The Shutdown the Human Microbiome Project Its Impact on NIH

Home , Human microbiome, Human microbiome project

NATIONAL INSTITUTES OF HEALTH • OFFICE OF THE DIRECTOR | VOLUME 21 ISSUE 6 • NOVEMBER-DECEMBER 2013

The Shutdown The Human Microbiome Project Its Impact on NIH ... And the Intramural Connection BY RICH MCMANUS, OD BY JOSEPH TIANO, NIDDK

On October 23, 2013, NIH Direc- There are 10 times as many tor Francis Collins held an hour-long bacteria, viruses, fungi, and town hall meeting in which he con- protozoa–collectively known as demned the effects of an “unnecessary the microbiome–living on and and ultimately pointless shutdown” that inside the human body as there closed the government October 1–16 are human cells. Although sci- NHGRI BAILEY, JONATHAN and idled 75 percent of the NIH work- entists have been aware of the force. He outlined a steadily deteriorat- microbiome for more than 30 ing political landscape that has included years, they knew little about multiple threats of shutdown, then the its diversity and role in human reality of budget sequestration, culminat- health and disease. Research- ing in a 16-day shutdown coinciding with ers tended to focus on disease- the start of FY2014. Federal regulations causing bacteria, and only 10 to The Human Microbiome Project, which was launched by NIH in 2007, provided the first glimpse of the microbial diversity of healthy humans and is barred any but “excepted” employees— 20 percent of these bacteria can exploring the possible relationships between particular human diseases those with responsibility for the preser- be cultured in the laboratory. and the microbiome. (Clockwise from top left): Streptococcus (Credit: Tom Schmidt); microbial biofilm of mixed species, from human body (Credit: vation of life (human and animal) and In 2005, at an international A. Earl, Broad Institute/MIT); Bacillus (Credit: Tom Schmidt); Malassezia property—from coming to work. Collins meeting in Paris, scientists pro- lopophilis (Credit: J.H. Carr, CDC). also answered questions submitted by the posed using state-of-the-art audience and via e-mail. genomic sequencing techniques There was, however, a silver lining to the to catalogue all the bacteria living on and inside the human body. They also discussed shutdown debacle, Collins said. “NIH was forming a consortium to catalogue the intestinal microbiome and its role in human health mentioned over and over again” in the media and disease. as a national treasure worth preserving; sev- On December 19, 2007, the NIH launched the Human Microbiome Project (HMP), eral members of Congress even introduced a two-phased, eight-year, $194 million initiative to support such an effort. The Intramural bills to reopen NIH during the shutdown. Research Program has been involved since the get-go and continues to participate. Looking to the new year, Collins noted Phase One of the HMP focuses on a survey of the microbiome in five areas of the “the only certainty these days is uncertainty,” body—the digestive tract, mouth, skin, nasal cavity, and vagina—and consists of two kinds but held out hope that congressional budget of cohort studies: the Healthy Cohort Study and a collection of Demonstration Projects. negotiators can reach a solution that includes CONTINUED ON PAGE 10 the abolition of sequestration. Collins said he was inspired by “the CONTENTS enthusiasm and commitment” of an NIH FEATURES • |1| The Shutdown |1| Microbiome |6| HIV and AIDS: Anthony Fauci |7| NEI: workforce that returned on October 17. He What Wei Li Is Learning from Squirrels |9| An Unlikely Route to Translational Research enumerated triumphs including a decision DEPARTMENTS • |2| DDIR: Recovering from the Shutdown |3| News You Can Use: NIH not to ditch the October grant-submission Library Offers Customized Services|4| Training Page |5| New Methods: New Microscopes

CONTINUED ON PAGE 14 That Capture Live Cellular Processes in 3-D |8| Research Briefs |9| Abbreviations |12| SIG Beat: Special Feature on Proteostasis |15| Announcements |16| Back Page: Sammies Winners FROM THE DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH

Recovering From the Shutdown: The Toll on Biomedical Research BY MICHAEL GOTTESMAN, DDIR

NIH is the largest purely biomedi- illnesses were accepted into existing proto- to being a biomedical research enterprise, cal research facility in the world, with cols—instead of the usual 200 new patients NIH is the largest training facility in the about 2,500 individual research projects per week. Only one of seven new proto- world for future biomedical researchers. and close to 1,500 clinical protocols. But cols was initiated. Elsewhere at NIH, all Right now we have approximately 4,000 during the 16-day federal government population-based and lab-based research postdoctoral fellows, 800 postbaccalaureate shutdown in October, the NIH Intra- was stopped. Still, every effort was made students, 500 graduate students, and 45 mural Program (IRP) was profoundly to assure that when the shutdown ended medical students. For many of these train- affected. Its loss of progress is a big deal. we could restart experiments as soon as ees, time is of the essence. Their appoint- Only 15 to 20 percent of IRP staff was possible. ments are time-limited (less than one year “excepted” from furlough so they for the medical students, up to two could protect life (mostly in the The government shutdown’s years for the postbac students, and Clinical Center, where 75 percent impact on NIH was enormous. usually three to four years for the of the staff were allowed to work), postdocs and grad students). Loss guarantee safety (infrastructure of a few weeks of work and mentor- support including security and the power Although NIH leadership has tried to ing as well as loss of a few more weeks of plant), and protect large investments in ameliorate the effect of the shutdown on our momentum—while cell lines are started up materials and property (in the lab, that physical property, the impact on the science again, animals are bred, and experiments meant animals, cell cultures, and expen- conducted at the NIH and on our scien- that may have suffered in the shutdown are sive equipment). tists was enormous. Biomedical research repeated—represent a significant percent- There was also a skeleton crew of senior is a continuum of experimental activity in age of a research experience that could leadership (most institute and center direc- which past experiments are evaluated, cur- affect their future careers. tors, scientific directors, clinical directors, rent experiments are being conducted, and There were other missed opportuni- and NIH deputy directors) to oversee the new experiments are being planned. All ties that we may not be able to recover. shutdown. Other staff were called back as must occur concurrently; breaks in ongoing Because of travel restrictions on all gov- needed to ensure that the huge intramu- experiments sometimes ruin years of work, ernment employees, arranging for travel ral investment of time, labor, and money requiring researchers to start over. to scientific meetings was already diffi- in science was not wasted. Owing to the Scientific effort doesn’t occur in a cult. During the shutdown, all travel was hard work of the NIH community, we vacuum, but requires interaction with other cancelled, and many NIH scientists had weathered this manmade disaster and are scientists. It is a creative, interactive, intel- to forgo important talks that they had now happily back at work. lectual activity that cannot simply be turned been invited to give. Furthermore, we NIH intramural research includes lab- off and on like a faucet. Dedicated NIH had to cancel many important lectures based, clinical, and population-based proj- scientists are thinking constantly about their that were supposed to occur at the NIH ects. During the shutdown, all new projects work, analyzing their results, generating in early October including a talk by Bill were put on hold and ongoing ones were hypotheses, and designing and conduct- Gates, Nobel Laureate Shinya Yamana- halted so we could spare any large losses in ing new experiments. Not being able to do ka, and Institute of Medicine President investments. At the NIH Clinical Center, research is uncomfortable and demoralizing Harvey Fineberg. The Research Festival ongoing clinical protocols continued, but and leads to the loss of momentum. was delayed and certain aspects—such as only 25 new patients—including seven The shutdown took a toll on our train- the graduate student component—were children—with serious or life-threatening ing programs and trainees too. In addition eliminated.

2 THE NIH CATALYST NOVEMBER-DECEMBER 2013 NEWS YOU CAN USE

NIH Library “Custom Information Solutions” Service BY MASHANA DAVIS, NIH LIBRARY

The NIH Library provides ready The IADRP allows users to search access to thousands of resources, so much funded projects by principal investigator, so that it may be difficult to find the best institution, funding agency, and funding resources for your research needs. The announcement. Access to such information Library recently introduced a new service, allows program officers and researchers from What are the long-term effects? “Custom Information Solutions,” that can around the world to: • Because of the delay and interrup- customize services and resources to address • Assess the changing landscape of tion in research, some of our scientists the specific needs of a group. Services Alzheimer disease research funded by dif- will lose their competitive edge and may include digitizing print materials; build- ferent agencies and countries. miss opportunities to get their work pub- ing databases to support research projects; • Identify funding gaps as well as areas lished in the most highly visible journals developing portfolio-analysis reports; and of possible overlap across funding agencies. and presented at important national and creating customized Web search tools. • Identify opportunities for coordina- international meetings. The National Institute on Aging (NIA) tion for Alzheimer disease research while • There was major inconvenience began using the service in 2011 in connection leveraging critical resources. because invitations, events, and other with its work on Alzheimer disease (AD). It For NIA, the funding information from activities had to be rescheduled. This began with a request to convert a spreadsheet the IADRP has helped to track and analyze rescheduling means doubling the amount of funding lines into a simple Web-enabled research goals and strategic objectives. of work many people had to do for the database. In June 2013, the IADRP team, includ- same activity. Alzheimer disease research has become ing NIH Library representatives James King • There was some loss in research a global priority requiring enhanced coor- and Terrie Wheeler, was presented with investment because experiments may have dination of funding strategies across both the NIH Director’s Award in recognition to be restarted. We have tried our best to public and private funders. Supported by the of “the planning and implementation of an ameliorate this problem, but it is inevitable “National Alzheimer’s Project Act” (http:// AD research initiative in response to the that some research dollars were wasted at aspe.hhs.gov/daltcp/napa), NIA first worked National Alzheimer’s Plan.” a time when budgets are very tight. with the Alzheimer’s Association to develop “Throughout the entire process, the • Although we have done our best to a shared ontology known as the Common NIH Library has gone above and beyond sustain the NIH research enterprise, we Alzheimer’s Disease Research Ontology. to provide outstanding customer service,” are concerned about the effect on recruit- Later, NIA began working with the NIH said NIA Senior Scientific Program Analyst ment in the future when trainees and more Library to develop a database to capture and Charlene Liggins. senior faculty are making decisions about track more than 6,000 Alzheimer-related The NIH Library is also collaborating where to apply and what offers to accept. grant-funded projects (2008 to the present) with the National Institute of Allergy and across all U.S. federal agencies and three non- Infectious Diseases to develop a pandemic My positive message to our current and federal funders. Discussions are now under influenza digital archive, which will be avail- future scientific staff is that even under the way with other organizations and countries. able to researchers within and outside NIH. most severe of circumstances—a complete As a result of months of consultations government shutdown—we have managed and support from the NIH Library, the The NIH Library, located in Building 10, to persevere, the public has become more NIA decided to pursue the library’s proposed supports the information needs of the NIH aware of the important work that we do, portfolio-analysis strategy. The first phase research community. For more information and we are back pursuing our mission of of this effort culminated in the July 2012 about the library go to http://nihlibrary.nih. conducting research to improve the public launch of the International Alzheimer’s Dis- gov/Pages/default.aspx. For more informa- health. We will be better prepared if this ease Research Portfolio, or IADRP (http:// tion on “Custom Information Solutions,” visit kind of lapse in funding happens again iadrp.nia.nih.gov/cadro-web). http://nihlibrary.nih.gov/Services/Pages/Cus- (hopefully not). tomInformationSolutions.aspx.

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

FROM THE OFFICE OF INTRAMURAL TRAINING AND EDUCATION Training to Work Well With Others BY LORI CONLAN AND SHARON MILGRAM, OITE

According to the book Lab Dynamics, a good fit for scientists looking for more For Further Reading: nearly two-thirds of scientists surveyed information on the MBTI. 1. C. Cohen and S. Cohen, Lab Dynamics: reported that interpersonal conflict had Conflict is perhaps the most stressful Management Skills for Scientists (Cold Spring hampered progress on a scientific project topic, with many trainees feeling they lack Harbor Press, New York, 2005) one to five times in their career. So how resources for dealing with and defusing con- 2. Myers-Briggs Type Indicator: http:// can we train scientists to work well with flict in the workplace. We use the Thomas- www.myersbriggs.org others and manage conflicts in order to Kilmann Conflict Mode instrument to help 3. MBTI articles: http://www.capt.org/ accomplish more science? After exten- participants identify the conflict style they research/MBTI-bibliography-search.htm sive discussions with mentors, trainees, use and the styles they struggle with. Other 4. O. Kroeger, J.M. Thuesen, and H. Rut- students, fellows, career counselors, and resources on conflict management include ledge, Type Talk at Work (Revised): How the experts in leadership development, the Becoming a Conflict Competent Leader, which 16 Personality Types Determine Your Success OITE developed workshops to provide an provides a way to explore the triggers that on the Job (Dell, New York, 2002) education in leadership and management. cause conflict and guidelines for approaching 5. Thomas-Kilmann Conflict Mode Instru- The resultingWorkplace Dynamics series the conflict constructively instead of destruc- ment (Xicom, Tuxedo, N.Y., 1974). (https://www.training.nih.gov/leadership_ tively; Crucial Confrontations, which provides 6. CPP Thomas-Kilmann Conflict Mode training) focuses on increased awareness tips on preparing for difficult conversations Instrument product page: https://www.cpp. of self and others using the Myers-Briggs and tense negotiations; and the Center for com/products/tki/index.aspx Type Indicator; communication styles and Creative Leadership’s method, “Situation, 7. C.E. Runde and T.A. Flanagan, Becoming influencing others; conflict dynamics; team Behavior and Impact,” to provide specific a Conflict Competent Leader: How You and theory; and diversity training. Our goal is feedback to both the giver and the receiver. Your Organization Can Manage Conflict to help participants gain self-awareness and We also include an introduction to diver- Effectively(Jossey-Bass, San Francisco, 2006) an appreciation that others may tackle prob- sity and difference because we all have a 8. K. Patterson, J. Grenny, R. McMillan, lems and approach conflict and group work responsibility to develop a scientific work- and A. Switzler, Crucial Confrontations differently. We augment the content and force that is diverse and welcoming. Mate- (McGraw-Hill, New York, 2004) examples with lab-based examples, which rials on diversity can be found in Readings 9. Center for Creative Leadership and S. resonate better with scientists. About 500 for Diversity and Social Justice, Third Edition. Weitzel, Feedback That Works: How to Build trainees have participated in the series, For trainees looking at an academic facul- and Deliver Your Message (Pfeifer, Somerset, and we have begun offering the training ty job, there are even resources for them. The N.J., 2007); http://www.ccl.org/leadership/ at national meetings such as Experimental Burroughs Wellcome Fund and the Howard pdf/community/SBIJobAid.pdf Biology. Some of our NIDDK and NHLBI Hughes Medical Institute’s Making the Right 10. M. Adams, W. Blumenfeld, C. Cas- fellows described their experiences with the Moves and Kathy Barker’s At the Helm offer taneda, and H.W. Hackman, Readings for series in their institute newsletters. practical advice on becoming a new faculty Diversity and Social Justice, Third Edition We learned that our trainees appreciate member and managing your staff. (Routledge, New York, 2013) workshops but also like to receive informa- 11. Burroughs Wellcome Fund and tion on resources on management topics. Howard Hughes Medical Institute, Many of these resources are available in the Adapted with permission from L. Conlan and Making the Right Moves: A Practical OITE Career Library on the second floor S. Milgram, “Workplace Dynamics: Under- Guide to Scientifıc Management for Postdocs of Building 2 on the Bethesda campus as standing How to Work Together in Research and New Faculty (Burroughs Wellcome well as in the libraries of satellite campuses. Environments,” Physiologist, 56:76–77, 2013; Fund, Research Triangle Park, N.C., There are a variety of personality assess- available online at http://www.the-aps. 2006); http://www.hhmi.org/resources/ ments, but we use the MBTI because it is org/mm/Careers/Mentor/Managing-a- labmanagement/moves.html widely used in academic and industry set- Lab-and-Personnel/Postdoctoral-Fellows/ 12. K. Barker, At the Helm (Cold Spring tings; we find that “Type Talk at Work” is Supervising-staff-/Workplace-Dynamics. Harbor Press, New York, 2010)

4 THE NIH CATALYST NOVEMBER-DECEMBER 2013 NEW METHODS

New Microscopes That Reveal Live Cellular Processes in 3–D May Help Scientists Observe How Viruses Attack BY JESSICA MEADE, NIBIB

NIH researchers have developed Most high-resolution two new high-resolution microscopes, microscopes, including both the first of their kind. The first— SIMs, use imaging soft- an instant linear structured illumina- ware to capture, store, tion microscope (iSIM)—captures and combine multiple high-resolution images of small, fast- camera exposures into moving cellular structures in real time. crisp, exquisitely detailed The second—a dual-view inverted images. Shroff and his selective plane illumination microscope lab equipped an iSIM (diSPIM)—displays large cell sam- microscope with power- NIBIB COURTESY: ples in three dimensions (3-D) while ful lenses and mirrors to decreasing the amount of harmful light produce high-resolution that cells are exposed to during imaging. images from the original

exposures more quickly. The resolution differences between standard microscopy (top) and SIM tech- Instant super resolution imaging “Before, we relied on nology (bottom) can be clearly seen. “Much of biology depends on the move- computer software and ment of very small proteins finding each algorithms to do things like sort through To fix this problem, Shroff, NIBIB other and interacting,” said Hari Shroff, hundreds of images, eliminate out-of-focus staff scientistYicong Wu, and colleagues chief of the High Resolution Optical light, and combine the individual images from NIH and other institutions devel- Imaging Lab in the National Institute of together,” said Shroff. The process was oped the dual-view inverted SPIM (Nature Biomedical Imaging and Bioengineering time consuming and could take hours Biotechnol DOI:10.1038/nbt.2713). The (NIBIB). “We really need to look at how or even days. “Now, we can do most of diSPIM can image cellular processes at things move in a live cell.” that optically with the microscope itself.” high speed without causing extensive light But it’s difficult to obtain good qual- In addition, the iSIM data use only one damage. Two detection cameras, set at a ity, high-resolution images in a living, percent of the hard-drive space that other 90-degree angle to each other, capture per- moving cell. Traditional linear structured types of high-resolution microscopes do. pendicular views of each sample. With illumination microscopy (SIM), which relatively simple modifications, traditional can provide high resolution in a fixed cell, The diSPIM single-camera SPIMs can be converted stumbles when it comes to imaging ele- The second microscope builds on tech- into the dual-camera diSPIM. ments moving quickly in a live cell. The nology called selective plane illumination But to combine the images from the higher the resolution, the harder it is to microscopy (SPIM) that uses a thin beam two cameras, the scientists had to create a eliminate the blur that comes from light of light to illuminate only a single plane of new post-processing software algorithm. diffraction and motion. tissue at a time. (Traditional microscopes With the diSPIM microscope, scien- Shroff and research fellowAndrew York expose a whole sample to light that can tists can obtain high-resolution images of (NIBIB), along with other NIH scientists, damage or even kill biological samples.) live cellular processes—such as fast-moving developed the iSIM to address these prob- The SPIM then rotates the sample so it viruses, migrating cancer cells, and inter- lems. Building on traditional SIM technol- can be imaged from many angles to create acting neurons—in a 3-D environment. ogy, the iSIM allows real-time, 3-D super a 3-D effect. “As scientists, it’s up to us to find ways resolution imaging of live cellular processes But the rotation process slows the imag- to observe cells as accurately as possible,” such as blood cells racing through a zebraf- ing speed, making it difficult to capture live Shroff said. “There are a lot of biological ish embryo. This kind of imaging is impos- cellular motion. Ironically, the sample is still processes that we can’t understand without sible with other microscopes (Nature Meth at risk of light damage because it is repeat- observing them and that’s something these 10:1122–1166, 2013). edly illuminated as each plane is imaged. devices can help us do.”

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

HIV and AIDS: Much Accomplished, Much to Do Says NIAID Director Anthony Fauci, One of the First to Study AIDS BY REBECCA G. BAKER, NIAID

Investigation, leaders in immunological of the estimated one million HIV-infected research: his mentor and lab chief, the late people have been diagnosed. Of the total Sheldon “Shelly” Wolff; John Gallin (now infected, only 66 percent receive care and the director of the NIH Clinical Center); 33 percent receive ART. Thanks to treat- and Charles Dinarello (no longer at NIH, ment, an estimated 25 percent of all HIV- but considered one of the founding fathers of infected persons in the United States have cytokine biology). When Fauci began read- a suppressed viral load. But many effective ing reports of AIDS cases, he soon made treatments and preventions fail to achieve the bold decision to redirect his lab’s focus their full potential because “people are not from investigating fundamental questions of adhering to something that works,” Fauci COURTESY: NIAID In a recent lecture, NIAID Director and AIDS pioneer Anothony immunology to studying HIV and AIDS. said. “We need to link human behavior Fauci celebrated the many advances made in HIV and AIDS He assembled a research team—Clifford research with biomedical interventions.” research but said there was still “much to do.” Lane (NIAID) and Henry Masur (Clinical Regarding the possibility of a cure for Center)—to investigate HIV and AIDS, HIV, Fauci explained that if one is found, Even though more than four million and together they made breakthroughs in it must be simple, safe, and expandable to lives have been saved, “it’s clearly too understanding how HIV destroys the body’s millions of people. In addition, he called soon for a victory lap” in the fight against immune system and in developing strat- for “new tools for prevention.” human immunodeficiency virus (HIV) egies to restore immune defenses. Other One of the new tools might one day be and AIDS, said Anthony Fauci, one of NIH pioneers included Robert Gallo, an HIV vaccine. Indeed, scientists at NIH the first scientists to begin studying HIV who co-discovered HIV and identified it and elsewhere are working to develop one, and AIDS when the illness emerged in as a cause of AIDS, and scientists in the but they face many challenges. In classical the early 1980s. A pioneer in understand- National Cancer Institute’s (NCI) AIDS vaccinology, vaccinologists develop vaccines ing human immunological diseases, Fauci Therapy Program. These includedRobert by copying “the body’s immune response to has led extensive basic and translational Yarchoan, Sam Broder (later became direc- the pathogen,” Fauci explained. “But it’s not research exploring HIV and AIDS. tor of NCI), and Hiroaki Mitsuya, who the same with HIV because the body is not At the September 11, 2013, Clinical together developed the first FDA-approved capable of responding adequately.” Center Grand Rounds Great Teachers antiretroviral therapies (ART). The world’s first HIV vaccine trial was Lecture, Fauci recalled his early research Globally, about 35 million people are led by Lane at NIH in 1988. Recently an in the immune-mediated and infectious dis- living with HIV infection, and 2.3 mil- HIV vaccine trial in Thailand has shown eases; saluted his NIH mentors; and offered lion are newly infected each year. Fauci some promise, but, Fauci cautioned, “It’s a tour de force of the current state of HIV expressed pride in research advances that not ready for prime time.” and AIDS prevention and treatment and have led to therapies that have prevented Fauci celebrated the many advances research efforts toward a cure. 4.2 million deaths. He outlined successful in HIV and AIDS research, trumpeting Fauci has been the director of the prevention strategies, including condom use them as “great news about the translation National Institute of Allergy and Infec- and behavior modification, pre-exposure of basic science to effective clinical interven- tious Diseases (NIAID) since 1984 and prophylaxis, voluntary medical circumci- tions.” Yet there remains “much to do, both serves as one of the key consultants to the sion for adult men, and early intervention to implement what we already have and in White House and Department of Health with ART. Untreated HIV almost always the discovery of new interventions.” and Human Services on global AIDS issues progresses to AIDS. as well as on emerging infectious disease Fauci is discouraged that it has been threats such as pandemic influenza. difficult to implement the strategies even To watch a videocast of Fauci’s talk “HIV/AIDS: He waxed eloquent about his former col- though they are known to be effective. In the Much Accomplished, Much To Do,” go to http:// leagues in NIAID’s Laboratory of Clinical United States, for example, only 82 percent videocast.nih.gov/launch.asp?18075.

6 THE NIH CATALYST NOVEMBER-DECEMBER 2013 FEATURE

Understanding the Human Retina Through the Eyes of a Ground Squirrel BY DUSTIN HAYS, NEI

Why is NIH scientist We i L i human retina are dominated by cone pho- ground squirrels’ retinal mitochondria studying a fanciful species of ground toreceptors. The retinas of most mammals during hibernation. SBEM allows for three- squirrels to understand the human eye? are made up mostly of rod photoreceptors, dimensional reconstruction of subcellular For one thing, both humans and the which are good for night vision but cannot structures through repeated fine-resolution thirteen-lined ground squirrel (Sper- discern color. scans. After each scan, a very thin layer (less mophilus tridecemlineatus), so named for Li and NEI staff scientistShan Chen than 30 nanometers) of the cell is cut away its beautiful pattern of white stripes, can were lauded in 2012 when they reported in and the underlying surface is scanned. A see in color. That’s something that most Nature Neuroscience the discovery of a unique computer program then assembles hundreds mammals can’t do. And when the ground type of neuron in the retina of the thirteen- of scans to construct a three-dimensional squirrels hibernate, their eyes experience lined ground squirrel that helps encode color representation—a little like reconstructing the same kind of metabolic stress that vision (Nat Neurosci 15:954–956, 2012). For a loaf of bread from individual slices. human eyes do when they have certain years, researchers suspected the existence of Li’s preliminary SBEM work shows that retinal disorders. an interneuron that modulates signals from the mitochondria inside the photoreceptors As a senior investigator at the National cone photoreceptors that principally capture look like tightly packed cable strands. He Eye Institute (NEI) and chief of the Retinal blue light. Li conceived of a technique to suggested that this orientation may help Neurophysiology Unit, Li studies how the hunt for such cells among retinal interneu- conduct light, similar to the way a fiber synaptic circuits in the retina are normally rons called amacrine cells, of which there optic cable works. He is collaborating with wired and how they are altered by disease. are 30 types. Chen painstakingly probed Robert Balaban, the scientific director of the On September 12, 2013, he presented his individual amacrine cells, measuring their National Heart, Lung, and Blood Institute, work at the annual Sayer Vision Research response to alternating blue and green light. to correlate retina structural changes with Lecture, which features scientists who have Li and Chen eventually found one type— functional changes such as enzymatic activity. made major contributions to vision research. the S-cone amacrine cell—that attenuates Uncovering the mechanisms that ground The retina, the light-sensitive layer transmission from blue cones. They suspect squirrels use to recover from hibernation lining the inside of the eye, contains two that the newly identified cells likely have a may help us understand metabolic stress that types of photoreceptors: rods, which are similar function in humans. occurs in human diseases of the retina such sensitive to changes in light, and cones, Li also suspects that hibernation- as diabetic retinopathy, age-related macular which are sensitive to color. The ground induced metabolic stress is similar to the degeneration, and retinitis pigmentosa, Li squirrel retina and the central region of the metabolic stress that occurs in retinal eye said. “Our hope is that these tricks will point diseases. When ground squirrels to therapeutic solutions for humans.” hibernate in winter, their retinas are subjected to a long period The Sayer Vision Research Fund was estab- of challenging metabolic condi- lished in 2006 at the Foundation for the tions. The retinal neurons power National Institutes of Health by Jane M. Sayer, down during hibernation, but a research scientist with NIDDK. In partnership their function is quickly restored with NEI, the fund supports the Sayer Vision when the animals awaken. Li Research Lecture Series, given by a scientist of wants to know how these seem- national or international prominence in a dis- ingly fragile circuits rebound so cipline with relevance to vision research. From quickly. time to time, the fund also supports an award COURTESY: NEI to a promising young NIH investigator in eye Ground squirrel photoreceptor mitochondria: (left) cross section of the ground Li is using serial block face squirrel retina, focusing on the photoreceptor layer and cones; (top right) scanning electron microscopy research, of which Wei Li is the first recipient. scanning electron microscopy image of photoreceptor mitochondria; (lower For more information visit http://www.nei.nih. right) 3-D reconstruction of mitochondria in a single cone photoreceptor. (SBEM) to explore the structural changes that occur in the gov/news/special/sayer.asp.

http://irp.nih.gov/catalyst 7 FEATURECATALYTIC RESEARCH Intramural Research Briefs

life span. The drug is derived from hydroxyl- ited by vaccination. Early-stage clinical trials amine, a molecule chemically similar to ammo- are planned. (NIH researchers: J.S. McLellan, nia. Hydroxylamine is toxic, but a slight change P.D. Kwon, B.S. Graham, and others; Science in the molecule’s chemical structure results in 342:592–598, 2013; and NIH researchers: J.S. a nontoxic molecule, called NtBuHA, short for McLellan, P.D. Kwon, B.S. Graham, and others; N-(tert-Butyl)-hydroxylamine. The researchers Science 340:1113–1117, 2013) hope NtBuHA will be useful for treating a particular subtype of the disease, infantile Batten NIDDK, CIT: MOLECULAR STRUCTURE OF disease. Children with this form of the dis- AMYLOID PLAQUES ease have a genetic deficiency of the enzyme Alzheimer disease (AD) is thought to be caused palmitoyl-protein thioesterase-1, which ordi- by abnormal protein deposits called amyloid

COURTESY: NIAID narily breaks down ceroid, a waxy substance. plaques in the brain. Until recently not much The respiratory syncytial virus (RSV) is responsible for a The researchers are also evaluating two other has been known about the molecular struc- common childhood illness. NIAID and VRC scientists have drugs—cysteamine bitartrate and acetylcyste- tures of the amyloid-beta (A-beta) fibrils within developed a candidate vaccine that show promise in animals and plan to conduct early-stage clinical trials in the future. ine—for the treatment of the disease. (NICHD these plaques. NIDDK and CIT investigators, authors: C. Sarkar, G. Chandra, S. Peng, Z. together with colleagues from the University NHLBI: ENTEROVIRUSES NEED CHOLES- Zhang, A. Liu, and A.B. Mukherjee; Nature Neu- of Chicago, have now developed methods for TEROL TO REPLICATE rosci 16:1608–1617, 2013) determining the molecular structures of A-beta Researchers at NHLBI discovered that the fibrils in brain tissue of AD patients, based on Enterovirus genus of viruses—which includes NIAID, VRC: CANDIDATE VACCINE AGAINST solid-state nuclear magnetic resonance spec- human pathogens such as polioviruses, Cox- RESPIRATORY SYNCYTIAL VIRUS troscopy. The investigators examined fibrils sackie viruses, and rhinoviruses (which cause An experimental vaccine to protect against grown from brain tissue of two AD patients the common cold)—depend on cholesterol for respiratory syncytial virus (RSV), a leading with different clinical histories and found that replication. These viruses actively rewire the cause of illness and hospitalization among each patient had developed a single fibril endocytic membrane trafficking pathways of very young children, elicited high concentra- structure, but that fibril structures in the two host cells to maximize cholesterol absorption tions of RSV-specific antibodies when tested patients were different from each other. More- and delivery to their replication platforms. in animals, according to NIH researchers. The over, fibrils that developed in brain tissue were By targeting the viral and host factors that scientists built on their previous findings about different from fibrils grown in the test tube. are required for cholesterol absorption and the structure of a critical viral protein to design The work represents the first detailed anal- delivery to the replication platforms (as iden- the vaccine. Earlier this year, the VRC team ysis of the molecular structures of the deposits tified in this study), scientists may be able to obtained atomic-level details of an RSV pro- that develop in AD patients’ brains. Information develop panviral therapeutics that can block tein—called the fusion (F) glycoprotein—bound gathered from examining molecular structures the replication of many different enteroviruses to a broadly neutralizing human RSV antibody. of A-beta fibrils may provide a way to accu- in humans. (NHLBI authors: M. Santiana, W.-L. Before it fuses with a human cell, the F glyco- rately diagnose mild cognitive impairment Du, Y.-H. Chen, N. Altan-Bonnet; Cell Host protein contains a region vulnerable to attack in still-living AD patients, allowing for early Microbe 14:281–293, 2013) by broadly neutralizing antibodies. intervention and potential inhibition of disease The researchers used this information to progression. The findings pave the way for new NICHD: NEW DRUG COULD SLOW PROGRESS design and engineer F glycoprotein variants patient-specific strategies to improve diagnosis OF FATAL CHILDHOOD DISORDER that were then used as vaccines in experiments and treatment of this common and debilitat- Batten disease is a fatal, inherited disorder of in mice and rhesus macaques. It turned out ing disease. (NIH authors: J.-X. Lu, W. Qiang, the nervous system that typically begins in that the more stable the protein, the higher the W.-M. Yau, C.D. Schwieters, and R. Tycko; Cell childhood. NICHD researchers have identified a concentration of neutralizing antibodies elic- 154:1257–1268, 2013) potential new drug that could help in the treatment of a form of the disease. When tested in CONTRIBUTORS: KRYSTEN CARRERA, Read more online at http://irp.nih.gov/ mice, the drug slowed the loss of coordination NIDDK; NICHOLAL ZAGORSKI, NHLBI catalyst/v21i6/research-briefs. seen in the disorder and extended the animals’

8 THE NIH CATALYST NOVEMBER-DECEMBERSEPTEMBER-OCTOBER 2013 2013 NIH ABBREVIATIONS CATALYTIC RESEARCH CBER: Center for Biologics Evaluation and Research, FDA CC: NIH Clinical Center From Zoo to Bedside CCR: Center for Cancer Research, NCI An Unlikely Route to Translational Research CDC: Centers for Disease Control and Prevention BY JENNIFER SARGENT, NIAMS CIT: Center for Information Technology DCEG: Division of Cancer Epidemiology and Genetics, NCI

R. STOWE, WIKIMEDIA COMMONS WIKIMEDIA STOWE, R. DOE: Department of Energy Koalas—those docile, undeniably FAES: Foundation for Advanced Education cute Australian marsupials—are a threat- in the Sciences ened species. Ever since the British colo- FelCom: Fellows Committee FDA: Food and Drug Administration nization of Australia in the late 1700s, FNL: Frederick National Laboratory these adorable creatures have suffered IRP: Intramural Research Program immensely, and their populations have HHS: U.S. Department of Health and Human Services been reduced as a result of their native NCATS: National Center for Advancing habitats being destroyed. Translational Sciences But a new, more insidious danger has NIMH scientist Maribeth Eiden is doing research that may NCCAM: National Center for lead to the optimization of gene-delivery vectors in humans Complementary and Alternative Medicine emerged in the last century—a cancer-caus- as well as ways to prevent deadly viral attacks in koalas. NCBI: National Center for Biotechnology ing virus. Today, leukemia and associated Above: A koala at the Greater Los Angeles Zoo. Information National Cancer Institute lymphomas are the leading cause of death NCI: NEI: National Eye Institute in koalas in northeastern Australia and in reaction to screen for pathogenic KoRV-B as NHGRI: National Human Genome zoos around the world. part of an effort to prevent disease transmis- Research Institute NHLBI: National Heart, Lung, Surprisingly, some human-related NIH sion among koalas (between individual ani- and Blood Institute research may help to rescue the koalas. mals and from mothers to their offspring). NIA: National Institute on Aging Maribeth Eiden, chief of the Section on Great news for koalas, but how does NIAAA: National Institute on Alcohol Abuse and Alcoholism Directed Gene Transfer at the National this relate to human gene therapy? NIAID: National Institute of Allergy Institute of Mental Health (NIMH), is For over two decades, Eiden has been and Infectious Diseases NIAMS: National Institute of Arthritis developing viral-based vectors for deliver- re-engineering GALV and other viruses to and Musculoskeletal and Skin Diseases ing genetic material to cells in the human construct vectors for human gene therapy. NIBIB: National Institute of Biomedical central nervous system (CNS). Her find- She is interested in the viral envelope pro- Imaging and Bioengineering NICHD: Eunice Kennedy Shriver ings may lead to the optimization of gene- teins that infect cells by targeting specific National Institute of Child Health and delivery vectors in humans as well as ways host receptors. And that’s where studying Human Development National Institute on Drug Abuse to prevent deadly viral attacks in koalas. koalas comes into play. NIDA: NIDCD: National Institute on Deafness The deadly koala virus, discovered in KoRV and GALV are closely related, and Other Communication Disorders 2000, is the endogenizing koala gamma- share many of the same genes, and even use NIDCR: National Institute of Dental and Craniofacial Research retrovirus (KoRV), which has been integrat- the same receptor to infect human cells. NIDDK: National Institute of Diabetes ing into the koala genome over the past 100 Eiden found, however, that the newly and Digestive and Kidney Diseases NIEHS: National Institute of years. KoRV is closely related to other retro- discovered pathogenic KoRV-B uses a Environmental Health Sciences viruses known to cause blood cancers such different receptor to infect cells and that NIGMS: National Institute of as the gibbon ape leukemia virus (GALV). that receptor is expressed in the human General Medical Sciences NIMH: National Institute of Mental Health KoRV is also found in healthy animals, so CNS. She is now examining the KoRV-B NIMHD: National Institute on Minority its association with cancers has remained envelope proteins with the goal of honing Health and Health Disparities enigmatic. the GALV-based vectors to more specifi- NINDS: National Institute of Neurological Disorders and Stroke Eiden’s lab and a team of scientists cally target the CNS. NINR: National Institute of Nursing Research from the Los Angeles and San Diego Zoos Although Eiden and her group are pri- NLM: National Library of Medicine showed that koalas infected with the virus marily interested in understanding retrovi- OD: Office of the Director ODS: Office of Dietary Supplements substrain KoRV-B had a higher incidence ruses and modifying vectors for continual OITE: Office of Intramural Training & Education of malignant tumors than did noninfected improvement of human therapeutics, this OIR: Office of Intramural Research koalas (Proc Natl Acad Sci U.S.A. 110:11547– collaborative project is a shining example ORS: Office of Research Services 11552, 2013). The researchers then devel- of the impact the NIH intramural research ORWH: Office of Research on Women’s Health OTT: Office of Technology Transfer oped an assay using the polymerase chain has in unlikely places . . . even at the zoo.

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

Microbiome CONTINUED FROM PAGE 1 Intramural Microbiome Research infected, but treated, individuals is shorter What follows are descriptions of three than that of healthy individuals. Recent The second phase of the HMP which started intramural research projects in the HMP. data have shown that the cause of death on September 8, 2013, focuses on a survey of in HIV patients is strongly associated with the biological properties of the microbiome, Julie Segre, senior investigator, NHGRI, inflammation and microbial translocation such as gene expression profiles, proteins, and and Heidi Kong, investigator, NCI-CCR: from the gastrointestinal (GI) tract lumen. metabolites, produced by the microbiome The microbiome of the skin During the acute phase of HIV infection under specific conditions such as in preterm These researchers have played a large role in there is a significant depletion of GI-tract- birth or in diabetic patients. helping us to understand the microbiome resident CD4+ T cells, apoptosis of gut The goal for the Phase One Healthy of the skin. Our skin is a diverse ecosystem epithelial cells, and a shift away from the Cohort Study was to create a reference analogous to Earth’s various ecosystems (oily normal immune-regulating cells. These microbiome that represents the normal versus dry, for example). changes make the gut epithelium suscep- collection of bacteria living on and inside What Segre and colleagues have found tible to microbial translocation into the healthy American adults. It has provided is that the moist areas of the body have the body, causing chronic low-grade systemic the first glimpse of the microbial diversity greatest number of bacteria but the least inflammation that over time can result in of healthy humans; the major findings are diversity, while the dry areas of the skin have cardiovascular disease. Using an animal described at the end of this article in an the fewest bacteria but the most diversity. model of HIV, Brenchley has found that interview with Lita Proctor and online at Segre’s laboratory studies atopic dermatitis bacteria that translocate across the gut epi- http://www.hmpdacc.org. (eczema) in young children, and she hopes thelium are not representative of the gut The goal for the Demonstration understanding the microbiome of the skin microbiota and that bacteria of the phylum Projects was to explore the relationships will lead to improved treatments. Atopic Proteobacteria (including invasive strains between human diseases and the microbi- dermatitis is characterized by asymptomatic such as brevundimonas and diaphorobacter) ome. Researchers collected and sequenced periods punctuated by periods of severe skin tended to translocate preferentially. microbiome samples from volunteer patients inflammation. Segre and Kong found that These studies led to a proposal for using and compared them with the reference the microbial population changes during probiotics (healthful bacteria) to increase microbiomes from healthy volunteers. The dermatitis flares, and they are exploring the percentage of beneficial, noninflam- microbiome from individuals with a dis- whether the microbial diversity can be matory microbes in the gut, thus reducing ease—such as Crohn’s Disease, eczema, or used to predict when dermatitis flare-ups the percentage of invasive proteobacteria. esophageal adenocarcinoma—is significantly will occur. In addition, there are multiple The probiotics produce factors that act on different from those of healthy individuals. treatments for atopic dermatitis and not all the gut epithelium to restore its structural Scientists are trying to determine whether children respond similarly. Because there integrity, reduce inflammation, and prevent the microbiome differences are a cause or is no adequate diagnostic to predict which microbial translocation. Ongoing studies in effect of disease. treatment will work best, Segre and Kong Brenchley’s laboratory aim to understand are investigating whether the microbial how HIV infection alters the gut microbial diversity of atopic dermatitis can be used composition and metabolism. to identify the most effective treatment. Yasmine Belkaid, senior investigator, Jason Brenchley, senior investigator, NIAID: Microbiome of infection bar- NIAID: Microbiome of the intestine rier sites (skin and gut) It may not seem intuitive, but the gut micro- Harmful bacteria and viruses gain entry to biome plays an important role in human the body by traversing its protective barriers immunodeficiency virus (HIV) infection. such as the skin, mucosal epithelium of the Although antiretroviral therapy has proven nasal passages, and the gut epithelium. Until successful in controlling the replication of recently it was thought that these protec- U.S. DEPARTMENT OF AGRICULTURE HIV in the blood and in reducing the tive barriers (especially the skin) functioned The bacterium, Enterococcus faecalis, which lives in the incidence of acquired immunodeficiency independently of the resident or commensal human gut, is just one type of microbe that is being studied as part of NIH’s Human Microbiome Project. syndrome (AIDS), the life expectancy of microbiota known to reside on them. We

10 THE NIH CATALYST NOVEMBER-DECEMBER 2013 FEATURE

now know that the commensal microbiota of Clostridium difficile infection (such as THE MICROBIOME CLOUD of the barrier sites are integral in keeping antibiotic-associated diarrhea). Doctors BY HILLARY HOFFMAN, NIAID harmful bacteria from entering our body. are using the technology developed for the The NIH Microbiome Cloud Project (MCP), Belkaid’s laboratory, in collaboration HMP to perform sequenced-based analy- led by NIAID and NHGRI, addresses one of with Julie Segre (NHGRI) and Heidi sis of donor and recipient stool to predict the greatest challenges facing microbiome Kong (NCI-CCR) was instrumental in how individuals will respond to tailored scientists: large-scale data analyses. A team demonstrating the importance of the skin treatments. The long-term benefits of the of scientists from NIH, academia, and indus- microbiome as a barrier against infection. HMP are predicted to be wide-ranging. try is developing a cloud, or Internet-based, She compared the response of two groups But at this early stage, researchers cannot platform that brings together Human Micro- of mice to infection. The first group was say with certainty what specific benefits biome Project (HMP) data and analysis tools. housed normally and were host to the will arise. They know very little about the The HMP produced 14 terabytes of genetic normal array of commensal microbiota; the human microbiome and its role in healthy information about the microbes that naturally second group was housed from birth in a and unhealthy individuals. colonize our bodies. That’s enough data to fill highly controlled environment free of germs, more than 3,000 standard DVDs. including commensal microbiota. When the What does the future hold for the HMP? Mining microbiome datasets promises to two groups were exposed to the pathogenic The HMP is only the tip of the iceberg for help scientists better understand the role of bacteria Leishmania major (which is trans- understanding the diversity of the human the microbiota in health and disease and iden- mitted by sandflies and causes cutaneous microbiome and its role in healthy and tify new targets for drugs and vaccines, but leishmaniasis), the normal group mounted unhealthy individuals. The next step is scientists need proper tools to make sense of a normal immune response whereas the to broaden the human subject sampling. these complex data. By bringing together the sterile-environment group failed to mount The 300 normal, healthy individuals who data and tools in the cloud, the MCP will give such a response. Additional experiments contributed to the reference microbiome researchers access to vast amounts of data demonstrated that the skin’s commensal had a mean age of 26, were all Americans, with high-performance computing power. microbiota are essential in priming the skin’s and were mostly white. Such a small and In September 2013, NIAID and NHGRI immune system to respond to noncommen- biased sample disregards the effects of age launched the first phase of the MCP, which sal pathogenic microbiota. and cultural practices on the diversity of makes a five-terabyte portion of HMP the microbiome. For example, it is known sequencing data publicly available on the Major Findings of the HMP that diet influences the diversity of the gut Amazon Web Services cloud. Cloud storage An edited interview with Lita Proctor, microbiome and that humans begin accu- facilitates analysis by reducing the need for HMP program officer, NHGRI mulating a microbiome following birth. It is time-consuming data downloads. The MCP What has been the most unexpected finding? unknown how (or if) the microbiome diver- team is developing the next phase of the The sheer magnitude of the genetic potential sity changes as individuals age. These are all project, which will add analysis tools, more in the thousands of microbes living on and questions that still need to be addressed. data, and supporting documentation such inside the human body. Humans are hosts as online tutorials. Before the platform is For more information, go to: to 10,000 different bacterial species; each released to the public, it will be evaluated • http://commonfund.nih.gov/hmp individual carries around 1,000 different by a team of NIH scientists and extramural • PLOS Series: http://www.ploscol- species. The global pool of unique microbial researchers. lections.org/article/browseIssue. genes associated with the 10,000 microbial action?issue=info:doi/10.1371/issue.pcol. species is estimated to be around eight mil- To access any of the cloud-based HMP v01.i13 lion. (Humans have about 23,000 genes.) datasets, visit http://aws.amazon.com/ datasets/1903160021374413. For more infor- What benefits can patients expect to see? mation about the MCP, contact Yentram TO READ AN EXPANDED VERSION Indirect benefits of the HMP are already Huyen ([email protected]), Maria Giovanni OF THIS ARTICLE, GO TO http:// being realized. Fecal microbiota transplan- ([email protected]), or Vivien Bonazzi (bonaz- irp.nih.catalyst.gov/v21i6/ tation, the process of transplanting fecal [email protected]). bacteria from a healthy individual into a the-human-microbiome-project recipient, is often used to treat the symptoms

http://irp.nih.gov/catalyst 11 THE SIG BEAT NEWS FROM AND ABOUT THE NIH SCIENTIFIC INTEREST GROUPS

Proteostasis One Name, Many Fields: “Proteostasis” Research at NIH BY JENNIFER SARGENT, NIAMS

Proteostasis, a seemingly straightforward fusion of the words “protein” and “homeostasis,” is actually a fer- tile and multifaceted concept. Ask any 10 scientists to define it, and you’re bound to get 10 different answers, and those opin- ions may change from year to year. In effect, proteostasis is greater than the sum of its parts, encompassing the study of all areas of protein health and fitness that contribute to maintaining cellular integrity and function. Derailed proteostasis leads to protein misfolding and aggregation that NIAAA OROSZ, A. COURTESY is implicated in many neurodegenerative diseases such as Alzheimer disease, Parkin- sonism, amyotrophic lateral sclerosis, type 2 diabetes, cancer, cardiomyopathy, cystic fibrosis, cataracts, prion disease, immune problems, metabolic deficiencies, alcoholic liver disease, and other chronic maladies. It is well established that proteostasis naturally investigators from across multiple fields The decline of proteostasis with aging declines during aging. and institutes to share knowledge about When protein homeostasis degenerates and At the NIH, the processes underlying the underlying molecular commonalities collapses, cells get old . . . and sick. Hall- such conditions traditionally have been of different diseases. mark features of cellular aging include a studied in isolation, with fields of study Proteostasis, a term coined in a land- buildup of proteotoxic stress, mistranslation delineated by disease classifications. But mark Science paper in 2008, is a broad con- of nascent polypeptides, and concentration Andras Orosz—a program director at cept that is relevant to all fields that involve of damaged, misfolded proteins and protein the National Institute of Alcohol Abuse protein synthesis, folding, processing, and aggregates. This accumulation of cellular and Alcoholism and driving force behind turnover (Science 319:916–919, 2008). waste is toxic to cells. That’s when things the recent formation of the Proteostasis Some major subgroups that fall under the start to fall apart. Scientific Interest Group (SIG)—thinks proteostasis umbrella include protein syn- Senior Investigator Jay Chung, head that it’s time we change our approach to thesis and degradation systems; chaperone of the National Heart, Lung, and Blood understanding and treating these devastat- proteins that bind to nascent polypeptide Institute’s (NHLBI) Laboratory of Obesity ing chronic diseases. chains and partially folded proteins to ensure and Aging Research, believes that the same He believes that “learning the basic proteins attain correct conformation; and molecular pathways that are affected under biology of proteostasis is important for post-translational modifications that can conditions of metabolic stress go awry in understanding a slew of debilitating pro- modulate protein activation states, specify natural aging. The common thread between tein misfolding and aggregation disorders intracellular location, or tag a protein for these seemingly disparate disorders boils and [for] developing cures.” degradation by the proteasome. As many down to the issue of unbalanced proteos- As such, the Proteostasis SIG brings as 2,000 proteins are involved in the pro- tasis. Chung says that understanding how together intramural research program (IRP) teostasis network. these stresses affect protein quality control is

12 THE NIH CATALYST NOVEMBER-DECEMBER 2013 THE SIG BEAT

tantamount to understanding how and why disorders including Huntington, Lou target specific prion aggregates. He has aging-associated diseases such as Alzheimer Gehrig’s, and Alzheimer diseases. Other shown that heat shock protein 70 (HSP70) disease and obesity-related health patholo- neurodegenerative diseases, such as acts with co-chaperones to propagate prion gies develop. Creutzfeldt-Jakob disease and bovine replication by breaking up amyloid struc- Central to quality control of proteins spongiform encephalopathy, are caused by tures into fragments, each of which can then in the cell is the molecular chaperone heat pathogenic amyloid structures comprising seed a new prion aggregate. shock protein 90 (HSP90). Chung has misfolded prion proteins. Masison collaborated with NHLBI’s observed that post-translational modifica- While it is known that these disorders Lois Greene to demonstrate that overex- tions of HSP90 can be drastically altered in arise through disparate genetic mechanisms pression of co-chaperone HSP104 resulted either aged or obese mice compared with and that the aggregates are formed from in complete disintegration of prion aggre- healthy and younger animals. He has also different proteins, there are striking similari- gates in hours. demonstrated that calorie restriction, a ties in their three-dimensional structures. Greene’s laboratory is using real-time method previously shown to increase lon- Understanding the basics of how and why cell imaging to study mammalian prion gevity in mice, can reverse the post-transla- these proteins aggregate may provide clues biology as well as the function of chaper- tion modifications associated with aging and about how to break apart amyloid plaques one proteins in the formation of clathrin- obesity, restoring proteostasis on a molecu- and potentially reverse disease pathologies. coated pits, a mechanism by which cells lar level. The full spectrum of mechanisms Reed Wickner, chief of the Labora- can internalize cargo-bound receptors on by which age and caloric restriction affects tory of Biochemistry and Genetics in the the cell surface. proteostasis is under intense investigation. National Institute of Diabetes and Digestive Lisa Cunningham, head of the Section Elsewhere in NHLBI, Toren Finkel and Kidney Diseases (NIDDK), uses yeast on Sensory Cell Biology in the National and his team in the Laboratory of Molecular prions as a model to study the dynamics of Institute on Deafness and Other Com- Biology are interested in understanding the amyloid structures. One finding from his munications Disorders, is investigating a basic mechanisms underlying natural aging. group that may yield clues about amyloid lesser-known role for HSP70. She and her His lab recently showed that lowering the turnover is the identification of a protein, team have discovered that HSP70 secreted expression levels of a gene encoding a sig- Batten-disease-related protein 2 (Btn2), that by neighboring cells is a critical factor in naling molecule called mammalian target of cures yeast cells of prions by sequestering protecting mechanosensory hair cells in rapamycin (mTOR) can increase the lifes- prion aggregates to a cellular compartment. ototoxic-mediated hearing loss. Tradition- pan of mice by up to 20 percent. This feat Some 2,300 miles away from Bethesda, ally the roles of chaperones and heat-shock would be equivalent to raising the average at the Rocky Mountain Laboratories (Ham- proteins in protein folding and trafficking lifespan of a human being from 75 to 90 ilton, Mont.), which is part of the National were thought to be limited to folding and years (Cell Rep 4:913-920, 2013). Institute of Allergy and Infectious Diseases stabilizing proteins within the cell in which Finkel says that one potential mecha- (NIAID), researchers are seeking to under- they are synthesized. nism by which mTOR controls life expec- stand prion biology in mammalian systems. Cunningham is working with the audi- tancy is through the proteostasis degradation Suzette Priola, chief of the Transmissible ology team at the NIH Clinical Center to pathway of autophagy. Autophagy, a process Spongiform Encephalopathy (TSE)/Prion restore hearing in patients by inducing by which cells clear damaged organelles and Molecular Biology Section, has identified HSP70 expression in the inner ears. proteins, is essential to maintaining healthy a region of mammalian prion protein that protein homeostasis. controls interspecies transmission. Her Proteostasis and cancer group is also deciphering those events that Leonard Neckers and his group at the Protein aggregates, amyloid, and prions trigger initial prion protein misfolding. National Cancer Institute’s (NCI) Uro- Protein aggregates are one type of cellular logic Oncology Lab, like Chung, also are trash that can accumulate when the pro- Molecular chaperones interested in the chaperone protein HSP90. teostatic balance is lost. Molecular chaperones are critical compo- Neckers has found that HSP90 is a critical Amyloids are a form of protein aggre- nents of the proteostasis network. Senior factor for cell survival and proliferation in gate comprising filaments of monomers Investigator Daniel Masison, in NIDDK’s many types of cancers. Called the “cancer bound by hydrogen bonds. Formation of Laboratory of Biochemistry and Genetics, is chaperone,” HSP90 stabilizes proteins in the amyloid is pathogenic in several neurological exploring mechanisms by which chaperones CONTINUED ON PAGE 14

http://irp.nih.gov/catalyst 13 COLLEAGUESFEATURES

Proteostasis The Shutdown CONTINUED FROM PAGE 13 CONTINUED FROM PAGE 1

cell, many of them protein kinases, that play cycle. Even though more than 200 peer- “No one could be in a lab without a important roles in cell growth, cell survival, review meetings were scuttled by the shut- supervisor,” Gottesman said. Not all lab apoptosis, and oncogenesis. down, affecting some 11,000 grants, NIH chiefs, nor all scientific directors, hold But stabilization is not always a desirable will work double-time so as not to delay this “excepted” positions, he noted. Those who outcome. In certain types of cancers, HSP90 process for another four months. were permitted to work found themselves stabilizes oncogenic proteins, shielding them Collins concluded, “I am humbled and handling such routine duties as checking from degradation. Thus, overactive HSP90 thankful to be associated with all of you … freezers and animal colonies. can sustain cancer-cell growth and survival your professionalism is a delight to behold.” “We were very careful with our animal by extending the lifespan of toxic proteins. A videocast of the town hall meeting [colonies],” Gottesman continued, allow- In the late 1990s, Neckers’s lab identified may be viewed (by NIHers only) at http:// ing continued breeding and ensuring that the first small-molecule HSP90 inhibitor videocast.nih.gov/launch.asp?18126. animals were genotyped to preserve needed and helped develop the first-in-human drug cage space. “We won’t have to start from targeting HSP90. Several chemically dis- Impact on Intramural Program scratch with our animals.” tinct HSP90 inhibitors are currently in The furlough of three-quarters of NIH’s On any given day, NIH as a whole man- phase 1 and phase 2 clinical trials and one workforce for 16 days dealt a particularly ages around 384,000 animals, including is in phase 3 clinical trial. hard blow to the Intramural Research Pro- more than 330,000 mice, said Terri Clark, Allan Weissman, chief of NCI’s Labo- gram, putting 2,500 research protocols and director of the Office of Animal Care and ratory of Protein Dynamics and Signaling 1,500 clinical protocols on hold, said NIH Use. There had been concerns that a pro- (Frederick, Md.), works on the ubiquitin Deputy Director for Intramural Research longed shutdown would have led to a need system, which he describes as “the major Michael Gottesman. to euthanize many mice due to overcrowd- player in regulating levels of cellular pro- “Suddenly coming to a complete halt— ing. But that did not happen, she said. A teins.” Ubiquitination is a post-translational that’s a big blow to the whole research estab- small number were culled and euthanized modification that can target proteins for lishment,” he said. Many experiments were in the normal course of breeding operations proteasomal degradation. In 1999 Weissman lost and will have to be repeated; it will take that occurred during the shutdown. and co-workers were the first to describe a few weeks for most research projects to Only critical animal studies already in (RING)-finger proteins as ubiquitin ligases. get back up to speed. midstream or experiments of particularly RING fingers are a family of enzymes that Troubling to Gottesman was the mes- high value, as determined by the scientific tag proteins for degradation and constitute sage a furlough sends to the wider research directors, were allowed to go forward. the majority of ubiquitin ligases. Although community. “NIH has compacts with all Gottesman was reluctant to name all the targets of RING-ubiquitin ligases sorts of organizations. Our scientists collab- heroes during the shutdown. “There are have not yet been identified, Weissman orate, give talks—all as part of our official more than I could enumerate,” he said. “It’s has shown that overexpression of a specific duties— and suddenly we were not reliably hard to single out individuals. Even those RING-ubiquitin ligase leads to a marked there to do that. All of a sudden, NIH looks who did what they were supposed to do by enhancement of metastasis—the primary like a less reliable partner.” staying home did their part.” cause of death in cancer. Although the Clinical Center remained “What was amazing to me, though, was Proteostasis research at the NIH is far open, only 75 percent of its staff was on that as soon as people came back, spirits greater than what this article could sum- hand, he said, and attendance varied from lifted enormously.” marize. As evidence of this emerging field’s institute to institute, based on the clinical importance within the IRP, it made a splash studies under way. Of seven protocols due This article was adapted, with permission, with a well-attended workshop in June and to begin during the shutdown, only one from one that appeared in the November symposium in September and was featured was allowed to go forward, based on its 8, 2013 issue of the NIH Record. To read the at the NIH Research Festival in November potentially life-saving effect. And only 25 entire article go to http://nihrecord.od.nih. 2013. To learn more about the Proteostasis of more than 400 scheduled patient visits gov/newsletters/2013/11_08_2013. To read SIG and related activities, contact Andras were permitted during the shutdown. more of Gottesman’s thoughts on recovering Orosz at [email protected]. from the shutdown, see his essay on page 2.

14 THE NIH CATALYST NOVEMBER-DECEMBER 2013 ANNOUNCEMENTS

SPECIAL NIH LECTURES: FROM BIG DATA TO LITTLE KNOWLEDGE A NEW FABRIC FOR CLINICAL RESEARCH: 2013 NOBEL PRIZE WINNERS IN CHEMISTRY Friday, December 13, 2013 APPLICATION TO THE PAIN PROBLEM 3:30–5:00 p.m. Monday, December 16, 2013 Michael Levitt: “The Birth and Future of Building 50, Room 1328/1334 9:00–10:00 a.m. Computational Structural Biology” Vladimir Cherkassky (University of Minnesota), Lipsett Amphitheater (Building 10) Monday, November 18, 2013 will present a critical discussion of the popular This year’s Stephen E. Straus Distinguished 4:00-5:00 p.m. view “more data generates more knowledge” Lecture in the Science of Complementary Masur Auditorium (Building 10) and on the methodological aspects of data- Health Therapies will be presented by Robert Arieh Warshel: “Computer Simulations of Bio- analytic knowledge discovery in the context of Califf (Duke University Medical Center), who logical Functions” applications in health care and life sciences. All will examine the advent of “big data” and how Wednesday, November 20, 2013 are welcome to a pre-event social at 3:00 p.m. they unite patients, families, providers, admin- 1:00-2:00 p.m. by the coffee shop outside the meeting room. istrators, and researchers; and the impact of Masur Auditorium (Building 10) For more information, contact Jim DeLeo big data on the management of chronic pain. ([email protected] or 301-496-3848). For more information, go to http://nccam.nih. CHEN LECTURE ON INNOVATION AND TECH- gov/news/events/lectures or contact NOLOGY TRANSFER DEMYSTIFYING MEDICINE 2014 Prachi Patel ([email protected] or 301-594- Friday, November 22, 2013 Tuesdays, starting January 7, 2014 1030). The event will also be videocast: http:// 10:00-11:00 a.m. (reception follows) 4:00–6:00 p.m. videocast.nih.gov. Lipsett Amphitheater (Building 10) Building 50 Conference Room Clifton Barry (NIAID) and Carol Nacy (co- The “DeMystifying Medicine” course, in its VOLUNTEER OPPORTUNITIES AT NATIONAL founder and CEO of Sequella, Inc): “TB: It 12th year, bridges the gap between advances MUSEUM OF HEALTH AND MEDICINE Takes More than a Village to Raise a Remedy.” in biology and their application to human dis- The National Museum of Health and Medicine ease. Each class features presentations by a (http://www.medicalmuseum.mil), in Silver WEDNESDAY AFTERNOON LECTURE SERIES clinician, a researcher, and often a patient. For Spring, Md., is seeking volunteer docents to Most Wednesdays, 3:00–4:00 p.m. more information, a complete schedule, and conduct outreach activities, support public pro- Masur Auditorium (Building 10) instructions on how to sign up, visit http:// grams, or lead tours of the permanent exhibits, Schedule at: http://wals.od.nih.gov demystifyingmedicine.od.nih.gov or contact “Innovations in Military Medicine,” “Anatomy November 20: Annual Astute Clinician Lecture, Win Arias at [email protected]. and Pathology,” “Civil War Medicine,” “Bio- Marston Linehan (NCI): “The Genetic Basis of medical Engineering,” and “Human Identifica- Kidney Cancer: Targeting the Metabolic Basis INVESTIGATIONAL NEW DRUG (IND) tion and Microscopes.” Prerequisites include of Disease” What You Need to Know for Successful Inter- being at least 21 years of age and having an December 4: Susan Rosenberg (Baylor): “How actions with the FDA open, flexible schedule (weekday and weekend Bacteria and Cancer Cells Regulate Mutagen- Thursday, December 12, 2013 opportunities are available). Training will be esis and Their Ability to Evolve” 8:00 a.m.–4:00 p.m. provided. To become a volunteer or to request December 11: Steve Holland (NIAID): “The Pro- Lipsett Amphitheater (Building 10) more information, call 301-319-3312. tean Manifestations of GATA2 Deficiency across Registration deadline: December 5, 2013 the Lifespan” This program is offered by the NIH Clini- KUDOS: December 18: Clyde Yancy (Northwestern): cal Center-FDA CDER Joint Task Force and Congralations to Ron Germain (NIAID), “Patient-centered Outcomes Research: New emphasizes regulatory requirements for clini- Warren Leonard (NHLBI), and Daniel Pine Directions, Major Challenges, Transformative cal trials of new and repurposed drugs, with a (NIMH) who are among the 70 new members Potential” special focus on rare diseases. To register, go elected to the Institute of Medicine this year. to https://ocrtme.cc.nih.gov/_layouts/Form- This honor reflects the scientists’ exemplary Server.aspx?XsnLocation=https://ocrtme. contributions to the medical sciences, health cc.nih.gov/Forms/INDRegistrationForm. care, and public health. Read more online at Read more online at http://irp.nih.gov/ xsn&OpenIn=browser. For more information, http://irp.nih.gov/catalyst/v21i6/announce- catalyst/v21i6/announcements. contact Juan Lertora ([email protected] or ments. 301-496-9425).

http://irp.nih.gov/catalyst 15 OFFICIAL WHITE HOUSE PHOTO BY PETE SOUZA

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DHHS/NIH Permit No. G-802 Permit No. FIRST-CLASS MAIL FIRST-CLASS POSTAGE & FEES PAID & POSTAGE Publication No. 13-6250 Publication Nora Volkow Nora (NHGRI) for their work in work their (NHGRI) for MICHAEL ESPEY, NIDDK ESPEY, MICHAEL NCI KOHN, C. ELISE CC LEITMAN, SUSAN NICHD LOUIS, BUCK GERMAINE NIEHSMILLER, DAVID NIAIDMOSS, BERNARD NCI PARK, HYUN NIAMS PLOTZ, PAUL RHODES,SARAHNIMH NHGRI SEGRE, JULIE NIASINGLETON, ANDY NICHD STORZ, GISELA SUMMERS,CC RONALD OIR WYATT, RICHARD EDITORIAL ADVISORY BOARD ADVISORY EDITORIAL APPELLA,NIDDK DAN NIDDK DAVIES, DAVID

Kevin Snitkin Kevin and NIDA Director NIDA and (CC), and and (CC), MichaelGottesman Tara Palmore Tara (CC), (CC), CONTRIBUTING WRITERS CONTRIBUTING REBECCA BAKER, LORI CONLAN KRYSTEN CARRERA MASHANA DAVIS, DUSTIN HAYS HILLARY HOFFMAN, RICH MCMANUS JESSICA MEADE, SHARON MILGRAM JOSEPH TIANO NICHOLAS ZAGORSKI PHOTOGRAPHERS/ILLUSTRATORS J.H.CARR, BAILEY, JONATHAN SCHMIDT, TOM OROSZ, A.EARL, A. SOUZA PETE STOWE, R. EDITORIAL INTERN EDITORIAL JENNIFER SARGENT David Henderson David

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story on the work of the Segre team, go to http://irp.nih.gov/catalyst/v20i6/intramural-detectives. http://irp.nih.gov/catalyst/v20i6/intramural-detectives. to go team, Segre the of work the on story OTHER NEWS OTHER WRITER-EDITOR WANJEK CHRISTOPHER OIR Communications, of Director EDITOR COPY ROBERTS SHAUNA PUBLISHER OD GOTTESMAN Research, MICHAEL Intramural for Director Deputy EDITORS GALLIN I. JOHN Center Clinical NIH Director, METZGER HENRY Emeritus Scientist EDITOR MANAGING CARTER STEPHENSONLAURA Sammies Honored at the White House White the at Honored Sammies information, go to http://servicetoamericamedals.org/SAM/recipients/profiles/fym13_segre-palmore.shtml. To read the http://servicetoamericamedals.org/SAM/recipients/profiles/fym13_segre-palmore.shtml.the read to To go information, President Barack Obama met with the Samuel J. Heyman Service to America Medal (Sammies) finalists and winners in the in winners finalists and America(Sammies) Medal Serviceto Heyman Samuel J. the with BarackObamamet President team the was Year” the of “FederalEmployee of honor top the House,October23,Receiving 2013. White the of Room East comprising genome sequencing.” Sammiesof use first-ever the through infection hospital-acquired deadly a of “thespread stopping Research Intramural finalistsfor included Deputy Director Catalyst Catalyst

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is published online: The NIH Catalyst Catalyst articles, go to (http://irp.nih. and can be recycled office white paper. as Printed on at least 20% recycled on paper content Printed NIH Catalyst gov/catalyst/v21i6). More Online More To read expanded versions of the Building 1, Room 333 Building 1, Room 0183 MSC 20892 Maryland Bethesda, U.S. DEPARTMENT OF HEALTH AND AND OF HEALTH DEPARTMENT U.S. SERVICES HUMAN of Health Institutes National your reactions to anythingto your reactions on the Also, we welcome “letters and publication for editor” the nih.gov; fax: 301-402-4303; or mail: 333. Room 1, Building the space to the right, why not not why right, the to space the send it via e-mail: catalyst@ a quotation or confession that that confession or quotation a and appreciate might scientists that would be fit to print in other graphic that reflectsan aspect of life(including laboratory life) or at NIH If you have a photo or e-mail: [email protected] The NIH Catalyst http://irp.nih.gov/catalyst Building Room 1, 333, NIH Bethesda, MD 20892 Ph: 301-402-1449 Fax: 301-402-4303 bimonthly for and by the intramural scientists at NIH. Address correspondence to: The NIH Catalyst CATALYTIC REACTIONS? CATALYTIC Official Business Use $300 Private for Penalty