offered no printing money, he quipped, the funds will assurance that redistributed funds would come from reprioritization of budgets by the go to early-stage investigators,” said ACD institute and center directors. member Dr. Richard Lifton, president of Rockefeller University. “The money could go from a 60-year-old with 6 grants to another Dr. W. Ian Lipkin (c) thinks a flu vaccine that 60-year-old with 2 grants.” reduces mortality is valuable, even if it can’t prevent the illness. Opioid Public Health Crisis “I have never seen anything like this drug Volkow also decried the dramatic crisis in my career,” said NIDA director Dr. underutilization of a tool called MAT— Nora Volkow, who described a burgeoning medications assisted therapies for opioid U.S. opioid epidemic notable for three use disorder—which includes methadone, things: an “enormous number of people buprenorphine and naltrexone. dying daily”; an origin in the health care “I know of no medical or dental schools Dr. M. Roy Wilson (l) said the language of setting itself, with a “massive over-prescrip- that require opioid training,” noted Dr. some critiques of GSI received at NIH was tion of medications” that, ironically, “hasn’t “really inappropriate.” M. Roy Wilson, president of Wayne State improved outcomes for those in pain”; University. “I intend to start it at Wayne.”

4 • NIH RECORD • JUNE 30, 2017 ‘KIDNEY SUNDAYS’ NIAMS, NIDDK Partner to Increase Lupus Awareness People often turn to their places of worship for guidance on how to live better. These faith-based settings offer “teachable moments” for providing relevant and reliable health information. Recently, NIAMS joined forces with NIDDK and Chi Eta Phi Sorority, Inc., to help community faith leaders raise awareness about lupus in their congregations as part of NIDDK’s Kidney Sundays annual outreach program. The initiative, promoted during National Kidney Month, brings attention to kidney disease as a prevalent health issue in the African-American community. This year, Dr. Michael Lauer (r), NIH deputy director for extramural research, said a paper in PNAS NIAMS helped hone the focus on lupus, an autoimmune disease that disproportion- concurred with NIH’s own estimate of the ately affects African Americans. “Although some people may have heard of lupus, many cost of redistributing resources to help early don’t know that it is a kidney-related disease,” said Priscilla Murphy, first vice president and mid-career scientists. Shown at left is Dr. Michael Gottesman, NIH deputy director for of Chi Eta Phi, a professional organization for nurses dedicated to leadership and intramural research. community service. PHOTOS: ERNIE BRANSON, RICH MCMANUS “Lupus is a complex disease and it can affect many parts of the body,” said Anita Linde, director of the NIAMS Office of Science Policy, Planning and Communications. Chasing After Pandemics Is Costly “This collaboration between NIH and Chi Eta Phi is a wonderful example of the power of partnerships to improve public health.” NIAID director Dr. Anthony Fauci made Lupus is most common in women, especially those in their childbearing years who a vigorous case for aggressive pursuit of a are in the prime of their lives—raising families, going to school and building careers. universal flu vaccine, given that seasonal African-American and Hispanic women tend to have more severe organ damage from flu vaccines are not consistently effective lupus, especially to the kidneys. Lupus is also common in women of Asian and Native (in a good year, they offer 60 percent American descent. With symptoms such as fatigue, achy joints and sun sensitivity, protection; in a bad year, none) and that lupus may look different for each person, making it difficult to diagnose. chasing after a potential pandemic is both “Working with NIAMS to highlight a condition that involves both our ICs’ research costly and ineffective. areas makes perfect sense and really serves the affected audience,” said Kathy “We shouldn’t be chasing each year and Kranzfelder, director of NIDDK’s Office of Communications and Public Liaison. “I’d then waiting for the big surprise,” he said, love to see more of this sort of cross-reliance on the subject matter experts and noting that a late June meeting sponsored by cross-promotion of the resulting messages.” NIAID would convene the best and brightest The collaboration reached 146 churches across 24 states nationwide. Each Kidney in the field. Sundays event provided opportunities to engage community members about healthier Of the universal vaccine effort, he said, living, while offering free blood pressure checks and informational handouts. “We’re going to do it with the resources we have, which is not a lot. We may have to reallocate some resources.” Some private funding may become available from a group of philanthropists that met recently in Palo Alto to discuss promising technologies such as a universal flu vaccine; Fauci addressed that group via video. ACD member Dr. W. Ian Lipkin, a professor of epidemiology at Columbia University, attended the meeting and expressed optimism. “A reduction in [flu] mortality might be a goal,” he noted, “not necessarily prevention.” Concluded Fauci, “Chasing after potential pandemic outbreaks costs a stunning amount of money—billions of dollars. It NIDDK’s Natalie Shuster (standing, fourth from l) and Eileen Newman (standing, r) and NIAMS’s doesn’t make any sense not to invest a Colleen Dundas (standing, second from r) pose with Chi Eta Phi volunteers and church members at a local Kidney Sundays event. fraction of that on universal flu vaccine research.”

NIH RECORD • JUNE 30, 2017 • 5 The late NIDDK biochemist and pharmacologist Dr. John W. Daly, renowned for his jungle explorations, traveled to such places as Colombia, Peru, Ecuador and Madagascar, tracking down would-be medicines from their herpetological sources—frogs, lizards and snakes. DALY PHOTOS: NIDDK LABORATORY OF BIOORGANIC CHEMISTRY, OFFICE OF NIH HISTORY

Marshall CONTINUED FROM PAGE 1 • • • traveled to remote locations in such places “There’s an increasing as Colombia, Peru, Ecuador and Madagascar, realization that GPCRs are tracking down would-be medicines from not simple. There are many their herpetological sources—frogs, lizards and snakes. complex binding sites that As a fellow laborer in pharmacological can be accessed all over chemistry—albeit several generations and even around the removed—Marshall, chief scientific officer at Heptares Therapeutics in Hertfordshire, receptor, and intracellular Marshall, founder and chief scientific officer at United Kingdom, recently presented “From sites as well…” Heptares Therapeutics in Hertfordshire, U.K., describes the history of natural substances the Jungle to the Synchrotron—Seven ~DR. FIONA MARSHALL Millennia of Discovering Medicines used as medicines. Targeting G Protein-Coupled Receptors.” • • • LECTURE PHOTOS: ANDREW PROPP Black mamba encounter aside, she Gila monster, black widow spider and the mainly described drug discovery done a lot worked, Marshall said the first GPCR drugs Australian green tree frog. closer to home. were most likely opioids and they were At NIH for nearly 50 years, Daly pub- “Although most venoms and toxins probably first used in religious ceremonies, lished more than 700 articles and worked on [secreted by animals] tend to work through then as medicines—some of the earliest the chemistry of ligands for several GPCRs, ion channels because that’s the fastest anesthetics—in ancient Samaria, or what is including adenosine, adrenergic, histamine, way of killing prey or getting away from now Iraq. serotonin and acetylcholine receptors. He predators, a number do work on GPCRs,” Opium, cannabis and atropine were died in 2008, but his legacy of natural drug Marshall pointed out. “That black mamba among the first known GPCR drugs. discovery survives him. that I met produces venom that acts on It wasn’t until the 1890s that the concept It was Daly who discovered the chemical potassium channels.” of chemoreceptors, substances in the human structure of batrachotoxin, the poisonous body that interacted with these plant-based Spiders and Lizards and Frogs, Oh My! substance found in some frog skin that medicines, was introduced. She showed several animals and their Amazon Indians used on blow darts. He GPCR-acting toxins: The green mamba described its mechanism of action through From Gut Baths to High-Throughput snake native to India emits MTX, which sodium channels and went on to reveal “The start of pharmaceutical drug dis- works on the muscarinic receptor, for how toxins react with different proteins covery of GPCRs as we know it today came example, while the king cobra’s venom acts in humans. Daly subsequently introduced about in the 1950s and 1960s,” Marshall on the beta adrenergic receptor. Both of several other tools still used today for said. “Tissues, mainly from animals such as those receptors are located on the heart; natural products research, including forsko- the guinea pig and rat, were strung up in gut blocking them leads to cardiac arrest. lin and epibatidine. baths and analogs were made of the ligands… Other critters with interesting venoms Tracing the history of natural substances By then we knew quite a lot of GPCR ligands, that act on GPCRs include the cone snail, back to before anyone realized how they although that’s not what they were called. We

6 • NIH RECORD • JUNE 30, 2017 Next Gen Tech Solutions Emerge been approved by the FDA. That represents It took another 7 years until the next about 20 percent of all drugs approved in GPCR was cloned—the beta2 receptor—by that time period. The newly discovered med- the teams of Brian Kolbilka of Stanford and icines modulate the activity of targets across Ray Stevens of Scripps. all disease fields, from the central nervous Enter Heptares Therapeutics, the system to the immune system. company Marshall cofounded in 2007 to take Marshall touched briefly on her group’s advantage of a uniquely designed technology most recent work with the identification of that makes GPCRs more stable. The technol- structures of receptors involved in irritable ogy was first developed at the Laboratory of bowel disease, Crohn’s disease and inflam- Molecular Biology in Cambridge, U.K. matory pain. She ended by summarizing “This has enabled us to do struc- what she described as a now wide-open field ture-based design, to design drugs that really for GPCR-structure drug development. fit the receptor much better, are much more “There’s an increasing realization that Dr. Kenneth Jacobson, chief of NIDDK’s specific and hopefully have a lower attrition GPCRs are not simple,” she concluded. Laboratory of Bioorganic Chemistry, presents rate as they go through development,” “There are many complex binding sites that the 2017 Daly Award to Marshall. Marshall explained. can be accessed all over and even around the receptor, and intracellular sites as well… knew a number of different chemicals that Hepatares’s first X-ray structure success was to solve the adenosine A receptor, These all will have different allosteric actions had a physiological effect.” 2A which Daly played such a crucial role in and different therapeutic actions. Getting Medicinal chemists, she explained, X-ray structures allows us to understand sketched out the analogs and tested them defining. Over the next decade, the team at Heptares identified potential drugs much more about the interaction of the on gut baths, the classical pharmacological drugs with the receptor and can enable screening tool used to gauge a compound’s for a wide range of ailments, including Alzheimer’s disease, migraine, schizophre- further GPCR drug discovery.” interaction with organ tissue. Visit https://videocast.nih.gov/summary. The field moved toward the molecular age nia, cancer, attention deficit hyperactivity disorder and Parkinson’s disease. asp?Live=23387&bhcp=1 to see the full in the 1970s, Marshall said, with the dawn of presentation. radio-labeling techniques—using a radio- In 20 years of GPCR drug discovery from active tracer to mark a substance. The new 1995 to 2015, 116 GPCR-targeted drugs have methods meant researchers could track the binding sites of substances as they interacted Administration, HHS in tissues. Officials Take NIH Tour Through radio-labeling, scientists first Reed Cordish (top, second from r), purified and then cloned the first receptor, assistant to the President for intragov- realizing that “GPCRs were actually part of ernmental and technology initiatives, a large, superfamily of proteins. This then and Mary Sumpter Lapinski, counselor to followed a great era in cloning all of the other HHS Secretary Tom Price, visited NIH on GPCRs,” said Marshall. May 31 for a brief tour. They met with NIH director Dr. Francis Collins (top, second About a decade later, with human genome from l), Clinical Center CEO Dr. James sequencing, researchers could list around Gilman (l) and NCI Surgery Branch chief 800 human GPCRs, “about half of which Dr. Steven Rosenberg (below, l). are olfactory receptors used for smell and In tours of his office and lab, Rosenberg taste. About 400 others are non-olfactory discussed research on immunotherapy, receptors that we consider to be potential walking the group through computer drug targets.” scans and other tumor images before High-throughput screening, in which and after treatment. large libraries of compounds are tested He also introduced the officials to a against GPCRs, became the next phase for 66-year-old patient with relapsed diffuse drug discovery, Marshall said. Not nearly large B-cell lymphoma who’d had three lines of therapy prior to treatment at NCI. as many substances made it to market this At NIH, he received low-dose chemo- way, however. Tissue bath techniques had therapy followed by anti-CD19 CAR cells produced far more viable drugs. in September 2015 and was declared The first GPCR structure was rhodopsin, a complete responder 2 months after purified from bovine retina and crystallized infusion. His scans remain clear now, 18 months after infusion, with no evidence of recurrent lymphoma. in 2000, giving scientists their first look at a GPCR in 3-D. PHOTOS: LISA HELFERT

NIH RECORD • JUNE 30, 2017 • 7 Valle augmented by a dose of steroids, which puts CONTINUED FROM PAGE 1 excessive demands on the urea cycle,” said Valle. “It wasn’t until his system was really genetics, so he had no way of explaining how stressed that this homeostatic vulnerability variations that were favorable were trans- came to light.” mitted from one generation to the next,” Researchers increasingly are uncovering said geneticist Dr. David Valle at a recent new gene variants for all kinds of Mendelian Clinical Center Grand Rounds in Lipsett disorders thanks to rapid genome sequenc- Amphitheater, Bldg. 10. ing. While there are different advantages A century after Darwin, in the 1960s to single-gene and panel (20-30 genes) when Valle was a medical student, he never sequencing, whole exome sequencing has heard evolution mentioned. “Evolution was been especially useful in diagnosing patients [thought to be] paleontology and fossils,” with phenotypes caused by variants in genes said Valle, director of the Institute of Genetic Valle presents at a Great Teachers edition of not previously known to be responsible for Medicine and professor of pediatrics, oph- CC Grand Rounds. disease. These efforts have not only identi- thalmology, molecular biology and genetics PHOTOS: ERNIE BRANSON fied hundreds of novel disease genes but also at Johns Hopkins University. “But nothing have explained many surprises. One example defects, he said, and present early, often could be more removed from medicine and is patients who have two rare Mendelian in childhood. They also are more likely to the biology of human beings.” disorders. These “multi-Mendels” have been inherit a rare variant from both sides of the Biology and medicine are rooted in difficult to diagnose because their blended family and have multiple siblings or genera- evolution, said Valle at this Great Teachers phenotypes are hard to recognize, said tions with the same disease. edition of rounds. “And genetics is emerging Valle. A precise diagnosis from whole exome In one curious case, a seemingly healthy as the basic science of all medicine,” he said. sequencing can be invaluable, he said, as it 34-year-old male contracted an infection “Our genomes have to stand us in good stead ends the diagnostic uncertainty, suggests but was unresponsive to treatment. He throughout our lifetime.” specific management and informs the family developed confusion and arrived at JHU We’ve come a long way from Mendel’s of recurrence risk. with cerebral edema. After interviewing cross-breeding of pea plants to advances NHGRI established four Centers for in recent decades that led to sequencing w w w Mendelian Genomics to recruit families whole genomes. With more than 60 million from around the world to sequence whole different SNPs (single nucleotide polymor- “Getting sick is really a exomes. The Baylor-Hopkins Center for phisms, or, genetic variations) in humans Mendelian Genomics, where Valle is a and more than 3 million between individu- consequence of variation, principal investigator, so far has discovered als, it’s a wonder people get sick. But when natural selection and, 913 novel disease genes in its first 5 years. genetic variations pull us from the median, [therefore], evolutionary Valle’s group also developed two online combined with environmental stresses that databases to promote resource sharing. bump us out of homeostasis, we’re suscepti- biology.” PhenoDB (www.phenodb.org) allows any ble to illness. ~DR. DAVID VALLE provider to submit a case and features an “Getting sick is really a consequence of w w w analysis tool. GeneMatcher (https://gene- variation, natural selection and, [therefore], matcher.org) connects clinicians worldwide. evolutionary biology,” said Valle. the family, Valle learned that the patient’s As of March 2017, more than 6,000 genes Human genome sequencing has given us brother had drowned as a teenager. Upon were submitted by nearly 3,000 people. a parts list, namely all 20,000 protein-coding further probing, Valle discovered that the Although two-thirds of the genes remain genes. The challenge is figuring out how teen showed signs of confusion the day he unmatched, so far more than 15,000 matches these proteins interact with each other in died and an autopsy revealed cerebral edema. have been found for some 2,000 genes. biological systems and how these systems The patient survived what turned out The late biophysicist Max Delbrück function in tissues and organs. A genetic to be ornithine transcarbamylase (OTC) once said, “Any living cell carries with it the strategy to meet this challenge is to identify deficiency. His parents kept his late brother’s experience of a billion years of experimen- patients with mutations that result in baby tooth and DNA testing confirmed the tation by its ancestors.” As we continue to malfunction of one of these systems and same variant; his mother and aunt also tested evolve and learn more about our genes and thereby tell us something about the role of positive. The late brother had an episode disease-causing variants, investigators can the system in health and disease, said Valle. of hyperammonemia secondary to OTC identify new drug targets and develop better Over the years, his lab has discovered the deficiency as a child; the surviving brother diagnostics and therapies. genetic causes of more than 20 diseases and didn’t show signs until adulthood. “If we look carefully and across large pop- continues to use genetic tools to find and “The only thing that got him was he ulations,” said Valle,” I predict we will find understand rare Mendelian disorders. Most had this severe environmental stress— Mendelian phenotypes for certain variants patients with these disorders have egregious which was infection and fever—perhaps for nearly all genes in our genome.”

8 • NIH RECORD • JUNE 30, 2017 Members of the Wong Family Lion Dance Group perform. Raymond Wong explained that the Sandra Oh (front, c) leads the Korean Mae-Hwa Dancing Group, a high school alumnae dance troupe tradition brings good luck to all and can be that reunites regularly to learn dance, share Korean culture and stay healthy. found throughout Asia.

Asian American Heritage Month Celebrated at NIH

The NIH community enjoyed an outdoor program of Asian food and culture on May 24. Opening the event, Dr. Michael Gottesman, NIH deputy director for intramural research, explained that Congress designated every May to be Asian Pacific American Heritage Month. He highlighted contributions of Asian American scientists at NIH and in academia, industry, nonprofit organizations and other government Art in progress at NIH’s 2017 Asian American Heritage Month Celebration: APAO members write out agencies to the betterment of the global community. names in Chinese calligraphy (Hui Chen) and teach Japanese origami folding (Shioko Kimura). The event, which included music, dance, tai chi, art demonstrations and information tables, was organized by the NIH Asian and Pacific Islander American Organization (APAO), which also coordi- nated with Eurest Food Services to provide different Asian cuisines. Attendees learned about services of the PHS Asian Pacific American officers committee, the NIH Employee Assistance Program, NIMHD, NIAMS, and the NIH Federal Credit Union. Area community groups provided information displays. APAO, active at NIH since 1996, sponsors lectures ABOVE: At left are Huonggiang Le and Thomas Tran of the Association of Vietnamese Americans, and discussions and works closely with the Office of which provides community services and promotes cultural understanding. In center photo, guest chef Equity, Diversity, and Inclusion to present training Robert Rivera is ready to serve Filipino chicken adobo platters. At right, Integral Tai Chi Group with opportunities to the NIH community. instructor Hoang-Tam Hiltons (c) of NIH, demonstrated how regular practice of Tai Chi benefits balance, strength and a sense of well-being. BELOW: Attendees learn basic movements, which are closely tied to observations of nature and animals. PHOTOS: KATIE CHAN

Dr. Xiaobin Guan of NHGRI plays the erhu, a two- string Chinese instrument.

NIH RECORD • JUNE 30, 2017 • 9 DIGEST

Researchers at NIAID identified the mutation in a Opioids are a class of drugs often used for pain young child with a history of severe HRV infections. relief. Approximately 91 people in the United The case, published online June 12 in the Journal States die every day from an opioid overdose, with of Experimental Medicine, reveals an important more than 33,000 deaths in 2015—the highest mechanism by which the immune system responds on record—according to the Centers for Disease to these viruses, say the study authors. Control and Prevention. Several weeks after birth, the child began expe- Opioid prescriptions have quadrupled since riencing life-threatening respiratory infections, 1999, putting large numbers of reproductive-age including colds, influenza and bacterial pneumo- women at risk for developing opioid use disorder nia. Because her physicians suspected she might and their newborns at risk for drug withdrawal or have a primary immune deficiency—a genetic neonatal abstinence syndrome. abnormality affecting her immune system—they Drinking Diet Beverages performed a genetic analysis. “Opioid use disorder is an accelerating crisis in the United States, particularly among pregnant During Pregnancy Linked to The analysis revealed that she had a mutation women,” said NICHD director Dr. Diana Bianchi. Child Obesity in the IFIH1 gene that caused her body to make “NICHD brought together experts to review the dysfunctional MDA5 proteins in cells in her current evidence on how to best recognize, treat Children born to women who had gestational respiratory tract. and manage this condition and to identify the diabetes and drank at least one artificially research needed to improve outcomes for affected sweetened beverage per day during pregnancy Previously, scientists had found that laboratory women, their newborn infants and their families.” were more likely to be overweight or obese at age mice lacking functional MDA5 could not detect 7, compared to children born to women who had genetic material from several viruses, making Researchers Aim to Repurpose gestational diabetes and drank water instead of them unable to launch appropriate immune artificially sweetened beverages, according to a responses against them. Cancer Therapy to Treat study led by researchers at NIH. Similarly, the NIH researchers found that mutant Muscular Dystrophy Childhood obesity is known to increase the risk MDA5 in the girl’s respiratory tissues could not Researchers at NCATS and the University of for certain health problems later in life, such as recognize HRVs, preventing her immune system Nevada, Reno School of Medicine (UNR Med) diabetes, heart disease, stroke and some cancers. from producing protective signaling proteins have demonstrated that a drug originally targeted The study appears online in the International called interferons. HRV thus replicated unchecked unsuccessfully to treat cancer may have new life Journal of Epidemiology. in the girl’s respiratory tract, causing severe as a potential treatment for Duchenne muscular illness. These observations led the researchers dystrophy (DMD). According to the study authors, as the volume of to conclude that functional MDA5 is critical to amniotic fluid increases, pregnant women tend protecting people against HRV. The candidate drug, SU9516, represents a different to increase their consumption of fluids. To avoid kind of approach for treating DMD, a degenerative extra calories, many pregnant women replace With intensive care, the child survived numerous muscle disease that usually begins in childhood sugar-sweetened soft drinks and juices with bouts of severe illness and her health improved as and has no known cure. It is caused by a faulty beverages containing artificial sweeteners. her immune system matured and formed protec- gene that leads to progressive muscle weakness, tive antibodies against various infectious agents. Citing prior research implicating artificially with death often occurring around age 25. sweetened beverages in weight gain, the study “The human immune response to common cold Rather than trying to fix or replace the broken authors sought to determine if diet beverage viruses is poorly understood,” said NIAID director gene, SU9516 ramps up the muscle repair process, consumption during pregnancy could influence Dr. Anthony Fauci. “By investigating this unique helping reinforce muscle structure. the weight of children. case, our researchers not only helped this child but also helped answer some important scientific NCATS Chemical Genomics Center acting branch “Our findings suggest that artificially sweetened questions about these ubiquitous infections that chief Dr. Juan Marugan and UNR Med professor beverages during pregnancy are not likely to be affect nearly everyone.” of pharmacology Dr. Dean Burkin led a team that any better at reducing the risk for later childhood screened more than 350,000 compounds to find obesity than sugar-sweetened beverages,” said Workshop Addresses Opioid SU9516, which had been previously developed study senior author Dr. Cuilin Zhang in the NICHD as a treatment for leukemia. The research Epidemiology Branch. “Not surprisingly, we also Misuse During Pregnancy demonstrated that this compound improved observed that children born to women who drank Research is essential to determining how best to muscle function in both laboratory and animal water instead of sweetened beverages were less screen pregnant women for opioid use disorder, to DMD models. likely to be obese by age 7.” treat pregnant women who have the disorder and The results, published in Molecular Therapy, may Scientists Discover Rare to care for infants provide a promising approach against the disorder as they experience and other muscle-wasting conditions. Genetic Susceptibility to withdrawal symp- Common Cold toms, according to Those with DMD lack dystrophin, a protein experts convened akin to a molecular shock-absorber that helps Scientists have identified a rare genetic mutation for a workshop keep muscle cells intact. Without dystrophin, that results in a markedly increased susceptibility co-sponsored by muscles are fragile and easily injured. Individuals to infection by human rhinoviruses (HRVs)—the NICHD. A summary lose muscle strength and the ability to repair main causes of the common cold. Colds contribute of the workshop damaged muscle tissue. Most die from heart or to more than 18 billion upper respiratory infections appears online respiratory problems. worldwide each year, according to the Global in Obstetrics and Burden of Disease Study. Gynecology.

10 • NIH RECORD • JUNE 30, 2017 MILESTONES FEEDBACK

NCI Mourns Former Have a question about some aspect of working at NIH? You can post anonymous queries Communications Staffer at https://nihrecord.nih.gov/ (click on the Anderson Feedback tab) and we’ll try to provide answers. Linda Frances Anderson, 67, formerly a Feedback: Hello, overall, I love working at member of the communications staff at the NIH. However, I would like to know how do I report bullying on behalf of someone else? National Cancer Institute, died on June 11 Is there an anonymous link, email address or at her home in Lake Charles, La., following a central mailbox for such matters? Thank you lengthy illness. for assistance. She was born in Houston and had relo- Response from the NIH Civil Program: cated to Louisiana in October 2016. She had Bullying is managed by the NIH Civil Program, resided in the Washington, D.C., area since which works to address and prevent workplace 1967, calling Kensington her home for the last violence. Civil defines violence broadly and 25 years. helps the ICs manage a range of situations, from Anderson graduated from the University bullying and other types of intimidating behavior to more direct or physical types of violence of North Carolina at Chapel Hill with a such as threats, suicidal ideation and domestic bachelor’s degree in journalism and earned violence. To keep the situation from escalating, her master’s in public administration from bullying interactions should be immediately Georgetown University. She worked for the documented and reported to Civil. To contact federal government for more than 30 years, a Civil Program coordinator, call 301-40C-IVIL (301-402-4845). most recently in the NCI communications Linda Frances Anderson, NCI alumna office and continuing after retirement as a Civil is part of the Office of Human Resources private contractor. and as such, is not confidential nor does it have an anonymous link or email address to report She was a member of several informal beach and bridge clubs, played on USTA-ranked concerning behavior. However, for situations teams (later officiating) and was a long-time member of the Ski Club of Washington D.C. where employees wish to talk about concerns and Same Time Next Year Club. She was an avid supporter of the Shakespeare Theatre, the and action plans in a confidential setting, National Symphony Orchestra, the White House Christmas decorating group, Hillwood they can contact the Employee Assistance Estate & Museum and Brookside Botanical Gardens. Program (301-496-3164) or the Office of the Ombudsman (301-594-7231). Civil is also not She is survived by siblings Sharon Anderson of Bryan, Tex.; Robin Conrad of Moss Bluff, a substitute for calling 911 when police or La.; Janet Anderson of League City, Tex.; and James R. Anderson of Sugarland, Tex.; and by emergency help is needed. two nephews and five grandnieces. She is also survived by her husband Frank Wilson of St. Mary’s, Ga.; stepdaughters Elizabeth Reichbart of New Jersey and Kate Wilson of North Carolina and six grandchildren. Anderson was laid to rest in Lake Charles, alongside her parents. Memorial donations can be sent to Hillwood Estate & Museum, 4155 Linnean Avenue, NW, Washington, D.C. 20008. VOLUNTEERS CC Program Assistant Frazier Dies Rhea Moore Frazier, program assistant in the Office of Clinical Vaccine Study Needs Healthy Research Training and Medical Education (OCRTME), passed away Volunteers on May 30 at the age of 69. Researchers at NIAID’s Vaccine Research Frazier joined OCRTME in 2009 and provided essential admin- Center need healthy volunteers 18-50 who istrative and program support services to allow OCRTME to fulfill are interested in participating in HIV vaccine its mission within the Clinical Center. She was also responsible development. Participants are not exposed to for communicating with medical students, physicians, researchers HIV and compensation is provided. To learn and administrators within NIH, and with extramural organiza- how to participate, call the Office of Patient Recruitment at 1-866-444-2214 (TTY 1-866-411- tions, institutions of higher education and training partners on 1010). Read more at https://go.usa.gov/xN9SQ. behalf of OCRTME. Refer to study 17-I-0030. Frazier will be greatly missed by her colleagues; she will be Rhea Moore Frazier remembered for her contributions to the professional development of her team and the next generation of clinician-scientists.

NIH RECORD • JUNE 30, 2017 • 11 SEEN

Above left, Vaccine Research Center deputy director Dr. Barney Graham (r) shows Bill Gates a molecule model produced using NIH’s 3-D print technology. In the center photo, wearing virtual reality goggles, Gates explores key immunologic epitopes of an influenza H1 hemagglutinin molecule, used to target next generation influenza vaccines, color coded to show the binding footprints of a set of broadly neutralizing antibodies (yellow), as well as several glycosylation sites (red). On his left is Dr. Phil Cruz, a structural biologist in NIAID’s Office of Cyberinfrastructure and Computational Biology, who collaborated with the translational sciences core in the Viral Pathogenesis Laboratory to adapt molecular structures for 3-D printing and VR visualization. At right, Gates talks with VR team member James Tyrwhitt-Drake (l), scientific visualization specialist in the NIAID Office of Cyberinfrastructure and Computational Biology, who put molecules into the VR software.

NIH Hosts 4th Workshop with Gates Foundation

For the fourth consecutive year, the Bill & Melinda Gates Foundation teamed with NIH for a consultative global health workshop. On June 2, researchers from the foundation, NIH and other federal agencies, academia and the public sector gathered for a full day of panel discussions on several topics including vaccine research and development on human papillomavirus prevention and therapy and structure-based immunogen design, point-of- care diagnostics for low-resource settings and the emergence of a coalition for African research and innovation. Foundation cochair and trustee Bill Gates, NIH director Dr. Francis Collins, NIAID director Dr. Anthony Fauci, Fogarty International Center director Dr. Roger Glass and NIBIB director Dr. Roderic Pettigrew were among officials on From left, Gates, NIH director Dr. Francis Collins, NIAID director Dr. hand for the session. Anthony Fauci and FIC director Dr. Roger Glass listen in on presentations at the recent global health workshop. While here, the world renowned IT pioneer and philanthropist Gates got to sample a bit of tech wizardry used at the Vaccine Research Center. Gates The day ended with working group/breakout sessions on such subjects as donned virtual reality goggles for a demonstration of how scientists explore HIV/AIDS; malaria and neglected tropical diseases; tuberculosis; maternal, the molecular structures of influenza in 3-D. A handheld molecule—produced neonatal and child health; pneumonia, enteric diseases and indoor air via 3-D printing technology—was also passed around. pollution; and contraceptive research.

ABOVE: Shown with Gates are (from l) Collins, Fauci and VRC scientists Dr. Mario Roederer, Dr. John Mascola, Dr. Rick Koup, Dr. Michelle Crank, Dr. Nancy Sullivan, Graham, and Dr. Marybeth Daucher. At right, NIBIB director Dr. Roderic Pettigrew, who moderated a panel session on point-of-care diagnostics for low- resource settings, chats with Gates.

PHOTOS: LISA HELFERT

12 • NIH RECORD • JUNE 30, 2017